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Everitt, Jeffrey Ira

Positions:

Professor Track - V in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

D.V.M. 1977

D.V.M. — Cornell University

Adjunct Professor Of Pathology, College Of Veterinary Medicine,, Department Of Pathology

North Carolina State University

Grants:

Mitigators of Radiation-Induced Endovascular Injury: Targeting Tie2 and Thrombocytopenia

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Clinical Professor
Start Date
June 06, 2017
End Date
May 31, 2022

Publications:

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642-two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS-U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS-U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.

Authors
Kim, Y; Lee, H-M; Xiong, Y; Sciaky, N; Hulbert, SW; Cao, X; Everitt, JI; Jin, J; Roth, BL; Jiang, Y-H
MLA Citation
Kim, Y, Lee, H-M, Xiong, Y, Sciaky, N, Hulbert, SW, Cao, X, Everitt, JI, Jin, J, Roth, BL, and Jiang, Y-H. "Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome." Nature medicine 23.2 (February 2017): 213-222.
PMID
28024084
Source
epmc
Published In
Nature Medicine
Volume
23
Issue
2
Publish Date
2017
Start Page
213
End Page
222
DOI
10.1038/nm.4257

HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism.

The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism. Thus, molecular mimicry by HIV-1 Env that promotes the evasion of host anti-HIV-1 Ab responses can be directed toward nonfunctional host protein epitopes that do not impair host protein function. Therefore, the 2F5 HIV Env gp41 region is a key and safe target for HIV-1 vaccine development.

Authors
Bradley, T; Yang, G; Ilkayeva, O; Holl, TM; Zhang, R; Zhang, J; Santra, S; Fox, CB; Reed, SG; Parks, R; Bowman, CM; Bouton-Verville, H; Sutherland, LL; Scearce, RM; Vandergrift, N; Kepler, TB; Moody, MA; Liao, H-X; Alam, SM; McLendon, R; Everitt, JI; Newgard, CB; Verkoczy, L; Kelsoe, G; Haynes, BF
MLA Citation
Bradley, T, Yang, G, Ilkayeva, O, Holl, TM, Zhang, R, Zhang, J, Santra, S, Fox, CB, Reed, SG, Parks, R, Bowman, CM, Bouton-Verville, H, Sutherland, LL, Scearce, RM, Vandergrift, N, Kepler, TB, Moody, MA, Liao, H-X, Alam, SM, McLendon, R, Everitt, JI, Newgard, CB, Verkoczy, L, Kelsoe, G, and Haynes, BF. "HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism." Journal of immunology (Baltimore, Md. : 1950) 197.12 (December 2016): 4663-4673.
PMID
27849170
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
197
Issue
12
Publish Date
2016
Start Page
4663
End Page
4673
DOI
10.4049/jimmunol.1601484

Current concepts of Harm-Benefit Analysis of Animal Experiments - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 1.

International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm-benefit analysis (HBA) and deemed the project to be appropriate. Although the process for conducting HBAs may not be new, the relevant factors and algorithms used in conducting them during the review process are deemed to be poorly defined or lacking by committees in many institutions. This paper presents the current concept of HBAs based on a literature review. References on cost or risk benefit from clinical trials and other industries are also included. Several approaches to HBA have been discovered including algorithms, graphic presentations and generic processes. The aim of this study is to better aid and harmonize understanding of the concepts of 'harm', 'benefit' and 'harm-benefit analysis'.

Authors
Brønstad, A; Newcomer, CE; Decelle, T; Everitt, JI; Guillen, J; Laber, K
MLA Citation
Brønstad, A, Newcomer, CE, Decelle, T, Everitt, JI, Guillen, J, and Laber, K. "Current concepts of Harm-Benefit Analysis of Animal Experiments - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 1." Laboratory animals 50.1 Suppl (June 2016): 1-20. (Review)
PMID
27188275
Source
epmc
Published In
Laboratory Animals
Volume
50
Issue
1 Suppl
Publish Date
2016
Start Page
1
End Page
20
DOI
10.1177/0023677216642398

Recommendations for Addressing Harm-Benefit Analysis and Implementation in Ethical Evaluation - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 2.

International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm-benefit analysis (HBA) and deemed the project to be appropriate. The AALAS-FELASA working group on HBA has performed a literature review and based on this review, proposed a method for HBA. Examples of the working group's approach are included in this report.

Authors
Laber, K; Newcomer, CE; Decelle, T; Everitt, JI; Guillen, J; Brønstad, A
MLA Citation
Laber, K, Newcomer, CE, Decelle, T, Everitt, JI, Guillen, J, and Brønstad, A. "Recommendations for Addressing Harm-Benefit Analysis and Implementation in Ethical Evaluation - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 2." Laboratory animals 50.1 Suppl (June 2016): 21-42. (Review)
PMID
27188276
Source
epmc
Published In
Laboratory Animals
Volume
50
Issue
1 Suppl
Publish Date
2016
Start Page
21
End Page
42
DOI
10.1177/0023677216642397

Recommendations for minimum information for publication of experimental pathology data: MINPEPA guidelines.

Animal models are essential research tools in modern biomedical research, but there are concerns about their lack of reproducibility and the failure of animal data to translate into advances in human medical therapy. A major factor in improving experimental reproducibility is thorough communication of research methodologies. The recently published ARRIVE guidelines outline basic information that should be provided when reporting animal studies. This paper builds on ARRIVE by providing the minimum information needed in reports to allow proper assessment of pathology data gathered from animal tissues. This guidance covers aspects of experimental design, technical procedures, data gathering, analysis, and presentation that are potential sources of variation when creating morphological, immunohistochemical (IHC) or in situ hybridization (ISH) datasets. This reporting framework will maximize the likelihood that pathology data derived from animal experiments can be reproduced by ensuring that sufficient information is available to allow for replication of the methods and facilitate inter-study comparison by identifying potential interpretative confounders.

Authors
Scudamore, CL; Soilleux, EJ; Karp, NA; Smith, K; Poulsom, R; Herrington, CS; Day, MJ; Brayton, CF; Bolon, B; Whitelaw, B; White, ES; Everitt, JI; Arends, MJ
MLA Citation
Scudamore, CL, Soilleux, EJ, Karp, NA, Smith, K, Poulsom, R, Herrington, CS, Day, MJ, Brayton, CF, Bolon, B, Whitelaw, B, White, ES, Everitt, JI, and Arends, MJ. "Recommendations for minimum information for publication of experimental pathology data: MINPEPA guidelines." The Journal of pathology 238.2 (January 2016): 359-367. (Review)
PMID
26387837
Source
epmc
Published In
The Journal of Pathology
Volume
238
Issue
2
Publish Date
2016
Start Page
359
End Page
367
DOI
10.1002/path.4642

Isolation and characterization of a novel Helicobacter species, Helicobacter jaachi sp. nov., from common marmosets (Callithrix jaachus).

Purpose-bred common marmosets from domestic sources housed in a US research facility, and used in multiple drug discovery programmes, were noted to have a high incidence of spontaneous inflammatory bowel disease and sporadic cholecystitis and cholangiohepatitis. Inflammatory infiltrates increased in incidence and severity with age. Because Helicobacter spp. have been linked to gastrointestinal diseases, samples from the gastrointestinal tracts of 39 marmosets were screened for Helicobacter spp. by culture and PCR. Helicobacter spp. were frequently detected in marmosets; 28.2% of the marmosets were positive for a proposed novel species, Helicobacter jaachi sp. nov., by culture, and 48.7% were positive by Helicobacter genus-specific PCR. Seventeen strains of Helicobacter sp. from 11 marmosets were cultured from various gastrointestinal sites. Older animals (age 6-11 years) had a higher helicobacter prevalence rate (57.1%) compared with younger animals (age 3-5 years), which had a 27.2% prevalence rate. Cells of H. jaachi sp. nov. were catalase, urease and oxidase positive and had fusiform morphology, with periplasmic fibres and multiple bipolar, sheathed flagella. All isolates had similar 16S and 23S rRNA sequences, which clustered as representatives of a novel Helicobacter species closely related to 'Helicobacter sanguini' (97%), a species isolated from cotton-top tamarins and 'Helicobacter callitrichis' (96%) isolated previously from the faeces of common marmosets. The whole genome sequence of one of the liver isolates, H. jaachi sp. nov. MIT 09-6949(T), had a 1.9 Mb genome length with a 41 mol% DNA G+C content. The type strain of Helicobacter jaachi sp. nov., MIT 09-6949(T), has been deposited in the BCCM/LMG Bacteria Collection as LMG 28613(T). These findings add to the increasing number of animal species with gastrointestinal disease in which novel enterohepatic Helicobacter spp. have been isolated.

Authors
Shen, Z; Feng, Y; Sheh, A; Everitt, J; Bertram, F; Paster, BJ; Fox, JG
MLA Citation
Shen, Z, Feng, Y, Sheh, A, Everitt, J, Bertram, F, Paster, BJ, and Fox, JG. "Isolation and characterization of a novel Helicobacter species, Helicobacter jaachi sp. nov., from common marmosets (Callithrix jaachus)." Journal of medical microbiology 64.9 (September 2015): 1063-1073.
PMID
26297446
Source
epmc
Published In
Journal of medical microbiology
Volume
64
Issue
9
Publish Date
2015
Start Page
1063
End Page
1073
DOI
10.1099/jmm.0.000113

The future of preclinical animal models in pharmaceutical discovery and development: a need to bring in cerebro to the in vivo discussions.

Animal models have provided an important tool to help make the decision to take potential therapies from preclinical studies to humans. In the past several years, the strong reliance of the pharmaceutical discovery and development process on the use of animal models has come under increasing scrutiny for ethical and scientific reasons. Several prominent and widely publicized articles have reported limited concordance of animal experiments with subsequent human clinical trials. Recent assessments of the quality of animal studies have suggested that this translational failure may be due in part to shortcomings in the planning, conduct, and reporting of in vivo studies. This article will emphasize methods to assure best practice rigor in animal study methods and reporting. It will introduce the so-called scientific 3Rs of relevance, robustness, and reproducibility to the in vivo study approach and will review important new trends in the animal research and pharmaceutical discovery and development communities.

Authors
Everitt, JI
MLA Citation
Everitt, JI. "The future of preclinical animal models in pharmaceutical discovery and development: a need to bring in cerebro to the in vivo discussions." Toxicologic pathology 43.1 (January 2015): 70-77.
PMID
25351920
Source
epmc
Published In
Toxicologic Pathology (Sage)
Volume
43
Issue
1
Publish Date
2015
Start Page
70
End Page
77
DOI
10.1177/0192623314555162

ICLAS Working Group on Harmonization: international guidance concerning the production care and use of genetically-altered animals.

Replacement, Reduction and Refinement, the ‘Three Rs’ of Russell & Burch, are accepted worldwide as fundamental to the ethics of animal experimentation. The production, care and use of genetically-altered animals can pose particular challenges to the implementation of the Three Rs,1 necessitating additional considerations by those responsible for overseeing the ethical use and appropriate care of animals involved in science. The International Council for Laboratory Animal Science brings representatives of the international laboratory animal science community together to recommend acceptance of guidance documents.The harmonization of guidance concerning genetically-altered animals was seen as a priority because of the increasing globalization of research involving these animals.

Authors
Rose, M; Everitt, J; Hedrich, H; Schofield, J; Dennis, M; Scott, E; Griffin, G; ICLAS Working Group on Harmonization,
MLA Citation
Rose, M, Everitt, J, Hedrich, H, Schofield, J, Dennis, M, Scott, E, Griffin, G, and ICLAS Working Group on Harmonization, . "ICLAS Working Group on Harmonization: international guidance concerning the production care and use of genetically-altered animals." Laboratory animals 47.3 (July 2013): 146-152.
PMID
23563121
Source
epmc
Published In
Laboratory Animals
Volume
47
Issue
3
Publish Date
2013
Start Page
146
End Page
152
DOI
10.1177/0023677213479338

Meeting report: Urinary Pathology; sixth Research Triangle Park Rodent Pathology Course.

Urinary system toxicity is a significant concern to pathologists in the hazard identification, drug and chemical safety evaluation, and diagnostic service industries worldwide. There are myriad known human and animal urinary system toxicants, and investigatory renal toxicology and pathology is continually evolving. The system-specific Research Triangle Park (RTP) Rodent Pathology Course biennially serves to update scientists on the latest research, laboratory techniques, and debates. The Sixth RTP Rodent Pathology Course, Urinary Pathology, featured experts from the government, pharmaceutical, academic, and diagnostic arenas sharing the state of the science in urinary pathology. Speakers presented on a wide range of topics including background lesions, treatment-related non-neoplastic and neoplastic lesions, transgenic rodent models of human disease, diagnostic imaging, biomarkers, and molecular analyses. These seminars were accompanied by case presentation sessions focused on usual and unusual lesions, grading schemes, and tumors.

Authors
Boyle, MC; Boyle, MH; Sixth Rodent Pathology Course Committee,
MLA Citation
Boyle, MC, Boyle, MH, and Sixth Rodent Pathology Course Committee, . "Meeting report: Urinary Pathology; sixth Research Triangle Park Rodent Pathology Course." Veterinary pathology 50.3 (May 2013): 563-568.
PMID
23645617
Source
epmc
Published In
Veterinary pathology
Volume
50
Issue
3
Publish Date
2013
Start Page
563
End Page
568
DOI
10.1177/0300985813480217

Ketamine effects on memory reconsolidation favor a learning model of delusions.

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.

Authors
Corlett, PR; Cambridge, V; Gardner, JM; Piggot, JS; Turner, DC; Everitt, JC; Arana, FS; Morgan, HL; Milton, AL; Lee, JL; Aitken, MRF; Dickinson, A; Everitt, BJ; Absalom, AR; Adapa, R; Subramanian, N; Taylor, JR; Krystal, JH; Fletcher, PC
MLA Citation
Corlett, PR, Cambridge, V, Gardner, JM, Piggot, JS, Turner, DC, Everitt, JC, Arana, FS, Morgan, HL, Milton, AL, Lee, JL, Aitken, MRF, Dickinson, A, Everitt, BJ, Absalom, AR, Adapa, R, Subramanian, N, Taylor, JR, Krystal, JH, and Fletcher, PC. "Ketamine effects on memory reconsolidation favor a learning model of delusions." PloS one 8.6 (January 2013): e65088-.
PMID
23776445
Source
epmc
Published In
PloS one
Volume
8
Issue
6
Publish Date
2013
Start Page
e65088
DOI
10.1371/journal.pone.0065088

Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis.

Environmental exposures during sensitive windows of development can reprogram normal physiologic responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyperresponsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein, a soy phytoestrogen, and the plasticizer bisphenol A, differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. Whereas both genistein and bisphenol A induce genomic estrogen receptor (ER) signaling in the developing uterus, only genistein induced phosphoinositide 3-kinase (PI3K)/AKT nongenomic ER signaling to the histone methyltransferase enhancer of zeste homolog 2 (EZH2). As a result, this pregenomic signaling phosphorylates and represses EZH2 and reduces levels of H3K27me3 repressive mark in chromatin. Furthermore, only genistein caused estrogen-responsive genes in the adult myometrium to become hyperresponsive to hormone; estrogen-responsive genes were repressed in bisphenol A-exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by genistein promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, whereas bisphenol A did not. These data show that environmental estrogens have distinct nongenomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis.

Authors
Greathouse, KL; Bredfeldt, T; Everitt, JI; Lin, K; Berry, T; Kannan, K; Mittelstadt, ML; Ho, S-M; Walker, CL
MLA Citation
Greathouse, KL, Bredfeldt, T, Everitt, JI, Lin, K, Berry, T, Kannan, K, Mittelstadt, ML, Ho, S-M, and Walker, CL. "Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis." Molecular cancer research : MCR 10.4 (April 2012): 546-557.
PMID
22504913
Source
epmc
Published In
Molecular cancer research : MCR
Volume
10
Issue
4
Publish Date
2012
Start Page
546
End Page
557
DOI
10.1158/1541-7786.mcr-11-0605

Non-neoplastic and neoplastic pleural endpoints following fiber exposure.

Exposure to asbestos fibers is associated with non-neoplastic pleural diseases including plaques, fibrosis, and benign effusions, as well as with diffuse malignant pleural mesothelioma. Translocation and retention of fibers are fundamental processes in understanding the interactions between the dose and dimensions of fibers retained at this anatomic site and the subsequent pathological reactions. The initial interaction of fibers with target cells in the pleura has been studied in cellular models in vitro and in experimental studies in vivo. The proposed biological mechanisms responsible for non-neoplastic and neoplastic pleural diseases and the physical and chemical properties of asbestos fibers relevant to these mechanisms are critically reviewed. Understanding mechanisms of asbestos fiber toxicity may help us anticipate the problems from future exposures both to asbestos and to novel fibrous materials such as nanotubes. Gaps in our understanding have been outlined as guides for future research.

Authors
Broaddus, VC; Everitt, JI; Black, B; Kane, AB
MLA Citation
Broaddus, VC, Everitt, JI, Black, B, and Kane, AB. "Non-neoplastic and neoplastic pleural endpoints following fiber exposure." Journal of toxicology and environmental health. Part B, Critical reviews 14.1-4 (January 2011): 153-178. (Review)
PMID
21534088
Source
epmc
Published In
Journal of Toxicology and Environmental Health Part B: Critical Reviews
Volume
14
Issue
1-4
Publish Date
2011
Start Page
153
End Page
178
DOI
10.1080/10937404.2011.556049

Guidelines for the welfare and use of animals in cancer research.

Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.

Authors
Workman, P; Aboagye, EO; Balkwill, F; Balmain, A; Bruder, G; Chaplin, DJ; Double, JA; Everitt, J; Farningham, DAH; Glennie, MJ; Kelland, LR; Robinson, V; Stratford, IJ; Tozer, GM; Watson, S; Wedge, SR; Eccles, SA; Committee of the National Cancer Research Institute,
MLA Citation
Workman, P, Aboagye, EO, Balkwill, F, Balmain, A, Bruder, G, Chaplin, DJ, Double, JA, Everitt, J, Farningham, DAH, Glennie, MJ, Kelland, LR, Robinson, V, Stratford, IJ, Tozer, GM, Watson, S, Wedge, SR, Eccles, SA, and Committee of the National Cancer Research Institute, . "Guidelines for the welfare and use of animals in cancer research." British Journal of Cancer 102.11 (May 2010): 1555-1577.
PMID
20502460
Source
epmc
Published In
British Journal of Cancer
Volume
102
Issue
11
Publish Date
2010
Start Page
1555
End Page
1577
DOI
10.1038/sj.bjc.6605642

Pleural effects of indium phosphide in B6C3F1 mice: nonfibrous particulate induced pleural fibrosis.

The mechanism(s) by which chronic inhalation of indium phosphide (InP) particles causes pleural fibrosis is not known. Few studies of InP pleural toxicity have been conducted because of the challenges in conducting particulate inhalation exposures, and because the pleural lesions developed slowly over the 2-year inhalation study. The authors investigated whether InP (1 mg/kg) administered by a single oropharyngeal aspiration would cause pleural fibrosis in male B6C3F1 mice. By 28 days after treatment, protein and lactate dehydrogenase (LDH) were significantly increased in bronchoalveolar lavage fluid (BALF), but were unchanged in pleural lavage fluid (PLF). A pronounced pleural effusion characterized by significant increases in cytokines and a 3.7-fold increase in cell number was detected 28 days after InP treatment. Aspiration of soluble InCl(3) caused a similar delayed pleural effusion; however, other soluble metals, insoluble particles, and fibers did not. The effusion caused by InP was accompanied by areas of pleural thickening and inflammation at day 28, and by pleural fibrosis at day 98. Aspiration of InP produced pleural fibrosis that was histologically similar to lesions caused by chronic inhalation exposure, and in a shorter time period. This oropharyngeal aspiration model was used to provide an initial characterization of the progression of pleural lesions caused by InP.

Authors
Kirby, PJ; Shines, CJ; Taylor, GJ; Bousquet, RW; Price, HC; Everitt, JI; Morgan, DL
MLA Citation
Kirby, PJ, Shines, CJ, Taylor, GJ, Bousquet, RW, Price, HC, Everitt, JI, and Morgan, DL. "Pleural effects of indium phosphide in B6C3F1 mice: nonfibrous particulate induced pleural fibrosis." Experimental lung research 35.10 (December 2009): 858-882.
PMID
19995279
Source
epmc
Published In
Experimental Lung Research (Informa)
Volume
35
Issue
10
Publish Date
2009
Start Page
858
End Page
882
DOI
10.3109/01902140902980961

Inhaled carbon nanotubes reach the subpleural tissue in mice.

Carbon nanotubes are shaped like fibres and can stimulate inflammation at the surface of the peritoneum when injected into the abdominal cavity of mice, raising concerns that inhaled nanotubes may cause pleural fibrosis and/or mesothelioma. Here, we show that multiwalled carbon nanotubes reach the subpleura in mice after a single inhalation exposure of 30 mg m(-3) for 6 h. Nanotubes were embedded in the subpleural wall and within subpleural macrophages. Mononuclear cell aggregates on the pleural surface increased in number and size after 1 day and nanotube-containing macrophages were observed within these foci. Subpleural fibrosis unique to this form of nanotubes increased after 2 and 6 weeks following inhalation. None of these effects was seen in mice that inhaled carbon black nanoparticles or a lower dose of nanotubes (1 mg m(-3)). This work suggests that minimizing inhalation of nanotubes during handling is prudent until further long-term assessments are conducted.

Authors
Ryman-Rasmussen, JP; Cesta, MF; Brody, AR; Shipley-Phillips, JK; Everitt, JI; Tewksbury, EW; Moss, OR; Wong, BA; Dodd, DE; Andersen, ME; Bonner, JC
MLA Citation
Ryman-Rasmussen, JP, Cesta, MF, Brody, AR, Shipley-Phillips, JK, Everitt, JI, Tewksbury, EW, Moss, OR, Wong, BA, Dodd, DE, Andersen, ME, and Bonner, JC. "Inhaled carbon nanotubes reach the subpleural tissue in mice." Nature nanotechnology 4.11 (November 2009): 747-751.
PMID
19893520
Source
epmc
Published In
Nature Nanotechnology
Volume
4
Issue
11
Publish Date
2009
Start Page
747
End Page
751
DOI
10.1038/nnano.2009.305

Early onset of spontaneous renal preneoplastic and neoplastic lesions in young conventional rats in toxicity studies.

Although occurring in aged laboratory rodents, spontaneous renal tumour are unknown in animals younger than 18 weeks. A survey on renal preneoplastic and neoplastic lesions has been performed on Sprague-Dawley rats from general toxicology studies over the period January 2004 - May 2006. Data from 2249 rats necropsied and 1206 rats (688 males and 518 females) examined microscopically from 52 studies, are reported. The age range at necropsy was between 12 and 18 weeks and all the animals were obtained from the same supplier. Three cases of tubular carcinoma, 1 tubular adenoma, and 4 cases of atypical tubular hyperplasia were observed in 5 females and 3 males from both control and treated groups from 6 studies with unrelated test compounds. In treated rats, the lesions were considered spontaneous in nature, rather than related to treatment, because of: (1) their sporadic incidence, (2) the short duration of the studies, and (3) the absence of similar lesions in other rats given the same test compound. These lesions are considered a recently occurring spontaneous finding, and the similarities with the familial renal cancer models, namely the Eker and the Nihon models, strongly suggest genetic factors as responsible for the lesions.

Authors
Lanzoni, A; Piaia, A; Everitt, J; Faustinelli, I; Defazio, R; Cavaliere, L; Cristofori, P
MLA Citation
Lanzoni, A, Piaia, A, Everitt, J, Faustinelli, I, Defazio, R, Cavaliere, L, and Cristofori, P. "Early onset of spontaneous renal preneoplastic and neoplastic lesions in young conventional rats in toxicity studies." Toxicologic pathology 35.4 (June 2007): 589-593.
PMID
17654399
Source
epmc
Published In
Toxicologic Pathology (Sage)
Volume
35
Issue
4
Publish Date
2007
Start Page
589
End Page
593
DOI
10.1080/01926230701383202

Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats.

PURPOSE: Transforming growth factor beta (TGF-beta), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-beta signaling could be efficacious for lesions in which TGF-beta promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions. EXPERIMENTAL DESIGN: We examined the effect of a TGF-beta inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency. RESULTS: Blockade of TGF-beta signaling with the ALK5/type I TGF-beta R kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals. CONCLUSION: Although pharmacologic inhibition of TGF-beta signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.

Authors
Laping, NJ; Everitt, JI; Frazier, KS; Burgert, M; Portis, MJ; Cadacio, C; Gold, LI; Walker, CL
MLA Citation
Laping, NJ, Everitt, JI, Frazier, KS, Burgert, M, Portis, MJ, Cadacio, C, Gold, LI, and Walker, CL. "Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats." Clinical cancer research : an official journal of the American Association for Cancer Research 13.10 (May 2007): 3087-3099.
PMID
17505012
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
10
Publish Date
2007
Start Page
3087
End Page
3099
DOI
10.1158/1078-0432.ccr-06-1811

Analysis of renal cell transformation following exposure to trichloroethene in vivo and its metabolite S-(dichlorovinyl)-L-cysteine in vitro.

Trichloroethene (TCE) is classified as a potential human carcinogen although there is a significant debate regarding the mechanism of TCE induced renal tumor formation. This controversy stems in part from the extremely high doses of TCE required to induce renal tumors and the potential contribution of the associated nephrotoxicity to tumorigenesis. We have used Eker rats, which are uniquely susceptible to renal carcinogens, to determine if exposures to TCE in vivo or exposure to its metabolite S-(dichlorovinyl)-L-cysteine (DCVC) in vitro can transform kidney epithelial cells in the absence of cytotoxicity. Treatment with TCE (0, 100, 250, 500, 1000 mg/kg bw by gavage, 5 days a week) for 13 weeks resulted in a significant increase in cell proliferation in kidney tubule cells, but did not enhance formation of preneoplastic lesions or tumor incidence in Eker rat kidneys as compared to controls. In vitro, concentrations of DCVC, which reduced cell survival to 50%, were able to transform rat kidney epithelial cells. However, no carcinogen-specific mutations were identified in the VHL or Tsc-2 tumor suppressor genes in the transformants. Taken together, the inability of TCE to enhance formation of preneoplastic changes or neoplasia and the absence of carcinogen-specific alteration of genes accepted to be critical for renal tumor development suggest that TCE mediated carcinogenicity may occur secondary to continuous toxic injury and sustained regenerative cell proliferation.

Authors
Mally, A; Walker, CL; Everitt, JI; Dekant, W; Vamvakas, S
MLA Citation
Mally, A, Walker, CL, Everitt, JI, Dekant, W, and Vamvakas, S. "Analysis of renal cell transformation following exposure to trichloroethene in vivo and its metabolite S-(dichlorovinyl)-L-cysteine in vitro." Toxicology 224.1-2 (July 2006): 108-118.
PMID
16730402
Source
epmc
Published In
TOXICOLOGY
Volume
224
Issue
1-2
Publish Date
2006
Start Page
108
End Page
118
DOI
10.1016/j.tox.2006.04.036

What's your diagnosis? Lethargy and hind limb paralysis in a day-23 timed pregnant rat.

Authors
Roberts, ES; Bonner, AM; Everitt, JI; Dorman, DC
MLA Citation
Roberts, ES, Bonner, AM, Everitt, JI, and Dorman, DC. "What's your diagnosis? Lethargy and hind limb paralysis in a day-23 timed pregnant rat." Lab animal 35.2 (February 2006): 19-20.
PMID
16446732
Source
epmc
Published In
Lab Animal
Volume
35
Issue
2
Publish Date
2006
Start Page
19
End Page
20
DOI
10.1038/laban0206-19

Preparation of animals for use in the laboratory: issues and challenges for the Institutional Animal Care and Use Committee (IACUC).

Preparation of animals is important for optimization of animal welfare as well as to minimize interanimal variation, thereby strengthening the quality of data for in vivo studies. These issues are important in the work of institutional animal care and use committees (IACUCs), but they pose many challenges as well. This article provides IACUC members with a resource for use in determining whether and how preparation of animals for research affects the IACUC's responsibilities. The topics addressed are intended to serve as a starting point for consideration and discussion. Questions related to subject selection and acclimation of subjects to experimental housing and procedures are emphasized and should provide IACUC members with a framework for discussion of relevant questions. Guidelines are provided for promoting the acclimation of a number of species to experimental settings. Additional, potentially controversial points are also raised, including the effects on longitudinal data sets of changing subject preparation procedures. The roles of the IACUC in the research endeavor are multifaceted and continuously evolving. As empirical data are produced that affect additional aspects of animal care and use, it is important for these committees to be able to evaluate and, when appropriate, stimulate the implementation of improved procedures and strategies.

Authors
Schapiro, SA; Everitt, JI
MLA Citation
Schapiro, SA, and Everitt, JI. "Preparation of animals for use in the laboratory: issues and challenges for the Institutional Animal Care and Use Committee (IACUC)." ILAR journal 47.4 (January 2006): 370-375.
PMID
16963817
Source
epmc
Published In
ILAR Journal
Volume
47
Issue
4
Publish Date
2006
Start Page
370
End Page
375
DOI
10.1093/ilar.47.4.370

The art and science of introducing animals to the research environment.

Authors
Everitt, JI; Shapiro, SJ
MLA Citation
Everitt, JI, and Shapiro, SJ. "The art and science of introducing animals to the research environment." ILAR journal 47.4 (January 2006): 281-282.
PMID
16963808
Source
epmc
Published In
ILAR Journal
Volume
47
Issue
4
Publish Date
2006
Start Page
281
End Page
282
DOI
10.1093/ilar.47.4.281

Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model.

To determine the effects of expression of mutant Ki-ras on lung tumorigenesis, we developed a bitransgenic mouse model that expresses the human Ki-ras(G12C) allele in alveolar type II and/or Clara cells in a tetracycline-inducible, lung-specific manner. Expression of Ki-ras(G12C) caused multiple, small lung tumors over a 12-month time period. Although tumor multiplicity increased upon continued Ki-ras expression, most lung lesions were hyperplasias or well-differentiated adenomas. This is in contrast to the more severe phenotypes observed in other transgenic mouse models in which different mutant Ki-ras alleles were expressed in the lung. Expression of Ki-ras(G12C) was associated with a 2-fold increase in the activation of the Ras and Ral signaling pathways and increased phosphorylation of Ras downstream effectors, including Erk, p90 ribosomal S6 kinase, ribosomal S6 protein, p38 and MAPKAPK-2. In contrast, expression of the transgene had no effect on the activation of the JNK and Akt signaling pathways. Withdrawal of doxycycline for 1 month resulted in almost a complete absence of proliferative pulmonary lesions, suggesting tumor regression in the absence of Ki-ras expression. Mutant Ki-ras(G12C) expression was sufficient for initial lung tumor transformation, required for maintenance of tumor phenotype, and induced transformation of lung epithelial cells by the activation of multiple effector pathways. These results describe a novel mouse lung tumor model demonstrating benign tumor development in the absence of tumor progression, which will provide a new tool for understanding the early stages of lung tumor pathogenesis.

Authors
Floyd, HS; Farnsworth, CL; Kock, ND; Mizesko, MC; Little, JL; Dance, ST; Everitt, J; Tichelaar, J; Whitsett, JA; Miller, MS
MLA Citation
Floyd, HS, Farnsworth, CL, Kock, ND, Mizesko, MC, Little, JL, Dance, ST, Everitt, J, Tichelaar, J, Whitsett, JA, and Miller, MS. "Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model." Carcinogenesis 26.12 (December 2005): 2196-2206.
PMID
16051643
Source
epmc
Published In
Carcinogenesis
Volume
26
Issue
12
Publish Date
2005
Start Page
2196
End Page
2206
DOI
10.1093/carcin/bgi190

Osteopontin expression in particle-induced lung disease.

Osteopontin (OPN) is a secreted cytokine with cell adhesive and chemoattractive functions whose expression is induced by a variety of environmental toxicants. It has been implicated in the pathogenesis of several pulmonary granulomatous and fibrotic conditions. For these reasons the authors investigated OPN expression in experimental particle-induced lung disease using a titanium dioxide exposure model in the rat. Under exposure conditions that resulted in fibroproliferative lung disease, rats had significant increases in total lung OPN mRNA expression and increased levels of OPN protein in bronchoalveolar lavage fluid (BALF) prior to the development of lesions. OPN immunoreactivity studies of lesion development provide evidence that this multifunctional cytokine may be important in the pathogenesis of particle-induced lung disease. Findings suggest that OPN may serve as an important biomarker for particle-induced lung disease.

Authors
Mangum, J; Bermudez, E; Sar, M; Everitt, J
MLA Citation
Mangum, J, Bermudez, E, Sar, M, and Everitt, J. "Osteopontin expression in particle-induced lung disease." Experimental lung research 30.7 (October 2004): 585-598.
PMID
15371094
Source
epmc
Published In
Experimental Lung Research (Informa)
Volume
30
Issue
7
Publish Date
2004
Start Page
585
End Page
598
DOI
10.1080/01902140490476346

Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors.

The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) suppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fasting-responsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1alpha (PGC-1alpha). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR, including peroxisome proliferator-activated receptor alpha (PPARalpha), liver X receptor, and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism and inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPARalpha. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPARalpha, including Cyp4a10 and Cyp4a14, involved in fatty acid omega-oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1alpha. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPARalpha-null mice due to inadequate tissue repair. These results demonstrate that PPARalpha mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.

Authors
Corton, JC; Apte, U; Anderson, SP; Limaye, P; Yoon, L; Latendresse, J; Dunn, C; Everitt, JI; Voss, KA; Swanson, C; Kimbrough, C; Wong, JS; Gill, SS; Chandraratna, RAS; Kwak, M-K; Kensler, TW; Stulnig, TM; Steffensen, KR; Gustafsson, J-A; Mehendale, HM
MLA Citation
Corton, JC, Apte, U, Anderson, SP, Limaye, P, Yoon, L, Latendresse, J, Dunn, C, Everitt, JI, Voss, KA, Swanson, C, Kimbrough, C, Wong, JS, Gill, SS, Chandraratna, RAS, Kwak, M-K, Kensler, TW, Stulnig, TM, Steffensen, KR, Gustafsson, J-A, and Mehendale, HM. "Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors." The Journal of biological chemistry 279.44 (October 2004): 46204-46212.
PMID
15302862
Source
epmc
Published In
The Journal of biological chemistry
Volume
279
Issue
44
Publish Date
2004
Start Page
46204
End Page
46212
DOI
10.1074/jbc.m406739200

Induction of ERK1/2 and histone H3 phosphorylation within the outer stripe of the outer medulla of the Eker rat by 2,3,5-tris-(glutathion-S-yl)hydroquinone.

2,3,5-tris-(glutathion-S-yl)-hydroquinone (TGHQ), a metabolite of hydroquinone (HQ), generates reactive oxygen species (ROS) in cultured renal epithelial cells and binds to tissue macromolecules within the rat kidney. The potential mechanisms by which TGHQ induces nephrotoxicity and nephrocarcinogenesis have been examined in cell culture models, but less is known concerning the molecular mechanisms of TGHQ-induced nephrotoxicity in vivo. In LLC-PK1 cells, TGHQ induces phosphorylation of both mitogen-activated protein kinase and histone H3, which likely promotes inappropriate chromatin condensation and mitotic catastrophe. Using the Eker (Tsc-2 mutant) rat as a model, we show by immunohistochemistry that TGHQ (7.5 micromol/kg) selectively induces ERK1/2 phosphorylation within the outer stripe of the outer medulla (OSOM) of the kidney. ERK1/2 phosphorylation is time-dependant, occurring as early as 1 h following treatment, and reaching maximal levels by 4 h. Subsequently, ERK1/2 phosphorylation returns to baseline levels by 24 h post treatment. ERK1/2 phosphorylation was confirmed by western blot analysis of OSOM tissue. Increases in histone H3 phosphorylation occurred subsequent to ERK1/2 phosphorylation (8 h), and reached a peak by 24 h, coincident with histological evidence of tissue necrosis. In contrast to studies in cell culture, neither JNK/SAPK nor p38 MAPK phosphorylation were significantly altered after TGHQ administration in vivo, as evidenced by western blot and immunohistochemical analyses. These data indicate that activation of the ERK1/2 pathway precedes overt cytotoxicity and that the signaling pathways activated by TGHQ in vivo and in vitro differ.

Authors
Dong, J; Everitt, JI; Lau, SS; Monks, TJ
MLA Citation
Dong, J, Everitt, JI, Lau, SS, and Monks, TJ. "Induction of ERK1/2 and histone H3 phosphorylation within the outer stripe of the outer medulla of the Eker rat by 2,3,5-tris-(glutathion-S-yl)hydroquinone." Toxicological sciences : an official journal of the Society of Toxicology 80.2 (August 2004): 350-357.
PMID
15129024
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
80
Issue
2
Publish Date
2004
Start Page
350
End Page
357
DOI
10.1093/toxsci/kfh160

Emission-particle-induced ventilatory abnormalities in a rat model of pulmonary hypertension.

Preexistent cardiopulmonary disease in humans appears to enhance susceptibility to the adverse effects of ambient particulate matter. Previous studies in this laboratory have demonstrated enhanced inflammation and mortality after intratracheal instillation (IT) and inhalation (INH) of residual oil fly ash (ROFA) in a rat model of pulmonary hypertension induced by monocrotaline (MCT). The present study was conducted to examine the effects of ROFA in this model on ventilatory function in unanesthetized, unrestrained animals. Sixty-day-old male CD rats were injected with MCT (60 mg/kg) or vehicle (VEH) intraperitoneally 10 days before IT of ROFA (8.3 mg/kg) or saline (SAL) (control) or nose-only INH of ROFA [15 mg/m3 for 6 hr on 3 consecutive days or air (control)]. At 24 and 72 hr after exposure, rats were studied individually in a simultaneous gas uptake/whole-body plethysmograph. Lungs were removed at 72 hr for histology. Pulmonary test results showed that tidal volume (VT) decreased 24 hr after IT of ROFA in MCT-treated rats. Breathing frequency, minute volume (VE), and the ventilatory equivalent for oxygen increased in MCT- and VEH-treated rats 24 hr after IT or INH of ROFA and remained elevated 72 hr post-IT. O2 uptake (VO2) decreased after IT of ROFA in MCT-treated rats. Carbon monoxide uptake decreased 24 hr after IT of ROFA, returning to control values in VEH-treated rats but remaining low in MCT-treated rats 72 hr post-IT. ROFA exposure induced histologic changes and abnormalities in several ventilatory parameters, many of which were enhanced by MCT treatment.

Authors
Gardner, SY; McGee, JK; Kodavanti, UP; Ledbetter, A; Everitt, JI; Winsett, DW; Doerfler, DL; Costa, DL
MLA Citation
Gardner, SY, McGee, JK, Kodavanti, UP, Ledbetter, A, Everitt, JI, Winsett, DW, Doerfler, DL, and Costa, DL. "Emission-particle-induced ventilatory abnormalities in a rat model of pulmonary hypertension." Environmental Health Perspectives 112.8 (June 2004): 872-878.
PMID
15175175
Source
epmc
Published In
Environmental health perspectives
Volume
112
Issue
8
Publish Date
2004
Start Page
872
End Page
878
DOI
10.1289/ehp.6583

Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following subchronic (13-week) inhalation exposure.

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO(4)) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO(4) (0.01, 0.1, and 0.5 mg Mn/m(3)), or hureaulite (0.1 mg Mn/m(3)). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO(4) exposure to > or = 0.01, > or = 0.1, and 0.5 mg Mn/m(3), respectively. Exposure to MnSO(4) or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO(4) (0.5 mg Mn/m(3)) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.

Authors
Dorman, DC; McManus, BE; Parkinson, CU; Manuel, CA; McElveen, AM; Everitt, JI
MLA Citation
Dorman, DC, McManus, BE, Parkinson, CU, Manuel, CA, McElveen, AM, and Everitt, JI. "Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following subchronic (13-week) inhalation exposure." Inhalation toxicology 16.6-7 (June 2004): 481-488.
PMID
15204764
Source
epmc
Published In
Inhalation Toxicology (Informa)
Volume
16
Issue
6-7
Publish Date
2004
Start Page
481
End Page
488
DOI
10.1080/08958370490439687

Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice.

The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of renal cell carcinoma (RCC) in humans. VHL functions as a ubiquitin E3 ligase, controlling the stability of hypoxia inducible factor (HIF) and tumor angiogenesis. Alterations in this tumor suppressor gene are rarely observed in spontaneous or chemically induced RCC that arise in conventional strains of rodents and Vhl knockout mice (Vhl+/-) do not develop spontaneous RCC. We tested whether Vhl knockout mice exhibited increased susceptibility to renal carcinogenesis using the well-characterized renal carcinogen streptozotocin. No differences were observed between wild-type and Vhl+/- animals in the frequency or type of renal lesions induced by 50-200 mg/kg streptozotocin. Carcinogen-induced RCC that developed in Vhl heterozygotes and wild-type mice did not contain mutations in the wild-type Vhl, as determined by direct sequencing of the primary tumors. While Vhl+/- mice exhibited no increase in renal lesions in response to streptozotocin, heterozygous animals did develop vascular proliferative lesions of the liver, uterus, ovary, spleen and heart. These lesions, ranging from angiectasis to hemangiosarcoma, were most prominent in the livers of Vhl+/- mice, where they were found in high incidence and high multiplicity. Wild-type mice developed a low-frequency of liver angiectasis (7-15%) only at the highest doses of carcinogen used (150 and 200 mg/kg, respectively) while Vhl+/- mice exhibited angiectasis, hemangioma and hemangiosarcomas with a frequency ranging from 19 to 46% at 50-200 mg/kg streptozotocin. Untreated Vhl+/- mice had a spontaneous incidence of hepatic vascular lesions of 21%. Furthermore, vascular lesions of the uterus, ovary, spleen and heart were observed only in Vhl+/- mice, with an incidence of (5-28%). Taken together, the data indicate that heterozygosity at the Vhl locus predisposes mice to a vascular phenotype ranging from angiectasis to hemangiosarcoma, consistent with the ability of this tumor suppressor gene to control the stability of HIF and regulate key proteins that participate in angiogenesis.

Authors
Kleymenova, E; Everitt, JI; Pluta, L; Portis, M; Gnarra, JR; Walker, CL
MLA Citation
Kleymenova, E, Everitt, JI, Pluta, L, Portis, M, Gnarra, JR, and Walker, CL. "Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice." Carcinogenesis 25.3 (March 2004): 309-315.
PMID
14604887
Source
epmc
Published In
Carcinogenesis
Volume
25
Issue
3
Publish Date
2004
Start Page
309
End Page
315
DOI
10.1093/carcin/bgh017

Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles.

A multispecies, subchronic, inhalation study comparing pulmonary responses to ultrafine titanium dioxide (uf-TiO(2)) was performed. Female rats, mice, and hamsters were exposed to aerosol concentrations of 0.5, 2.0, or 10 mg/m(3) uf-TiO(2) particles for 6 h/day, 5 days/week, for 13 weeks. Following the exposure period, animals were held for recovery periods of 4, 13, 26, or 52 weeks (49 weeks for the uf-TiO(2)-exposed hamsters) and, at each time point, uf-TiO(2) burdens in the lung and lymph nodes and selected lung responses were examined. The responses studied were chosen to assess a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathological alterations. Retained lung burdens increased in a dose-dependent manner in all three species and were at a maximum at the end of exposures. Mice and rats had similar retained lung burdens at the end of the exposures when expressed as mg uf-TiO(2)/mg dry lung, whereas hamsters had retained lung burdens that were significantly lower. Lung burdens in all three species decreased with time after exposure, and, at the end of the recovery period, the percentage of the lung particle burden remaining in the 10 mg/m(3) group was 57, 45, and 3% for rat, mouse, and hamster, respectively. The retardation of particle clearance from the lungs in mice and rats of the 10 mg/m(3) group indicated that pulmonary particle overload had been achieved in these animals. Pulmonary inflammation in rats and mice exposed to 10 mg/m(3) was evidenced by increased numbers of macrophages and neutrophils and increased concentrations of soluble markers in bronchoalveolar lavage fluid (BALF). The initial neutrophil response in rats was greater than in mice, whereas the relative increase of macrophages was less than in mice. The neutrophilic response of rats, but not mice, declined in a time-dependent manner correlating with declining lung burdens; however, the fraction of recovered neutrophils at 52 weeks postexposure was equivalent in the two species. Consistent increases in soluble indicators of toxicity in the BALF (LDH and protein) occurred principally in rats and mice exposed to 10 mg/m(3) and diminished with time postexposure. There were no significant changes in cellular response or with markers indicating toxicity in hamsters, reflecting the capacity of these animals to rapidly clear particles from the lung. Progressive epithelial and fibroproliferative changes were observed in rats of the 10 mg/m(3) group. These lesions consisted of foci of alveolar epithelial proliferation of metaplastic epithelial cells (so-called alveolar bronchiolization) circumscribing aggregated foci of heavily particle-laden macrophages. The observed epithelial proliferative changes were also manifested in rats as an increase in alveolar epithelial cell labeling in cell proliferation studies. Associated with these foci of epithelial proliferation were interstitial particle accumulation and alveolar septal fibrosis. These lesions became more pronounced with increasing time postexposure. Epithelial, metaplastic, and fibroproliferative changes were not noted in either mice or hamsters. In summary, there were significant species differences in the pulmonary responses to inhaled uf-TiO(2) particles. Under conditions where the lung uf-TiO(2) burdens were equivalent, rats developed a more severe inflammatory response than mice and, subsequently, developed progressive epithelial and fibroproliferative changes. Clearance of particles from the lung was markedly impaired in mice and rats exposed to 10 mg/m(3) uf-TiO(2), whereas clearance in hamsters did not appear to be affected at any of the administered doses. These data are consistent with the results of a companion study using inhaled pigmentary (fine mode) TiO(2) (Bermudez et al., 2002) and demonstrate that the pulmonary responses of rats exposed to ultrafine particulate concentrations likely to induce pulmonary overload are different from similarly exposed mice and hamsters. These differences can be explained both by pulmonary respy response and by particle dosimetry differences among these rodent species.

Authors
Bermudez, E; Mangum, JB; Wong, BA; Asgharian, B; Hext, PM; Warheit, DB; Everitt, JI
MLA Citation
Bermudez, E, Mangum, JB, Wong, BA, Asgharian, B, Hext, PM, Warheit, DB, and Everitt, JI. "Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles." Toxicological sciences : an official journal of the Society of Toxicology 77.2 (February 2004): 347-357.
PMID
14600271
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
77
Issue
2
Publish Date
2004
Start Page
347
End Page
357
DOI
10.1093/toxsci/kfh019

Laboratory animal science issues in the design and conduct of studies with endocrine-active compounds.

The use of rodent models for research and testing on endocrine-active compounds necessitates an awareness of a number of laboratory animal science issues to standardize bioassay methods and facilitate reproducibility of results between laboratories. These issues are not unique to endocrine research but are particularly important in this field due to the complexities and interdependencies of the endocrine system, coupled with the inherently sensitive and variable nature of physiological endpoints. Standardization of animal models and the control of animal environments depend on the establishment of strong scientific partnerships between research investigators and laboratory animal scientists. Laboratory animal care and use programs are becoming increasingly complex and are constantly changing, fueled in part by technological advances, changes in regulations concerning animal care and use, and economic pressures. Since the early 1980s, many institutions have moved to centralization of animal facility operations concomitant with numerous changes in housing systems, barrier concepts, equipment, and engineering controls of the macro- and microenvironment. These and other changes can have an impact on animals and the conduct of endocrine experiments. Despite the potential impact of animal care and use procedures on research endpoints, many investigators are surprisingly naive to the animal facility conditions that can affect in vivo studies. Several key animal care and use issues that are important to consider in endocrine experiments with rodent models are described.

Authors
Everitt, JI; Foster, PMD
MLA Citation
Everitt, JI, and Foster, PMD. "Laboratory animal science issues in the design and conduct of studies with endocrine-active compounds." ILAR journal 45.4 (January 2004): 417-424. (Review)
PMID
15454680
Source
epmc
Published In
ILAR Journal
Volume
45
Issue
4
Publish Date
2004
Start Page
417
End Page
424
DOI
10.1093/ilar.45.4.417

Uterine leiomyoma in the Eker rat: a unique model for important diseases of women.

Eker rats carry a defect in the Tsc-2 tumor suppressor gene and female Eker rats develop uterine leiomyoma with a high frequency. The presentation, response to hormones and molecular alterations in these mesenchymal smooth muscle tumors, closely resembles their cognate human disease. Female rats and tumor-derived cell lines from Eker rat leiomyomas (ELT lines) have been developed as an in vivo/in vitro model system for preclinical studies to identify novel therapeutic agents for this disease and for studying disease pathogenesis. In addition to serving as a model for uterine leiomyoma, Eker rats have proven valuable for studying lymphangioleiomyomatosis, a related proliferative smooth muscle disease of women.

Authors
Walker, CL; Hunter, D; Everitt, JI
MLA Citation
Walker, CL, Hunter, D, and Everitt, JI. "Uterine leiomyoma in the Eker rat: a unique model for important diseases of women." Genes, chromosomes & cancer 38.4 (December 2003): 349-356. (Review)
PMID
14566855
Source
epmc
Published In
Genes, Chromosomes and Cancer
Volume
38
Issue
4
Publish Date
2003
Start Page
349
End Page
356
DOI
10.1002/gcc.10281

Variations in Prkdc and susceptibility to benzene-induced toxicity in mice.

Benzene, a carcinogen that induces chromosomal breaks, is strongly associated with leukemias in humans. Possible genetic determinants of benzene susceptibility include proteins involved in repair of benzene-induced DNA damage. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), encoded by Prkdc, is one such protein. DNA-PKcs is involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Here we compared the toxic effects of benzene on mice (C57BL/6 and 129/Sv) homozygous for the wild-type Prkdc allele and mice (129/SvJ) homozygous for a Prkdc functional polymorphism that leads to diminished DNA-PK activity and enhanced apoptosis in response to radiation-induced damage. Male and female mice were exposed to 0, 10, 50, or 100 ppm benzene for 6 h/d, 5 d/week for 2 weeks. Male mice were more susceptible to benzene toxicity compared with females. Hematotoxicity was evident in all male mice but was not seen in female mice. We observed similar, large increases in both micronucleated erythrocyte populations in all male mice. Female mice had smaller but significant increases in micronucleated cells. The p53-dependent response was induced in all strains and genders of mice following benzene exposure, as indicated by an increase in p21 mRNA levels in bone marrow that frequently corresponded with cell cycle arrest in G2/M. Prkdc does not appear to be a significant genetic susceptibility factor for acute benzene toxicity. Moreover, the role of NHEJ, mediated by DNA-PK, in restoring genomic integrity following benzene-induced DSB remains equivocal.

Authors
Faiola, B; Bauer, AK; Fuller, ES; Wong, VA; Pluta, LJ; Abernethy, DJ; Mangum, JB; Everitt, JI; Recio, L
MLA Citation
Faiola, B, Bauer, AK, Fuller, ES, Wong, VA, Pluta, LJ, Abernethy, DJ, Mangum, JB, Everitt, JI, and Recio, L. "Variations in Prkdc and susceptibility to benzene-induced toxicity in mice." Toxicological sciences : an official journal of the Society of Toxicology 75.2 (October 2003): 321-332.
PMID
12857942
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
75
Issue
2
Publish Date
2003
Start Page
321
End Page
332
DOI
10.1093/toxsci/kfg186

Soluble ICAM-1, MCP-1, and MIP-2 protein secretion by rat pleural mesothelial cells following exposure to amosite asbestos.

Pleural inflammation is a sequela of exposure to toxic mineral fibers such as amosite asbestos. This inflammatory response involves the influx of leukocytes from the vasculature into the pleural space. Adhesion molecules such as intercellular adhesion molecule-1 (ICAM)-1 and chemokines such as monocyte chemoattractant protein-1 (MCP)-1 and macrophage inhibitory protein-2 (MIP)-2 are known to be important in pulmonary inflammation following inhalation of particulate matter. However, little is known about their role in pleural inflammation secondary to amosite asbestos exposure. Because the pleural mesothelial cell is believed to be a key target cell of asbestos exposure, the purpose of this study was to determine if ICAM-1, MCP-1, and MIP-2 proteins were secreted by these mesothelial cells following in vitro and in vivo exposure to amosite asbestos. Increased levels of ICAM-1 and MCP-1 protein were measured following 24 or 48 hours exposure of cultured rat pleural mesothelial cells to amosite fibers (1.5 to 5.0 micro g/cm(2)). Increased levels of ICAM-1, MCP-1, and MIP-2 protein were found in pleural lavage fluid from Fischer-344 rats exposed to amosite asbestos for 4 and 12 weeks and after a 12-week recovery period (following the 12-week exposure period). These findings suggest that the secretion of ICAM-1, MCP-1, and MIP-2 by rat pleural mesothelial cells may contribute to amosite-induced pleural inflammation.

Authors
Hill, GD; Mangum, JB; Moss, OR; Everitt, JI
MLA Citation
Hill, GD, Mangum, JB, Moss, OR, and Everitt, JI. "Soluble ICAM-1, MCP-1, and MIP-2 protein secretion by rat pleural mesothelial cells following exposure to amosite asbestos." Experimental lung research 29.5 (July 2003): 277-290.
PMID
12746042
Source
epmc
Published In
Experimental Lung Research (Informa)
Volume
29
Issue
5
Publish Date
2003
Start Page
277
End Page
290
DOI
10.1080/01902140303788

Pleural dosimetry and pathobiological responses in rats and hamsters exposed subchronically to MMVF 10a fiberglass.

Interspecies differences in pulmonary and pleural responses to the inhalation of natural mineral and synthetic vitreous fibers have been observed in chronic and subchronic studies. However, the reasons for these differences are not clearly understood. There are also fiber-specific differences in the outcome of chronic inhalation exposure to natural mineral and synthetic vitreous fibers. Whether these differences are dependent upon the ability of these fibers to translocate to the pleural space is unknown. The present study was conducted to compare retained fiber burdens and selected pathological responses in the pleural compartments of rats and hamsters following subchronic inhalation of MMVF 10a fiberglass, a fiber negative for tumorigenesis or fibrosis in chronic studies. Fischer 344 rats and Syrian golden hamsters were exposed for 4 or 12 weeks by nose-only inhalation at nominal aerosol mass concentrations of 45 mg/m3 (610 WHO fibers/cc). Pulmonary fiber burdens and pulmonary inflammatory responses were greater in rats than in hamsters. The total number of fibers in the lung was approximately three orders of magnitude greater than in the pleural compartment. Pleural burdens in the hamster (160 fibers/cm2 surface area) were significantly greater than burdens in similarly exposed rats (60 fibers/cm2 surface area) following 12 weeks of exposure. With time postexposure, pleural burdens decreased in hamsters but were essentially unchanged in rats. Pleural inflammatory responses in both species were minimal. In rats, pleural inflammation was characterized by increased numbers of macrophages and increases in mesothelial cell replication during the period of fiber exposure. In contrast, hamsters had increased numbers of macrophages and lymphocytes, and mesothelial-cell replication indices were elevated on the parietal pleura of the costal wall and diaphragm, with some of these responses persisting through 12 weeks of postexposure recovery. Taken together, the results suggest that differences among rodent species in pleural responses to inhaled fibers are due to a delivered dose of fibers and to the biological responses to the presence of the fibers.

Authors
Bermudez, E; Mangum, JB; Moss, OR; Wong, BA; Everitt, JI
MLA Citation
Bermudez, E, Mangum, JB, Moss, OR, Wong, BA, and Everitt, JI. "Pleural dosimetry and pathobiological responses in rats and hamsters exposed subchronically to MMVF 10a fiberglass." Toxicological sciences : an official journal of the Society of Toxicology 74.1 (July 2003): 165-173.
PMID
12773778
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
74
Issue
1
Publish Date
2003
Start Page
165
End Page
173
DOI
10.1093/toxsci/kfg092

Ultrafine carbon black particles enhance respiratory syncytial virus-induced airway reactivity, pulmonary inflammation, and chemokine expression.

Exposure to particulate matter (PM) may exacerbate preexisting respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and pneumonia. However, few experimental studies have addressed the effects of PM on lower respiratory tract (LRT) viral infection. Respiratory syncytial virus (RSV) is a major etiological agent for LRT infections in infants, the elderly, and the immunocompromised and may lead to chronic wheezing and the development of asthma in children. In this study, we examined the effects of carbon black (CB) on RSV-induced pulmonary inflammation, chemokine and cytokine expression, and airway hyperresponsiveness in a mouse model of RSV. Female BALB/c mice were instilled via the trachea (i.t.) with 1 x 106 plaque forming units (pfu) RSV or with uninfected culture media. On day 3 of infection, mice were i.t. instilled with either 40 micro g ultrafine CB particles or with saline. End points were examined on days 4, 5, 7, and 14 of RSV infection. Viral titer and clearance in the lung were unaffected by CB exposure. Neutrophil numbers were elevated on days 4 and 7, and lymphocyte numbers were higher on days 4 and 14 of infection in CB-exposed, RSV-infected mice. CB exposure also enhanced RSV-induced airway hyperresponsiveness to methacholine, bronchoalveolar lavage (BAL) total protein, and virus-associated chemokines monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein (MIP-1 alpha), and regulated upon activation, normal T cell expressed and secreted (RANTES). MIP-1 alpha mRNA expression was increased in the alveolar epithelium, where ultrafine particles deposit in the lung. These data demonstrate a synergistic effect of ultrafine CB particles on RSV infection, and suggest a potential mechanism for increased respiratory infections in human populations after PM exposure.

Authors
Lambert, AL; Mangum, JB; DeLorme, MP; Everitt, JI
MLA Citation
Lambert, AL, Mangum, JB, DeLorme, MP, and Everitt, JI. "Ultrafine carbon black particles enhance respiratory syncytial virus-induced airway reactivity, pulmonary inflammation, and chemokine expression." Toxicological sciences : an official journal of the Society of Toxicology 72.2 (April 2003): 339-346.
PMID
12655033
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
72
Issue
2
Publish Date
2003
Start Page
339
End Page
346
DOI
10.1093/toxsci/kfg032

Male mice deficient in microsomal epoxide hydrolase are not susceptible to benzene-induced toxicity.

Enzymes involved in benzene metabolism are likely genetic determinants of benzene-induced toxicity. Polymorphisms in human microsomal epoxide hydrolase (mEH) are associated with an increased risk of developing leukemia, specifically those associated with benzene. This study was designed to investigate the importance of mEH in benzene-induced toxicity. Male and female mEH-deficient (mEH-/-) mice and background mice (129/Sv) were exposed to inhaled benzene (0, 10, 50, or 100 ppm) 5 days/week, 6 h/day, for a two-week duration. Total white blood cell counts and bone marrow cell counts were used to assess hematotoxicity and myelotoxicity. Micronucleated peripheral blood cells were counted to assess genotoxicity, and the p21 mRNA level in bone marrow cells was used as a determinant of the p53-regulated DNA damage response. Male mEH-/- mice did not have any significant hematotoxicity or myelotoxicity at the highest benzene exposure compared to the male 129/Sv mice. Significant hematotoxicity or myelotoxicity did not occur in the female mEH-/- or 129/Sv mice. Male mEH-/- mice were also unresponsive to benzene-induced genotoxicity compared to a significant induction in the male 129/Sv mice. The female mEH-/- and 129/Sv mice were virtually unresponsive to benzene-induced genotoxicity. While p21 mRNA expression was highly induced in male 129/Sv mice after exposure to 100-ppm benzene, no significant alteration was observed in male mEH-/- mice. Likewise, p21 mRNA expression in female mEH-/- mice was not significantly induced upon benzene exposure whereas a significant induction was observed in female 129/Sv mice. Thus mEH appears to be critical in benzene-induced toxicity in male, but not female, mice.

Authors
Bauer, AK; Faiola, B; Abernethy, DJ; Marchan, R; Pluta, LJ; Wong, VA; Gonzalez, FJ; Butterworth, BE; Borghoff, SJ; Everitt, JI; Recio, L
MLA Citation
Bauer, AK, Faiola, B, Abernethy, DJ, Marchan, R, Pluta, LJ, Wong, VA, Gonzalez, FJ, Butterworth, BE, Borghoff, SJ, Everitt, JI, and Recio, L. "Male mice deficient in microsomal epoxide hydrolase are not susceptible to benzene-induced toxicity." Toxicological sciences : an official journal of the Society of Toxicology 72.2 (April 2003): 201-209.
PMID
12655032
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
72
Issue
2
Publish Date
2003
Start Page
201
End Page
209
DOI
10.1093/toxsci/kfg024

Effect of preexposure to ultrafine carbon black on respiratory syncytial virus infection in mice.

Epidemiological studies have indicated that exposure to elevated levels of particulate matter exacerbates several pulmonary diseases, including asthma, bronchitis, and viral infections. Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in infants and may lead to the development of asthma in childhood. To determine whether particle exposure modulates the immune response to RSV, eight-week-old female BALB/c mice received an intratracheal (i.t.) instillation of either 40 micro g ultrafine carbon black (CB) particles or vehicle. The following day, mice were i.t. instilled with either 106 pfu RSV or uninfected media. End points were examined 1, 2, 4, 7, and 10 days during RSV infection. Compared with RSV alone, tumor necrosis factor-alpha (TNF-alpha) protein was reduced in the bronchoalveolar lavage fluid (BALF) on days 1 and 2 of infection; there was also a reduction in BALF lymphocyte numbers on day 4, which correlated with reductions in both IFN-gamma-inducible protein (IP-10), lymphotactin, and IFN-gamma mRNAs in the lungs of RSV + CB mice. Multiprobe ribonuclease protection assays of RSV + CB lung tissue showed no changes in the RSV-associated chemokines regulated upon activation, normal T cell expressed and secreted (RANTES), eotaxin, monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein (MIP)-1 alpha or MIP-1 beta. Viral titers in RSV + CB mice were lower than RSV on days 2-4 of infection. By day 7 of infection, however, neutrophil numbers, proinflammatory cytokine mRNA expression, and protein levels of TNF-alpha and the Th2 cytokine interleukin (IL)-13 were increased in the lungs of RSV + CB mice, indicating an exacerbation of infection. These data indicate that preexposure to ultrafine particles induces an inflammatory milieu promoting allergic immune responses rather than IFNgamma production necessary for microbial defense.

Authors
Lambert, AL; Trasti, FS; Mangum, JB; Everitt, JI
MLA Citation
Lambert, AL, Trasti, FS, Mangum, JB, and Everitt, JI. "Effect of preexposure to ultrafine carbon black on respiratory syncytial virus infection in mice." Toxicological sciences : an official journal of the Society of Toxicology 72.2 (April 2003): 331-338.
PMID
12660365
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
72
Issue
2
Publish Date
2003
Start Page
331
End Page
338
DOI
10.1093/toxsci/kfg031

Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1.

Enzymes that activate and detoxify benzene are likely genetic determinants of benzene-induced toxicity.NAD(P)H: quinone oxidoreductase-1 (NQO1) detoxifies benzoquinones, proposed toxic metabolites of benzene. NQO1 deficiency in humans is associated with an increased risk of leukemia, specifically acute myelogenous leukemia, and benzene poisoning. We examined the importance of NQO1 in benzene-induced toxicity by hypothesizing that NQO1-deficient (NQO1-/-) mice are more sensitive to benzene than mice with wild-type NQO1 (NQO1+/+; 129/Sv background strain). Male and female NQO1-/- and NQO1+/+ mice were exposed to inhaled benzene (0, 10, 50, or 100 ppm) for 2 weeks, 6 h/day, 5 days/week. Micronucleated peripheral blood cells were counted to assess genotoxicity. Peripheral blood counts and bone marrow histology were used to assess hematotoxicity and myelotoxicity. p21 mRNA levels in bone marrow cells were used as determinants of DNA damage response. Female NQO1-/- mice were more sensitive (6-fold) to benzene-induced genotoxicity than the female NQO1+/+ mice. Female NQO1-/- mice had a 9-fold increase (100 versus 0 ppm) in micronucleated reticulocytes compared with a 3-fold increase in the female NQO1+/+ mice. However, the induced genotoxic response in male mice was similar between the two genotypes (> or = 10-fold increase at 100 ppm versus 0 ppm). Male and female NQO1-/- mice exhibited greater hematotoxicity than NQO1+/+ mice. p21 mRNA levels were induced significantly in male mice (>10-fold) from both strains and female NQO1-/- mice (> 8-fold), which indicates an activated DNA damage response. These results indicate that NQO1 deficiency results in substantially greater benzene-induced toxicity. However, the specific patterns of toxicity differed between the male and female mice.

Authors
Bauer, AK; Faiola, B; Abernethy, DJ; Marchan, R; Pluta, LJ; Wong, VA; Roberts, K; Jaiswal, AK; Gonzalez, FJ; Butterworth, BE; Borghoff, S; Parkinson, H; Everitt, J; Recio, L
MLA Citation
Bauer, AK, Faiola, B, Abernethy, DJ, Marchan, R, Pluta, LJ, Wong, VA, Roberts, K, Jaiswal, AK, Gonzalez, FJ, Butterworth, BE, Borghoff, S, Parkinson, H, Everitt, J, and Recio, L. "Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1." Cancer research 63.5 (March 2003): 929-935.
PMID
12615705
Source
epmc
Published In
Cancer Research
Volume
63
Issue
5
Publish Date
2003
Start Page
929
End Page
935

Polycystic kidney disease as a result of loss of the tuberous sclerosis 2 tumor suppressor gene during development.

Somatic loss of function of the tuberous sclerosis 2 (TSC2) tumor suppressor gene leads to the development of benign and malignant lesions of the kidney, brain, uterus, spleen, and liver and germline loss of function of this tumor suppressor gene is embryonic lethal. In addition, the gene product of TSC2, tuberin, is necessary for normal function of the polycystic kidney disease 1 (PKD1) gene product, polycystin-1, which is required for normal cell-cell and cell-matrix interactions. We report here the development of severe polycystic kidney disease in three cases of young Eker rats carrying a germline inactivation of one allele of the Tsc2 gene. Extrarenal tumors were also noted in the spleen and uterus of these animals, which was remarkable given their young age and in the case of the spleen, diffuse involvement of the affected organ. A cell line (EKT2) was established from an affected kidney of one of these animals and used in conjunction with tissues from affected animals to elucidate the defect responsible for the development of these lesions. Affected cells were determined to have lost the wild-type Tsc2 allele while retaining two copies of chromosome 10 containing the mutant Tsc2 allele along with two normal copies of the Pkd1 gene. The genetic data, bilateral nature of the observed kidney disease, and extent of involvement of the spleen and kidney indicate that, in affected animals, loss of the wild-type Tsc2 allele occurred during embryogenesis, probably as a result of chromosome nondisjunction, with affected animals being mosaics for loss of Tsc2 gene function.

Authors
Cai, S; Everitt, JI; Kugo, H; Cook, J; Kleymenova, E; Walker, CL
MLA Citation
Cai, S, Everitt, JI, Kugo, H, Cook, J, Kleymenova, E, and Walker, CL. "Polycystic kidney disease as a result of loss of the tuberous sclerosis 2 tumor suppressor gene during development." The American Journal of Pathology 162.2 (February 2003): 457-468.
PMID
12547704
Source
epmc
Published In
The American journal of pathology
Volume
162
Issue
2
Publish Date
2003
Start Page
457
End Page
468
DOI
10.1016/s0002-9440(10)63840-0

The effect of chronic progressive nephropathy on the incidence of renal tubule cell neoplasms in control male F344 rats.

Chronic progressive nephropathy (CPN) is the most frequently diagnosed lesion in the rat kidney. It has many components including degeneration and regeneration of renal tubule (RT) epithelium, glomerular lesions and interstitial inflammation and fibrosis. The incidence and severity of CPN is strain, age, and sex dependent and may be altered by a number of factors including exposure to xenobiotics. In National Toxicology Program (NTP) 2-year bioassays, xenobiotic-associated increased severity (exacerbation) of CPN often occurs in association with a marginal increased incidence of renal tubule cell neoplasms (RTCN). The relationship between CPN and RTCN development has not been definitively determined. The present study evaluated the association between severity of CPN and the occurrence of RTCN in control male F344 rats. A slight but statistically significant increase in CPN severity was present in those animals with RTCN compared to aged-matched controls without RTCN. Although these data suggest there is a positive correlation between CPN and RTCN, cause and effect were not determined. This marginal association suggests that the number of RTCNs that may develop secondary to chemically exacerbated nephropathy would be few.

Authors
Seely, JC; Haseman, JK; Nyska, A; Wolf, DC; Everitt, JI; Hailey, JR
MLA Citation
Seely, JC, Haseman, JK, Nyska, A, Wolf, DC, Everitt, JI, and Hailey, JR. "The effect of chronic progressive nephropathy on the incidence of renal tubule cell neoplasms in control male F344 rats." Toxicologic pathology 30.6 (November 2002): 681-686.
PMID
12512869
Source
epmc
Published In
Toxicologic Pathology (Sage)
Volume
30
Issue
6
Publish Date
2002
Start Page
681
End Page
686
DOI
10.1080/01926230290166779

Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles.

Female mice, rats, and hamsters were exposed to 10, 50, or 250 mg/m(3) pigmentary titanium dioxide (p-TiO(2)) particles for 6 h per day and 5 days per week for 13 weeks with recovery groups held for an additional 4, 13, 26, or 52 weeks postexposure (46 weeks for the p-TiO(2)-exposed hamsters). At each time point p-TiO(2) burdens in the lung and lymph nodes and selected lung responses were examined. The responses studied were chosen to assess a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathologic alterations. Burdens of p-TiO(2) in the lungs and in the lung-associated lymph nodes increased in a concentration-dependent manner. Retained lung burdens following exposure were greatest in mice. Rats and hamsters had similar lung burdens immediately postexposure when assessed as milligrams of p-TiO(2) per gram of dried lung. Particle retention data suggested that pulmonary overload was achieved in both rats and mice at the exposure levels of 50 and 250 mg/m(3). Under the conditions of the present study, hamsters were better able to clear p-TiO(2) particles than were similarly exposed mice and rats. Pulmonary histopathology revealed both species and concentration-dependent differences in p-TiO(2) particle retention patterns. Inflammation was noted in all three species at 50 and 250 mg/m(3), as evidenced by increases in macrophage and neutrophil numbers and in soluble indices of inflammation in bronchoalveolar lavage fluid (BALF; rats > mice, hamsters). In mice and rats, the BALF inflammatory responses remained elevated relative to controls throughout the entire postexposure recovery period in the most highly exposed animals. In comparison, inflammation in hamsters eventually disappeared, even at the highest exposure dose, due to the more rapid clearance of particles from the lung. Pulmonary lesions were most severe in rats, where progressive epithelial- and fibroproliferative changes were observed in the 250 mg/m(3) group. These epithelial proliferative changes were also manifested in rats as an increase in alveolar epithelial cell labeling in cell proliferation studies. Associated with these foci of epithelial proliferation were interstitial particle accumulation and alveolar septal fibrosis. In summary, there were significant species differences in pulmonary responses to inhaled p-TiO(2) particles. Under conditions in which the lung p-TiO(2) burdens were similar and likely to induce pulmonary overload, rats developed a more severe and persistent pulmonary inflammatory response than either mice or hamsters. Rats also were unique in the development of progressive fibroproliferative lesions and alveolar epithelial metaplasia in response to 90 days of exposure to a high concentration of p-TiO(2) particles.

Authors
Bermudez, E; Mangum, JB; Asgharian, B; Wong, BA; Reverdy, EE; Janszen, DB; Hext, PM; Warheit, DB; Everitt, JI
MLA Citation
Bermudez, E, Mangum, JB, Asgharian, B, Wong, BA, Reverdy, EE, Janszen, DB, Hext, PM, Warheit, DB, and Everitt, JI. "Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles." Toxicological sciences : an official journal of the Society of Toxicology 70.1 (November 2002): 86-97.
PMID
12388838
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
70
Issue
1
Publish Date
2002
Start Page
86
End Page
97
DOI
10.1093/toxsci/70.1.86

Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity.

Although 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 2.5 micromol/kg ip) markedly increased cell proliferation within the outer stripe of the outer medulla (OSOM) of the kidney in both wild-type (Tsc2(+/+)) and mutant Eker rats (Tsc2(EK/+)), only TGHQ-treated Tsc2(EK/+) rats developed renal tumors, indicating that cell proliferation per se was not sufficient for tumor development. Tuberin expression was initially induced within the OSOM after TGHQ treatment but was lost within TGHQ-induced renal tumors. High extracellular signal-regulated kinase (ERK) activity occurred in the OSOM of Tsc2(EK/+) rats at 4 mo and in TGHQ-induced renal tumors. Cyclin D1 was also highly expressed in TGHQ-induced renal tumors. Reexpression of Tsc2 in tuberin-negative cells decreased ERK activity, consistent with the growth-suppressive effects of this tumor suppressor gene. Thus 1) stimulation of cell proliferation after toxicant insult is insufficient for tumor formation; 2) tuberin induction after acute tissue injury suggests that Tsc2 is an acute-phase response gene, limiting the proliferative response after injury; and 3) loss of Tsc2 gene function is associated with cell cycle deregulation.

Authors
Yoon, H-S; Monks, TJ; Everitt, JI; Walker, CL; Lau, SS
MLA Citation
Yoon, H-S, Monks, TJ, Everitt, JI, Walker, CL, and Lau, SS. "Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity." American journal of physiology. Renal physiology 283.2 (August 2002): F262-F270.
PMID
12110509
Source
epmc
Published In
American Journal of Physiology: Renal Physiology
Volume
283
Issue
2
Publish Date
2002
Start Page
F262
End Page
F270

Chloroform inhalation exposure conditions necessary to initiate liver toxicity in female B6C3F1 mice.

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodent liver and kidney, including the female B6C3F1 mouse liver. Because tumors are secondary to events associated with cytolethality and regenerative cell proliferation, these end points are valid surrogates for tumor formation in cancer risk assessments. The purpose of the experiments presented here was to more clearly define the combinations of atmospheric concentration and duration of exposure necessary to induce cytolethality and regenerative cell proliferation in the sensitive female B6C3F1 mouse liver. Female B6C3F1 mice were exposed to chloroform by inhalation for 7 consecutive days using atmospheres of 10, 30, or 90 ppm and selected exposure times of 2, 6, 12, or 18 h/day. Bromodeoxyuridine (BrdU) was given the last 3.5 days via an implanted osmotic pump to label cells in S-phase. Labeled hepatocytes were visualized immunohistochemically, and the labeling index (LI) was determined as the percentage of cells in S-phase. LI was a more sensitive indicator of cellular damage than histopathological examination and is the more conservative end point for use in risk assessments. Significant concentration and exposure time related increases in LI were observed at 30 and 90 ppm but not at any 10-ppm exposure. These data defined an empirical relationship for the combinations of airborne exposure concentration and duration needed to induce cytolethality. These results suggest that concentrations of about 10 ppm or below will not induce hepatotoxicity in these mice regardless of exposure duration. Thus, the rate of production of toxic metabolites and the subsequent rate of cellular damage produced by a continual exposure of approximately 10 ppm chloroform are less than the maximum rates at which hepatocytes can detoxify those metabolites and repair any induced cellular damage. A physiologically based pharmacokinetic (PBPK) dosimetry model was used to compare anticipated responses in mice and humans and predicted that chloroform concentrations of approximately an order of magnitude greater than 10 ppm would be required to induce human liver toxicity. Thus, no safety factor to account for species to species extrapolation should be required in formulating a chloroform inhalation cancer risk assessment based on the dose x time inhalation data presented here.

Authors
Constan, AA; Wong, BA; Everitt, JI; Butterworth, BE
MLA Citation
Constan, AA, Wong, BA, Everitt, JI, and Butterworth, BE. "Chloroform inhalation exposure conditions necessary to initiate liver toxicity in female B6C3F1 mice." Toxicological sciences : an official journal of the Society of Toxicology 66.2 (April 2002): 201-208.
PMID
11896286
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
66
Issue
2
Publish Date
2002
Start Page
201
End Page
208
DOI
10.1093/toxsci/66.2.201

Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor.

Humans and wildlife are frequently exposed to mixtures of endocrine active-compounds (EAC). The objective of the present study was to investigate the potential of the phytoestrogen genistein to influence the reproductive developmental toxicity of the endocrine-active pesticide methoxychlor. Three levels of genistein (0, 300, or 800 ppm) and two levels of methoxychlor (0 or 800 ppm) were used in this study. Sprague-Dawley rats were exposed to the two compounds, either alone or in combinations, through dietary administration to dams during pregnancy and lactation and to the offspring directly after weaning. Both compounds, methoxychlor in particular, were associated with reduced body growth at 800 ppm, but pregnancy outcome was not affected by either treatment. An acceleration of vaginal opening (VO) in the exposed female offspring was the only observed effect of genistein at 300 ppm. Exposure to 800 ppm genistein or 800 ppm methoxychlor caused accelerated VO and also altered estrous cyclicity toward persistent estrus in the female offspring. The estrogenic responses to genistein and methoxychlor administered together were apparently accumulative of the effects associated with each compound alone. Methoxychlor, but not genistein, delayed preputial separation (PPS) in the male rats. When administered with methoxychlor, genistein at 800 ppm enhanced the effect of methoxychlor on delaying PPS. Genistein and methoxychlor treatment did not change gender-specific motor activity patterns in either sex. To explore possible mechanisms for interaction between the two compounds on development, we performed estrogen receptor (ER)- and androgen receptor (AR)-based in vitro transcriptional activation assays using genistein and the primary methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). While the in vitro assays supported the estrogenic effects of genistein and methoxychlor and the antiandrogenic effects of methoxychlor, the reactivity of these compounds with ERs alpha and beta could not predict the greater in vivo estrogenic potency of methoxychlor over genistein; nor could the potentiation of the methoxychlor effect on PPS by genistein be predicted based on in vitro HPTE and genistein reactions with the AR. Data from this study indicate that phytoestrogens are capable of altering the toxicological behaviors of other EACs, and the interactions of these compounds may involve complexities that are difficult to predict based on their in vitro steroid receptor reactivities.

Authors
You, L; Casanova, M; Bartolucci, EJ; Fryczynski, MW; Dorman, DC; Everitt, JI; Gaido, KW; Ross, SM; Heck Hd, HD
MLA Citation
You, L, Casanova, M, Bartolucci, EJ, Fryczynski, MW, Dorman, DC, Everitt, JI, Gaido, KW, Ross, SM, and Heck Hd, HD. "Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor." Toxicological sciences : an official journal of the Society of Toxicology 66.1 (March 2002): 91-104.
PMID
11861976
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
66
Issue
1
Publish Date
2002
Start Page
91
End Page
104
DOI
10.1093/toxsci/66.1.91

Use of short-term assays to evaluate the potential toxicity of two new biosoluble glasswool fibers.

Two new glasswools were developed for optimal biosolubility in the lung: JM 902, for insulation and filtration; and JM 901F, for standard thermal and acoustical insulation. Both were tested for lung biopersistence and their potential to induce persistent pulmonary inflammation in rats. Their dissolution rate constants (k(dis)) were estimated in vitro. Results for 902 were: in vitro k(dis) (pH 7.4) = 150 ng/cm2/h; after 5 days of fiber inhalation (IH), lung clearance of fibers > 20 microm length (F > 20 microm) indicated a weighted half-time (WT(1/2)) of 6.8 days and 90% clearance time (T90) of 33 days; following intratracheal instillation (IT), lung clearance half-time (T(1/2)) for F > 5 microm was 20 days. Results for 901F were: k(dis) (pH 7.4) = 500-560; after 5 days of fiber inhalation exposure, WT(1/2) (F > 20 microm) = 8.1 days and T90 = 38 days. After 5 days of fiber inhalation, both fibers induced initial pulmonary inflammation followed by return to normal within 3 wk postexposure. Lung clearance half-times for 902 and 901F passed the European Union (EU) criteria for noncarcinogenic fibers (IH WT(1/2) F > 20 microm was < 10 days); 902 passed the noncarcinogenic criterion of the German government (IT T(1/2) F > 5 microm was < 45 days). Thus, carcinogenicity labeling is not required for either fiber in the EU. Short-term test results for 902 and 901F were similar to results for synthetic vitreous fibers (SVFs) that were innocuous in rodent chronic inhalation studies, but short-term test results for 902 and 901F differed sharply from results for other SVFs that were pathogenic in chronic studies. Thus, these short-term tests indicate that 902 and 901F are biosoluble fibers and would be nonpathogenic in the rat exposed by inhalation.

Authors
Hesterberg, TW; Hart, GA; Miiller, WC; Chase, G; Rogers, RA; Mangum, JB; Everitt, JI
MLA Citation
Hesterberg, TW, Hart, GA, Miiller, WC, Chase, G, Rogers, RA, Mangum, JB, and Everitt, JI. "Use of short-term assays to evaluate the potential toxicity of two new biosoluble glasswool fibers." Inhalation toxicology 14.3 (March 2002): 217-246.
PMID
12028814
Source
epmc
Published In
Inhalation Toxicology (Informa)
Volume
14
Issue
3
Publish Date
2002
Start Page
217
End Page
246
DOI
10.1080/08958370252809022

Nephrotoxicity and hepatotoxicity induced by inhaled bromodichloromethane in wild-type and p53-heterozygous mice.

Bromodichloromethane (BDCM) is a common municipal drinking water disinfection by-product, resulting in widespread trace human exposure via ingestion and inhalation. The present studies were designed to define organ-specific, BDCM-induced toxicity in wild type (p53(+/+)) and heterozygous (p53(+/-)) mice on both the FVB/N and C57BL/6 genetic backgrounds. Mice were exposed to BDCM vapor daily for 6 h/day and 7 days/week at concentrations of 0, 1, 10, 30, 100, or 150 ppm for 1 week and at 0, 0.3, 1, 3, 10, or 30 ppm for 3 weeks. In the 1-week exposure study, dose-dependent mortality and morbidity were observed at concentrations of 30 ppm and above and were as high as 100% at 150 ppm. In the 3-week exposure study, mortality and morbidity were found only in the 30-ppm exposure groups and were 0, 17, 67, and 33% for the wild-type C57BL/6, p53(+/-) C57BL/6, wild-type FVB/N, and p53(+/-) FVB/N mice, respectively. BDCM was a particularly potent kidney cytotoxicant. Dose-dependent tubular degeneration, necrosis, and associated regenerative cell proliferation greater than 10-fold over controls were seen at concentrations as low as 10 ppm in the kidneys of all strains at 1 week. Similar dose-dependent increases in hepatic necrosis, degeneration, and regenerative cell proliferation were observed but were induced only at concentrations of 30 ppm and higher. Pathological changes were more severe in the FVB/N compared to the C57BL/6 mice and were more severe in the heterozygotes compared to the wild-type mice. However, recovery and return of the percentage of kidney cells in S-phase to control levels was seen at 3 weeks. The estimated maximum tolerated dose for longer-term exposures was 15 ppm, based on mortality, induced kidney pathology, and regenerative cell proliferation. A one-year cancer bioassay was initiated with doses of 0, 0.5, 3, 10, and 15 ppm, based on this information. No pathological changes in the livers were found at the 13-week time point of that study. At 13 weeks, the kidney lesions and regenerative cell proliferation seen at the 1-week time point at doses of 10 ppm and above had resolved, and the cell proliferation rates had returned to baseline. Differences in toxicity indicate that caution be used in substituting wild-type mice for transgenic mice for range-finding studies to select doses for p53(+/-) cancer studies. Resolution of the kidney lesions indicates that periods of very high regenerative cell proliferation, potentially important in the carcinogenic process, may not be observed if measurements are taken only at 3 weeks of exposure or later.

Authors
Torti, VR; Cobb, AJ; Everitt, JI; Marshall, MW; Boorman, GA; Butterworth, BE
MLA Citation
Torti, VR, Cobb, AJ, Everitt, JI, Marshall, MW, Boorman, GA, and Butterworth, BE. "Nephrotoxicity and hepatotoxicity induced by inhaled bromodichloromethane in wild-type and p53-heterozygous mice." Toxicological sciences : an official journal of the Society of Toxicology 64.2 (December 2001): 269-280.
PMID
11719710
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
64
Issue
2
Publish Date
2001
Start Page
269
End Page
280
DOI
10.1093/toxsci/64.2.269

Use of genetically modified mouse models for evaluation of carcinogenic risk: considerations for the laboratory animal scientist.

There has been increasing interest in the use of selected genetically modified (GM) mouse models for the testing of chemicals to determine their carcinogenic potential. GM mouse models are believed to be useful tools that offer mechanistically relevant insights for understanding and predicting the human response to chemical exposure. They have been proposed as alternatives to the traditional 2-year mouse oncogenicity bioassay. In this overview we will review the GM mouse models that have been proposed as bioassay alternatives and present some of the key laboratory animal science challenges that need to be considered when using these unique animals.

Authors
Recio, L; Everitt, J
MLA Citation
Recio, L, and Everitt, J. "Use of genetically modified mouse models for evaluation of carcinogenic risk: considerations for the laboratory animal scientist." Comparative medicine 51.5 (October 2001): 399-405. (Review)
PMID
11924798
Source
epmc
Published In
Comparative medicine
Volume
51
Issue
5
Publish Date
2001
Start Page
399
End Page
405

Acute pulmonary toxicity of particulate matter filter extracts in rats: coherence with epidemiologic studies in Utah Valley residents.

Epidemiologic reports by C.A. Pope III et. al. demonstrated that in the Utah Valley, closure of an open-hearth steel mill over the winter of 1987 was associated with reductions in respiratory disease and related hospital admissions in valley residents. To better examine the relationship between plant-associated changes in ambient particulate matter (PM) and respiratory health effects, we obtained total suspended particulate filters originally collected near the steel mill during the winter of 1986 (before closure), 1987 (during closure), and 1988 (after plant reopening). PM subcomponents were water-extracted from these filters and Sprague-Dawley rats were intratracheally instilled with equivalent masses of extract. Data indicated that 24 hr later, rats exposed to 1986 or 1988 extracts developed significant pulmonary injury and neutrophilic inflammation. Additionally, 50% of rats exposed to 1986 or 1988 extracts had increased airway responsiveness to acetylcholine, compared to 17 and 25% of rats exposed to saline or the 1987 extract, respectively. By 96 hr, these effects were largely resolved except for increases in lung lavage fluid neutrophils and lymphocytes in 1986 extract-exposed rats. Analogous effects were observed with lung histologic assessment. Extract analysis using inductively coupled plasma-mass spectroscopy demonstrated in all three extracts nearly 70% of the mass appeared to be sodium-based salts derived from the glass filter matrix. Interestingly, relative to the 1987 extract, the 1986/1988 extracts contained more sulfate, cationic salts (i.e., calcium, potassium, magnesium), and certain metals (i.e., copper, zinc, iron, lead, strontium, arsenic, manganese, nickel). Although total metal content was (3/4) 1% of the extracts by mass, the greater quantity detected in the 1986 and 1988 extracts suggests metals may be important determinants of the pulmonary toxicity observed. In conclusion, the pulmonary effects induced by exposure of rats to water-based extracts of local ambient PM filters were in good accord with the cross-sectional epidemiologic reports of adverse respiratory health effects in Utah Valley residents.

Authors
Dye, JA; Lehmann, JR; McGee, JK; Winsett, DW; Ledbetter, AD; Everitt, JI; Ghio, AJ; Costa, DL
MLA Citation
Dye, JA, Lehmann, JR, McGee, JK, Winsett, DW, Ledbetter, AD, Everitt, JI, Ghio, AJ, and Costa, DL. "Acute pulmonary toxicity of particulate matter filter extracts in rats: coherence with epidemiologic studies in Utah Valley residents." Environmental health perspectives 109 Suppl 3 (June 2001): 395-403.
PMID
11427389
Source
epmc
Published In
Environmental health perspectives
Volume
109 Suppl 3
Publish Date
2001
Start Page
395
End Page
403
DOI
10.1289/ehp.01109s3395

Acute Pulmonary Toxicity of Particulate Matter Filter Extracts in Rats: Coherence with Epidemiologic Studies in Utah Valley Residents

Authors
Dye, JA; Lehmann, JR; McGee, JK; Winsett, DW; Ledbetter, AD; Everitt, JI; Ghio, AJ; Costa, DL
MLA Citation
Dye, JA, Lehmann, JR, McGee, JK, Winsett, DW, Ledbetter, AD, Everitt, JI, Ghio, AJ, and Costa, DL. "Acute Pulmonary Toxicity of Particulate Matter Filter Extracts in Rats: Coherence with Epidemiologic Studies in Utah Valley Residents." Environmental Health Perspectives 109 (June 2001): 395-395.
Source
crossref
Published In
Environmental health perspectives
Volume
109
Publish Date
2001
Start Page
395
End Page
395
DOI
10.2307/3434787

alpha 2u-Globulin nephropathy, renal cell proliferation, and dosimetry of inhaled tert-butyl alcohol in male and female F-344 rats.

tert-Butyl alcohol (TBA) has been shown to cause kidney tumors in male rats following chronic administration in drinking water. The objective of the present study was to determine whether TBA induces alpha 2u-globulin (alpha 2u) nephropathy (alpha 2u-N) and enhanced renal cell proliferation in male, but not female, F-344 rats, and whether the dosimetry of TBA to the kidney is gender specific. Male and female F-344 rats were exposed to 0, 250, 450, or 1750 ppm TBA vapors 6 h/day for 10 consecutive days to assess alpha 2u-nephropathy and renal cell proliferation and for 1 and 8 days to evaluate the dosimetry of TBA following a single and repeated exposure scenario. Protein droplet accumulation was observed in kidneys of male rats exposed to 1750 ppm TBA, with alpha 2u-globulin immunoreactivity present in these protein droplets. A statistically significant increase in alpha 2u concentration in the kidney, as measured by an enzyme-linked immunosorbent assay, was observed in male rats exposed to 1750 ppm TBA with a exposure-related increase in renal cell proliferation. Renal alpha 2u concentration was positively correlated with cell proliferation in male rat kidney. No histological lesions or increased renal cell proliferation was observed in female rats exposed to TBA compared to controls. The TBA kidney:blood ratio was higher at all concentrations and time points in male rats compared with female rats, which suggests that TBA is retained longer in male rat kidney compared with female rat kidney. Together these data suggest that TBA causes alpha 2u-N in male rats, which is responsible for the male rat-specific increase in renal cell proliferation.

Authors
Borghoff, SJ; Prescott, JS; Janszen, DB; Wong, BA; Everitt, JI
MLA Citation
Borghoff, SJ, Prescott, JS, Janszen, DB, Wong, BA, and Everitt, JI. "alpha 2u-Globulin nephropathy, renal cell proliferation, and dosimetry of inhaled tert-butyl alcohol in male and female F-344 rats." Toxicological sciences : an official journal of the Society of Toxicology 61.1 (May 2001): 176-186.
PMID
11294988
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
61
Issue
1
Publish Date
2001
Start Page
176
End Page
186
DOI
10.1093/toxsci/61.1.176

Tuberin-Dependent Membrane Localization of Polycystin-1

Authors
Kleymenova, E; Ibraghimov-Beskrovnaya, O; Kugoh, H; Everitt, J; Xu, H; Kiguchi, K; Landes, G; Harris, P; Walker, C
MLA Citation
Kleymenova, E, Ibraghimov-Beskrovnaya, O, Kugoh, H, Everitt, J, Xu, H, Kiguchi, K, Landes, G, Harris, P, and Walker, C. "Tuberin-Dependent Membrane Localization of Polycystin-1." Molecular Cell 7.4 (April 2001): 823-832.
Source
crossref
Published In
Molecular Cell
Volume
7
Issue
4
Publish Date
2001
Start Page
823
End Page
832
DOI
10.1016/S1097-2765(01)00226-X

Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene.

The PKD1 gene accounts for 85% of autosomal dominant polycystic kidney disease (ADPKD), the most common human genetic disorder. Rats with a germline inactivation of one allele of the Tsc2 tumor suppressor gene developed early onset severe bilateral polycystic kidney disease, with similarities to the human contiguous gene syndrome caused by germline codeletion of PKD1 and TSC2 genes. Polycystic rat renal cells retained two normal Pkd1 alleles but were null for Tsc2 and exhibited loss of lateral membrane-localized polycystin-1. In tuberin-deficient cells, intracellular trafficking of polycystin-1 was disrupted, resulting in sequestration of polycystin-1 within the Golgi and reexpression of Tsc2 restored correct polycystin-1 membrane localization. These data identify tuberin as a determinant of polycystin-1 functional localization and, potentially, ADPKD severity.

Authors
Kleymenova, E; Ibraghimov-Beskrovnaya, O; Kugoh, H; Everitt, J; Xu, H; Kiguchi, K; Landes, G; Harris, P; Walker, C
MLA Citation
Kleymenova, E, Ibraghimov-Beskrovnaya, O, Kugoh, H, Everitt, J, Xu, H, Kiguchi, K, Landes, G, Harris, P, and Walker, C. "Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene." Molecular cell 7.4 (April 2001): 823-832.
PMID
11336705
Source
epmc
Published In
Molecular Cell
Volume
7
Issue
4
Publish Date
2001
Start Page
823
End Page
832
DOI
10.1016/s1097-2765(01)00226-x

Carcinogenicity of a nephrotoxic metabolite of the "nongenotoxic" carcinogen hydroquinone.

Hydroquinone (HQ) is a potential human carcinogen to which many people are exposed. HQ generally tests negative in standard mutagenicity assays, making it a "nongenotoxic" carcinogen whose mechanism of action remains unknown. HQ is metabolized to 2,3,5-tris(glutathion-S-yl)HQ (TGHQ), a potent toxic and redox active compound. To determine if TGHQ is a carcinogen in the kidney, TGHQ was administered to Eker rats (2 months of age) for 4 or 10 months. Eker rats carry a germline mutation in the tuberous sclerosis 2 (Tsc-2) tumor suppressor gene, which makes them highly susceptible to the development of renal tumors. As early as 4 months after the initiation of treatment (2.5 micromol/kg, i.p.), TGHQ-treated rats developed numerous toxic tubular dysplasias of a form rarely present in vehicle-treated rats. These preneoplastic lesions are believed to represent early transformation within tubules undergoing regeneration after injury by TGHQ, and adenomas subsequently arose within these lesions. After treatment for 10 months (2.5 micromol/kg for 4 months followed by 3.5 micromol/kg for 6 months), there were 6-, 7-, and 10-fold more basophilic dysplasias, adenomas, and renal cell carcinomas, respectively, in TGHQ-treated animals than in controls. Most of these lesions were in the region of TGHQ-induced acute renal injury, the outer stripe of the outer medulla. Loss of heterozygosity (LOH) at the Tsc-2 locus was demonstrated in both the toxic tubular dysplasias and tumors from rats treated with TGHQ for 10 months, consistent with TGHQ-induced loss of tumor suppressor function of the Tsc-2 gene. Thus, although HQ is generally considered a nongenotoxic carcinogen, our data suggest that HQ nephrocarcinogenesis is probably mediated by the formation of the quantitatively minor yet potent nephrotoxic metabolite TGHQ, which induces sustained regenerative hyperplasia, loss of tumor suppressor gene function, and the subsequent formation of renal adenomas and carcinomas. In addition, our data demonstrate that assumptions regarding mechanisms of action of nongenotoxic carcinogens should be considered carefully in the absence of data on the profiles of metabolites generated by these compounds in specific target organs for tumor induction.

Authors
Lau, SS; Monks, TJ; Everitt, JI; Kleymenova, E; Walker, CL
MLA Citation
Lau, SS, Monks, TJ, Everitt, JI, Kleymenova, E, and Walker, CL. "Carcinogenicity of a nephrotoxic metabolite of the "nongenotoxic" carcinogen hydroquinone." Chemical research in toxicology 14.1 (January 2001): 25-33.
PMID
11170505
Source
epmc
Published In
Chemical Research in Toxicology
Volume
14
Issue
1
Publish Date
2001
Start Page
25
End Page
33
DOI
10.1021/tx000161g

Mutagenicity and carcinogenicity of biological reactive intermediate's derived from a "non-genotoxic" carcinogen.

Authors
Lau, SS; Yoon, HS; Patel, SK; Everitt, JI; Walker, CL; Monks, TJ
MLA Citation
Lau, SS, Yoon, HS, Patel, SK, Everitt, JI, Walker, CL, and Monks, TJ. "Mutagenicity and carcinogenicity of biological reactive intermediate's derived from a "non-genotoxic" carcinogen." Advances in experimental medicine and biology 500 (January 2001): 83-92. (Review)
PMID
11765020
Source
epmc
Published In
Advances in experimental medicine and biology
Volume
500
Publish Date
2001
Start Page
83
End Page
92

Advances in Uterine Leiomyoma Research: Conference Overview, Summary, and Future Research Recommendations

Authors
Newbold, RR; DiAugustine, RP; Risinger, JI; Everitt, JI; Walmer, DK; Parrott, EC; Dixon, D
MLA Citation
Newbold, RR, DiAugustine, RP, Risinger, JI, Everitt, JI, Walmer, DK, Parrott, EC, and Dixon, D. "Advances in Uterine Leiomyoma Research: Conference Overview, Summary, and Future Research Recommendations." Environmental Health Perspectives 108 (October 2000): 769-769.
Source
crossref
Published In
Environmental health perspectives
Volume
108
Publish Date
2000
Start Page
769
End Page
769
DOI
10.2307/3454304

Advances in uterine leiomyoma research: conference overview, summary, and future research recommendations.

Uterine leiomyomas (fibroids, myomas) are the most common tumors occurring in the genital tract of women over 30 years of age. These benign uterine smooth-muscle tumors are estimated to be clinically significant in at least 25% of the American female population during their reproductive years. Furthermore, when thorough pathologic examination of hysterectomy specimens has been performed in patients with or without clinical history of myomatous uteri, the incidence of fibroids is 77%, suggesting that these tumors are far more prevalent than estimated by clinical cases. In spite of their high prevalence, little is known concerning the etiology or the molecular basis of their development and growth. It is well known that leiomyoma growth is regulated by ovarian steroid hormones, yet the exact molecular pathway(s) involved in tumor growth and the role of genetic susceptibility/predisposition and the environment are unclear. This article is an overview of some of the topics addressed at the conference on Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research. A summary of research needs and recommendations for future research directions based on conference discussions are also presented.

Authors
Newbold, RR; DiAugustine, RP; Risinger, JI; Everitt, JI; Walmer, DK; Parrott, EC; Dixon, D
MLA Citation
Newbold, RR, DiAugustine, RP, Risinger, JI, Everitt, JI, Walmer, DK, Parrott, EC, and Dixon, D. "Advances in uterine leiomyoma research: conference overview, summary, and future research recommendations." Environmental Health Perspectives 108 Suppl 5 (October 2000): 769-773. (Review)
PMID
11035980
Source
epmc
Published In
Environmental health perspectives
Volume
108 Suppl 5
Publish Date
2000
Start Page
769
End Page
773
DOI
10.1289/ehp.00108s5769

Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats.

Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model. First, a subchronic concentration-response study was conducted in wild-type male Long-Evans rats to determine increased cell proliferation without severe nephrotoxicity. Rats were dosed with sodium barbital in the feed at 0, 50, 250, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation within the cortex and nephrotoxicity were quantitated. Enhanced proliferation with minimal nephrotoxicity occurred at 500 p.p.m. A second study was conducted in male Tsc2 mutant rats given sodium barbital in the feed at 0, 100 or 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additional group of rats was treated with sodium barbital for 6 months and then provided control feed until 12 months of age. Rats necropsied at 6 months of age had a concentration-dependent increase in preneoplastic and total renal lesions. Sodium barbital-treated rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Total combined preneoplastic and neoplastic lesions in the 6 month, high dose group was the same as the 12 month control group. These data show that sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant rats but did not increase their overall number. These data suggest that enhanced cell proliferation without significant cytotoxicity exerted a promotional influence in this hereditary model.

Authors
Wolf, DC; Goldsworthy, TL; Janszen, DB; Harden, R; Donner, EM; David, CS; Everitt, JI
MLA Citation
Wolf, DC, Goldsworthy, TL, Janszen, DB, Harden, R, Donner, EM, David, CS, and Everitt, JI. "Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats." Carcinogenesis 21.8 (August 2000): 1553-1558.
PMID
10910958
Source
epmc
Published In
Carcinogenesis
Volume
21
Issue
8
Publish Date
2000
Start Page
1553
End Page
1558
DOI
10.1093/carcin/21.5.553

Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma.

OBJECTIVE: Uterine leiomyoma are the most common gynecologic neoplasm and a primary cause of hysterectomy in premenopausal women. Preclinical studies were conducted in the Eker rat model to investigate the potential efficacy of selective estrogen receptor modulators (SERMs) as therapeutic agents for this tumor. METHODS: Twelve-month-old Eker rats were randomized into five treatment arms including tamoxifen, placebo, LY 326315, vehicle, and no treatment. Additional animals received ovariectomy or sham surgery at 4 months of age to determine the effect of ovarian ablation on tumor development. The study was terminated after 2 to 4 months of treatment, and tumor incidence, size, proliferative and apoptotic indices were determined. Size and incidence data were subjected to chi-square analysis. One-way analysis of variance and Fisher's least significant difference tests were used to compare proliferative and apoptotic indices. RESULTS: Ovariectomy virtually ablated leiomyoma development, indicating that these tumors were dependent on ovarian hormones for growth and development. Treatment with tamoxifen or raloxifene analog LY 326315 reduced leiomyoma incidence by 40-60% and reduced the size of remaining tumors. The effect of SERMs on leiomyomas was mediated by a decrease in cell proliferation without a decrease in apoptotic index. CONCLUSION: SERMs have been shown to be therapeutically efficacious against breast cancer and to reduce tumor incidence in women at increased risk for this disease. The present data indicate that therapeutic efficacy may also be extended to uterine leiomyoma and demonstrate the utility of this animal model for preclinical studies to identify new therapeutic modalities.

Authors
Walker, CL; Burroughs, KD; Davis, B; Sowell, K; Everitt, JI; Fuchs-Young, R
MLA Citation
Walker, CL, Burroughs, KD, Davis, B, Sowell, K, Everitt, JI, and Fuchs-Young, R. "Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma." Journal of the Society for Gynecologic Investigation 7.4 (July 2000): 249-256.
PMID
10964025
Source
epmc
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
7
Issue
4
Publish Date
2000
Start Page
249
End Page
256
DOI
10.1016/s1071-5576(00)00056-3

Protein Carbonyls in Bronchoalveolar Lavage Fluid in Mice, Rats and Hamsters Following Inhalation of Pigmentary Titanium Dioxide Particles.

Elevation of protein carbonyls has been implicated in the clinical setting as a result of oxidant damage associated with a number of disease states in both humans and laboratory animals. Protein carbonyls, the product of oxidative modification of amino acid residues, may result from macrophage and neutrophil inflammatory responses to inhaled particles. We hypothesized that increased levels of protein carbonyl groups in the bronchoalveolar lavage fluid (BALF) may serve as a biomarker of oxidative stress in rodents exposed to extremely high airborne concentrations of poorly soluble particles (PSP) of low toxicity. The objective of the present study was to compare the BALF protein carbonyl levels in three rodent species following a subchronic PSP exposure known to result in pulmonary pathology in chronically exposed rats under similar conditions. Female Fischer 344 rats, B6C3F1 mice, and Syrian golden hamsters were identically exposed by whole-body inhalation to concentrations of aerosolized pigmentary titanium dioxide (TiO2)(MMAD and GSD, 1.42 and 1.3 μm, respectively) for 6 h/day and 5 days/wk for 13 wk. Groups of animals were exposed to 0, 10, 50, or 250 mg/m(3) of pigmentary TiO2. Levels of protein carbonyl groups in BALF were measured at the termination of the 13-wk exposure with an ELISA assay utilizing a 2,4-dinitrophenylhydrazine fluorescent probe. Protein carbonyl levels were elevated in rats at both the mid and high dose (50 and 250 mg/m(3)), while in mice and hamster the levels were elevated only at the high dose (250 mg/m(3)). The elevations in protein carbonyl levels paralleled changes in BALF-associated cytologic and biochemical inflammatory indices, including total protein levels and neutrophil counts. Inflammatory changes in all three species were limited to animals exposed to the highest concentrations of particles. Rats were the only species tested that had coincidental elevation of both protein carbonyls and a high inflammatory response measured in BALF following the 50-mg/m(3) exposure. These results suggest that the measurement of protein carbonyl groups in BALF may be a useful biomarker of particle-induced oxidant change, although this endpoint should be used in conjunction with other oxidative endpoints as a total assessment of oxidant stress.

Authors
Reverdy, EE; Bermudez, E; Mangum, JB; Asgharian, B; Wong, B; Everitt, JI
MLA Citation
Reverdy, EE, Bermudez, E, Mangum, JB, Asgharian, B, Wong, B, and Everitt, JI. "Protein Carbonyls in Bronchoalveolar Lavage Fluid in Mice, Rats and Hamsters Following Inhalation of Pigmentary Titanium Dioxide Particles." Inhalation toxicology 12 Suppl 3 (January 2000): 283-289.
PMID
26368627
Source
epmc
Published In
Inhalation Toxicology (Informa)
Volume
12 Suppl 3
Publish Date
2000
Start Page
283
End Page
289
DOI
10.1080/08958378.2000.11463224

Comparison of Selected Pulmonary Responses of Rats, Mice, and Syrian Golden Hamsters to Inhaled Pigmentary Titanium Dioxide.

We present a preliminary report of a bioassay designed to compare and contrast selected pulmonary responses of female B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters to inhaled pigmentary titanium dioxide (TiO2). Animals were administered 10, 50, or 250 mg/m(3) TiO2 for 6 h/day and 5 days/wk, for 13 wk. Recovery groups were held for an additional 4-, 13-, or 26-wk period. Following exposure and at each recovery time, TiO2 burdens in the lung and lung-associated lymph nodes were determined. A separate group of animals was used at each time point to assess the inflammatory response of the lung by assaying total protein in bronchoalveolar lavage fluid (BALF) and cytologic examination of cells recovered in BALF. Burdens (mg/mg dry weight) of TiO2 in the lung following exposure to 10, 50, or 250 mg/m(3) TiO2 were 5.2, 53.5, and 170.2 for the mouse; 7.1, 45.1, and 120.4 for the rat; and 2.6, 14.9, and 120.3 for the hamster. With time after exposure, lung burdens of TiO2 particles were decreased and lymph-node burdens increased. Changes in the hamsters' burdens were more rapid than those in mice and rats. Increases in BALF cell numbers (macrophages and neutrophils) and in total protein were observed in all 3 species following exposure to 50 and 250 mg/m(3) TiO2, with the magnitude of response being the grea test in the rat. These responses remained elevated relative to control levels at 26 wk postexposure. Histopathologic examination of lungs showed a concentration-dependent retention pattern of particles that varied by species. Hypertrophy and hyperplasia of alveolar epithelium along with alveolar metaplastic and fibrotic changes were observed in rats exposed to 250 mg/m(3) TiO2. Alveolar epithelial proliferative changes were associated with inflammation in mice and hamsters, but the metaplastic and fibrotic changes noted in rats were not present in similarly exposed mice or hamsters. These data suggest that rats exposed subchronically to extremely high concentrations of pigmentary TiO2 differ from mice and hamsters in their cellular responses in the lung as well as in the way they clear and sequester particles. These differences may partly explain the differential outcome of pulmonary responses in various rodent species following chronic inhalation exposure to poorly soluble particles.

Authors
Everitt, JI; Mangum, JB; Bermudez, E; Wong, BA; Asgharian, B; Reverdy, EE; Hext, PM; Warheit, DB
MLA Citation
Everitt, JI, Mangum, JB, Bermudez, E, Wong, BA, Asgharian, B, Reverdy, EE, Hext, PM, and Warheit, DB. "Comparison of Selected Pulmonary Responses of Rats, Mice, and Syrian Golden Hamsters to Inhaled Pigmentary Titanium Dioxide." Inhalation toxicology 12 Suppl 3 (January 2000): 275-282.
PMID
26368626
Source
epmc
Published In
Inhalation Toxicology (Informa)
Volume
12 Suppl 3
Publish Date
2000
Start Page
275
End Page
282
DOI
10.1080/08958378.2000.11463223

Mesotheliomas induced in rats by the fibrous mineral erionite are independent from p53 alterations.

The development of human malignant mesothelioma (MM) is strongly associated with occupational or environmental exposure to certain natural mineral fibers, although the genetic mechanisms underlying this malignancy remain unclear. Although the p53 gene is frequently mutated in various tumors, human asbestos-associated MMs appear to develop independently from p53 alterations. The high mesotheliomagenic potency of natural fibrous mineral erionite is well established in humans and rodents, but no data regarding genetic alterations in erionite-associated tumors are currently available. Previous speculations that the oncogenic mechanisms underlying asbestos and erionite carcinogenesis may differ led us to examine whether the p53 gene is targeted in erionite carcinogenesis. Fifteen erionite-induced rat MMs as well as six cell lines derived from asbestos-induced and spontaneous rat MM were analyzed for p53 mutations by direct DNA sequencing and immunohistochemical analysis. Both approaches did not reveal p53 alterations in rat MM samples used in the study indicating that, similar to asbestos carcinogenesis, erionite carcinogenesis does not target the p53 tumor suppressor gene.

Authors
Kleymenova, EV; Horesovsky, G; Pylev, LN; Everitt, J
MLA Citation
Kleymenova, EV, Horesovsky, G, Pylev, LN, and Everitt, J. "Mesotheliomas induced in rats by the fibrous mineral erionite are independent from p53 alterations." Cancer letters 147.1-2 (December 1999): 55-61.
PMID
10660089
Source
epmc
Published In
Cancer Letters
Volume
147
Issue
1-2
Publish Date
1999
Start Page
55
End Page
61
DOI
10.1016/s0304-3835(99)00275-x

Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice.

Chloroform is a nongenotoxic-cytotoxic liver and kidney carcinogen and nasal toxicant in some strains and sexes of rodents. Substantial evidence indicates that tumor induction is secondary to events associated with cytolethality and regenerative cell proliferation. Therefore, pathways leading to toxicity, such as metabolic activation, become critical information in mechanism-based risk assessments. The purpose of this study was to determine the degree to which chloroform-induced cytotoxicity is dependent on the cytochromes P450 in general and P450 2E1 in particular. Male B6C3F(1), Sv/129 wild-type (Cyp2e1+/+), and Sv/129 CYP2E1 knockout (Cyp2e1-/- or Cyp2e1-null) mice were exposed 6 h/day for 4 consecutive days to 90 ppm chloroform by inhalation. Parallel control and treated groups, excluding Cyp2e1-null mice, also received an i.p. injection (150 mg/kg) of the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) twice on the day before exposures began and 1 h before every exposure. Cells in S-phase were labeled by infusion of BrdU via an implanted osmotic pump for 3.5 days prior to necropsy, and the labeling index was quantified immunohistochemically. B6C3F(1) and Sv/129 wild-type mice exposed to chloroform alone had extensive hepatic and renal necrosis with significant regenerative cell proliferation. These animals had minimal toxicity in the nasal turbinates with focal periosteal cell proliferation. Administration of ABT completely protected against the hepatic, renal, and nasal toxic effects of chloroform. Induced pathological changes and regenerative cell proliferation were absent in these target sites in Cyp2e1-/- mice exposed to 90 ppm chloroform. These findings indicate that metabolism is obligatory for the development of chloroform-induced hepatic, renal, and nasal toxicity and that cytochrome P450 2E1 appears to be the only enzyme responsible for this cytotoxic-related metabolic conversion under these exposure conditions.

Authors
Constan, AA; Sprankle, CS; Peters, JM; Kedderis, GL; Everitt, JI; Wong, BA; Gonzalez, FL; Butterworth, BE
MLA Citation
Constan, AA, Sprankle, CS, Peters, JM, Kedderis, GL, Everitt, JI, Wong, BA, Gonzalez, FL, and Butterworth, BE. "Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice." Toxicology and applied pharmacology 160.2 (October 1999): 120-126.
PMID
10527910
Source
epmc
Published In
Toxicology and Applied Pharmacology
Volume
160
Issue
2
Publish Date
1999
Start Page
120
End Page
126
DOI
10.1006/taap.1999.8756

Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster. Part II. Results of chronic exposure.

Fiberglass (FG) is the largest category of man-made mineral fibers (MMVFs). Many types of FG are manufactured for specific uses building insulation, air handling, filtration, and sound absorption. In the United States, > 95% of FG produced is for building insulation. Several inhalation studies in rodents of FG building insulation have shown no indication of pulmonary fibrosis or carcinogenic activity. However, because of increasing use and potential for widespread human exposure, a chronic toxicity/carcinogenicity inhalation study of a typical building insulation FG (MMVF 10a) was conducted in hamsters, which were shown to be highly sensitive to the induction of mesotheliomas with another MMVF. A special-application FG (MMVF 33) and amosite asbestos were used for comparative purposes. Groups of 140 weanling male Syrian golden hamsters were exposed via nose-only inhalation for 6 h/day, 5 days/wk for 78 wk to either filtered air (chamber controls) or MMVF 10a, MMVF 33, or amosite asbestos at 250-300 WHO fibers/cm(3) with two additional amosite asbestos groups at 25 and 125 WHO fibers/cm(3). They were then held unexposed for 6 wk until approximately 10-20% survival. After 13, 26, 52, and 78 wk, various pulmonary parameters and lung fiber burdens were evaluated. Groups hamsters were removed from exposure at 13 and 52 wk and were held until 78 wk (recovery groups). Initial lung deposition of long fibers (>20 microm in length) after a single 6-h exposure was similar for all 3 fibers exposed to 250-300 fibers/cm(3). MMVF 10a lungs showed inflammation (which regressed in recovery hamsters) but no pulmonary or pleural fibrosis or neoplasms. MMVF 33 induced more severe inflammation and mild interstitial and pleural fibrosis by 26 wk that progressed in severity until 52 wk, after which it plateaued. While the inflammatory lesions regressed in the recovery animals, pulmonary or pleural fibrosis did not. A single multicentric mesothelioma was observed at 32 wk. No neoplasms were found in the remainder of the study. Amosite asbestos produced dose-related inflammation and pulmonary and pleural fibrosis as early as 13 wk in all 3 exposure levels. The lesions progressed during the course of the study, and at 78 wk severe pulmonary fibrosis with large areas of consolidation was observed in the highest 2 exposure groups. Progressive pleural fibrosis with mesothelial hypertrophy and hyperplasia was present in the thoracic wall and diaphragm in most animals and increased with time in the recovery hamsters. While no pulmonary neoplasms were observed in the amosite exposed hamsters, a large number of mesotheliomas were found; 25 fibers/cm(3), 3.6%; 125 fibers/cm(3), 25.9%; and 250 fibers/cm(3), 19.5%. For the 3 fiber types, the severity of the lung and pleural lesions generally paralleled the cumulative fiber burden, especially those >20 microm length, in the lung, thoracic wall, and diaphragm. They also inversely paralleled the in vitro dissolution rates; that is, the faster the dissolution, the lower were the cumulative lung burdens and the less severe the effects.

Authors
McConnell, EE; Axten, C; Hesterberg, TW; Chevalier, J; Miiller, WC; Everitt, J; Oberdörster, G; Chase, GR; Thevenaz, P; Kotin, P
MLA Citation
McConnell, EE, Axten, C, Hesterberg, TW, Chevalier, J, Miiller, WC, Everitt, J, Oberdörster, G, Chase, GR, Thevenaz, P, and Kotin, P. "Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster. Part II. Results of chronic exposure." Inhalation toxicology 11.9 (September 1999): 785-835.
PMID
10477659
Source
epmc
Published In
Inhalation Toxicology (Informa)
Volume
11
Issue
9
Publish Date
1999
Start Page
785
End Page
835
DOI
10.1080/089583799196754

Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the syrian golden hamster. Part I. Results of a subchronic study and dose selection for a chronic study.

A multidose, subchronic inhalation study was used to estimate the maximum tolerated dose (MTD) of 901 fiberglass (MMVF10.1) for a chronic inhalation study using hamsters. Subchronic study results indicated that 30 mg/m(3) [250-300 WHO fibers (>5 microm long)/cm(3) and 100-130 fibers/cm(3) >20 microm long] meets or exceeds the estimated MTD, and chronic study results confirmed this. For the subchronic study, hamsters were exposed 6 h/day, 5 days/wk, for 13 wk to MMVF10.1 at 3, 16, 30, 45, and 60 mg/m(3) (36, 206, 316, 552, or 714 WHO fibers/cm(3)), then monitored for 10 wk. Results demonstrating MTD were: inflammatory response (all fiber exposures); elevated lung cell proliferation with @ges;16 mg/m(3); lung lavage neutrophil elevations with @ges;16 mg/m(3) and lactate dehydrogenase (LDH) and protein elevations with > or = 30 mg/m(3); and persistent abnormal macrophage/fiber clumps in lungs exposed to 45 and 60 mg/m(3), which suggest overloading of clearance mechanisms. For the chronic study, hamsters were exposed for 78 wk to MMVF10a (901 fiber glass) or MMVF33 (special-application 475 fiberglass) at approximately 300 WHO fibers/cm(3) ( approximately 100 fibers/cm(3) @gt;20 @mu;m long), or to amosite asbestos at an equivalent concentration and 2 lower concentrations. All fiber-exposed animals had pulmonary inflammation, elevated lung lavage cells, and increased lung cell proliferation. Between 52 and 78 wk of exposure, lung burdens of all fibers increased at an accelerated rate, suggesting impairment of clearance mechanisms. MMVF33 and amosite induced fibrosis and pleural mesothelioma. These findings substantiate that exposures in the chronic study adequately tested the toxic potential of fiberglass.

Authors
Hesterberg, TW; Axten, C; McConnell, EE; Hart, GA; Miiller, W; Chevalier, J; Everitt, J; Thevenaz, P; Oberdörster, G
MLA Citation
Hesterberg, TW, Axten, C, McConnell, EE, Hart, GA, Miiller, W, Chevalier, J, Everitt, J, Thevenaz, P, and Oberdörster, G. "Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the syrian golden hamster. Part I. Results of a subchronic study and dose selection for a chronic study." Inhalation toxicology 11.9 (September 1999): 747-784.
PMID
10477658
Source
epmc
Published In
Inhalation Toxicology (Informa)
Volume
11
Issue
9
Publish Date
1999
Start Page
747
End Page
784
DOI
10.1080/089583799196745

Comparison of pulmonary and pleural responses of rats and hamsters to inhaled refractory ceramic fibers.

The present study was designed to determine whether pleural fiber burdens or subchronic pleural fibroproliferative and inflammatory changes can help explain the marked interspecies differences in pleural fibrosis and mesothelioma that are observed following long-term inhalation of RCF-1 ceramic fibers by rats and hamsters. Fischer 344 rats and Syrian golden hamsters were exposed to RCF-1 for 4 h per day, 5 days per week, for 12 consecutive weeks. Lung and pleural fiber burdens were characterized during and after exposure. For all time points, approximately 67% of fibers associated with lung tissues from both rats and hamsters were longer than 5 microns in length. In comparison, fibers longer than 5 microns recovered from the pleural compartment, following a 12-week exposure and 12 weeks of recovery, accounted for 13% (hamsters) and 4% (rats) of the distribution. In the 12 weeks after the cessation of exposure, the number of fibers longer than 5 microns in length remained constant in the hamster at approximately 150 fibers per cm2 pleura. This was 2 to 3 times the corresponding fiber surface density in the rat. Significant pulmonary and pleural inflammation was detected at all time points and for both species. DNA synthesis by pleural mesothelial cells was quantified by bromodeoxyuridine uptake following 3 days of labeling. Labeling indices were higher in hamsters than in rats, both for RCF-1-exposed and filtered air-control animals and was highest for the parietal surface of the pleura. Significantly greater collagen deposition was measured in the visceral pleura of hamsters 12 weeks post-exposure but was not significantly elevated in rats. These findings demonstrate that subchronic inhalation exposure to RCF-1 induces pleural inflammation, mesothelial-cell turnover, pleural fibrosis, and an accumulation of fibers with a length greater than 5 microns in the hamster. The accumulation of long fibers in the pleural space may contribute to the pathology observed in the hamster following chronic inhalation of RCF-1, whereas the presence of short, thin fibers may play a role in the acute-phase biological response seen in both species.

Authors
Gelzleichter, TR; Bermudez, E; Mangum, JB; Wong, BA; Janszen, DB; Moss, OR; Everitt, JI
MLA Citation
Gelzleichter, TR, Bermudez, E, Mangum, JB, Wong, BA, Janszen, DB, Moss, OR, and Everitt, JI. "Comparison of pulmonary and pleural responses of rats and hamsters to inhaled refractory ceramic fibers." Toxicological sciences : an official journal of the Society of Toxicology 49.1 (May 1999): 93-101.
PMID
10367346
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
49
Issue
1
Publish Date
1999
Start Page
93
End Page
101
DOI
10.1093/toxsci/49.1.93

Estrogen treatment enhances hereditary renal tumor development in Eker rats.

Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.

Authors
Wolf, DC; Goldsworthy, TL; Donner, EM; Harden, R; Fitzpatrick, B; Everitt, JI
MLA Citation
Wolf, DC, Goldsworthy, TL, Donner, EM, Harden, R, Fitzpatrick, B, and Everitt, JI. "Estrogen treatment enhances hereditary renal tumor development in Eker rats." Carcinogenesis 19.11 (November 1998): 2043-2047.
PMID
9855022
Source
epmc
Published In
Carcinogenesis
Volume
19
Issue
11
Publish Date
1998
Start Page
2043
End Page
2047
DOI
10.1093/carcin/19.11.2043

Experimental approaches for studies of particulate matter: the case for stronger consideration of dosimetric and exposure issues.

Authors
Everitt, J
MLA Citation
Everitt, J. "Experimental approaches for studies of particulate matter: the case for stronger consideration of dosimetric and exposure issues." Experimental lung research 24.6 (November 1998): 705-707. (Review)
PMID
9839159
Source
epmc
Published In
Experimental Lung Research (Informa)
Volume
24
Issue
6
Publish Date
1998
Start Page
705
End Page
707
DOI
10.3109/01902149809099590

Redistribution and enhanced protein kinase C-mediated phosphorylation of alpha- and gamma-adducin during renal tumor progression.

Tumor promotion/progression is known to be due in part to increased signaling through a variety of mitogenic pathways, including protein kinase C (PKC). To determine whether increased PKC activity could play a role in promotion and progression of renal cancer, we monitored PKC activity in normal and progressively transformed renal neoplasias from Eker rats. Eker rats carry a defect in the tumor suppressor TSC2 gene that predisposes them to renal carcinoma, whereas additional factors influence tumor promotion/progression in accordance with a "two-hit" model. We used the phosphorylation of adducins at Ser-660, a known PKC phosphorylation site, as a reporter for endogenous PKC activity. In normal proximal tubules, total adducin levels (measured with a phosphorylation state-insensitive antibody) were relatively high, whereas pSer660-adducin (measured with a phosphorylation state-sensitive antibody) levels were very low. In comparison, in renal carcinomas, total adducin levels were decreased, and pSer-660-adducin levels were increased. Changes in phosphorylation correlated with changes in localization. In normal tissue, alpha- and gamma-adducin are targeted to the apical and basal membranes of proximal tubules, respectively, implying unique functions for these related proteins. In early lesions (atypical tubules), differential targeting is lost, and both alpha- and gamma-adducins localize to the basal membrane. In more advanced lesions, staining in lateral membranes at cell-cell contacts becomes apparent. Furthermore, in cells that have lost basement membrane contact, plasma membrane targeting is no longer apparent. These changes in adducin expression levels, phosphorylation state, and localization parallel the increased growth potential and dedifferentiation of the progressive tumor phenotypes. These data demonstrate the utility of phosphorylation state-selective antibodies in immunohistochemical applications as reporters of endogenous PKC activity in tissue samples. We also provide the first evidence that increased PKC activity and phosphorylation of important target proteins occurs during progressive transformation in a non-phorbol ester tumor promotion model in vivo.

Authors
Fowler, L; Everitt, J; Stevens, JL; Jaken, S
MLA Citation
Fowler, L, Everitt, J, Stevens, JL, and Jaken, S. "Redistribution and enhanced protein kinase C-mediated phosphorylation of alpha- and gamma-adducin during renal tumor progression." Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 9.5 (May 1998): 405-413.
PMID
9607561
Source
epmc
Published In
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
Volume
9
Issue
5
Publish Date
1998
Start Page
405
End Page
413

Long-term mutagenicity studies with chloroform and dimethylnitrosamine in female lacI transgenic B6C3F1 mice.

The weight of evidence indicates that chloroform induces cancer in the female B6C3F1 mouse liver via a nongenotoxic-cytotoxic mode of action. However, it is probable that DNA damage occurs secondary to events associated with cytolethality and regenerative cell proliferation. The purpose of the present study was to evaluate the potential mutagenic activity of chloroform in the B6C3F1 lacI transgenic mouse liver mutagenesis assay including mutagenic events that might occur secondary to cytolethality. The positive control, dimethylnitrosamine (DMN) is a DNA-reactive mutagen and carcinogen. DMN-induced mutations were anticipated to require only a brief exposure and without further treatment were predicted to remain unchanged over time at those frequencies. Chloroform-induced mutations secondary to toxicity were anticipated to require longer exposure periods and to occur only under conditions that produced sustained cytolethality and regenerative cell proliferation. Female B6C3F1 lacI transgenic mice were treated with daily doses of 2, 4, or 8 mg/kg of DMN by gavage for 4 days and then held until analysis 10, 30, 90, and 180 days postexposure. Livers from DMN-treated mice exhibited a dose-related 2- to 5-fold increase over control mutant frequencies and remained at those levels for 10 through 180 days postexposure. Thus, following the initial induction by DMN no selective mutation amplification or loss was seen for this extended period of time. Female B6C3F1 lacI mice were exposed daily for 6 hr/day 7 days/week to 0, 10, 30, or 90 ppm chloroform by inhalation, representing nonhepatotoxic, borderline, or overtly hepatotoxic chloroform exposures. Timepoints for determination of lacI mutant frequency were 10, 30, 90, and 180 days of exposure. No increase in lacI mutant frequency in the liver was observed at any dose or timepoint with chloroform, indicating a lack of DNA reactivity. DNA alterations secondary to toxicity either did not occur or were of a type not detectable by lacI mutant frequency analysis, such as large deletions.

Authors
Butterworth, BE; Templin, MV; Constan, AA; Sprankle, CS; Wong, BA; Pluta, LJ; Everitt, JI; Recio, L
MLA Citation
Butterworth, BE, Templin, MV, Constan, AA, Sprankle, CS, Wong, BA, Pluta, LJ, Everitt, JI, and Recio, L. "Long-term mutagenicity studies with chloroform and dimethylnitrosamine in female lacI transgenic B6C3F1 mice." Environmental and molecular mutagenesis 31.3 (January 1998): 248-256.
PMID
9585263
Source
epmc
Published In
Environmental and Molecular Mutagenesis
Volume
31
Issue
3
Publish Date
1998
Start Page
248
End Page
256
DOI
10.1002/(sici)1098-2280(1998)31:3<248::aid-em6>3.0.co;2-g

Comparison of pleural responses of rats and hamsters to subchronic inhalation of refractory ceramic fibers

Authors
Everitt, JI; Gelzleichter, TR; Bermudez, E; Mangum, JB; Wong, BA; Janszen, DB; Moss, OR
MLA Citation
Everitt, JI, Gelzleichter, TR, Bermudez, E, Mangum, JB, Wong, BA, Janszen, DB, and Moss, OR. "Comparison of pleural responses of rats and hamsters to subchronic inhalation of refractory ceramic fibers." Environmental Health Perspectives 105.Suppl 5 (September 1, 1997): 1209-1213.
Source
crossref
Published In
Environmental health perspectives
Volume
105
Issue
Suppl 5
Publish Date
1997
Start Page
1209
End Page
1213
DOI
10.1289/ehp.97105s51209

Comparison of pleural responses of rats and hamsters to subchronic inhalation of refractory ceramic fibers.

In the present subchronic study, we compared pleural inflammation, visceral pleural collagen deposition, and visceral and parietal pleural mesothelial cell proliferation in rats and hamsters identically exposed to a kaolin-based refractory ceramic fiber, (RCF)-1 by nose-only inhalation exposure, and correlated the results to translocation of fibers to the pleural cavity. Fischer 344 rats and Syrian golden hamsters were exposed to 650 fibers/cc of RCF-1, for 4 hr/day, 5 days/week for 12 weeks. Following 4 and 12 weeks of exposure, and after a 12-week recovery period, pleural lavage fluid was analyzed for cytologic and biochemical evidence of inflammation. Visceral and parietal pleural mesothelial cell proliferation was assessed by immunocytochemical detection of bromodeoxyuridine incorporation. Pleural collagen was quantitated using morphometric analysis of lung sections stained with Sirius Red. Fiber-exposed rats and hamsters had qualitatively similar pleural inflammation at each time point. Mesothelial cell proliferation was more pronounced in hamsters than in rats at each time point and at each site. In both species, the mesothelial cell labeling index was highest in the parietal pleural mesothelial cells lining the surface of the diaphragm at each time point. Hamsters but not rats had significantly elevated collagen in the visceral pleura at the 12-week postexposure time point. Fibers were found in the pleural cavities of both species at each time point. These fibers were generally short and thin. These results suggest that mesothelial cell proliferation and fibroproliferative changes in the pleura of rodents following short-term inhalation exposure are associated with fiber translocation to the pleura and may be predictive of chronic pleural disease outcomes following long-term exposure.

Authors
Everitt, JI; Gelzleichter, TR; Bermudez, E; Mangum, JB; Wong, BA; Janszen, DB; Moss, OR
MLA Citation
Everitt, JI, Gelzleichter, TR, Bermudez, E, Mangum, JB, Wong, BA, Janszen, DB, and Moss, OR. "Comparison of pleural responses of rats and hamsters to subchronic inhalation of refractory ceramic fibers." Environmental health perspectives 105 Suppl 5 (September 1997): 1209-1213.
PMID
9400725
Source
epmc
Published In
Environmental health perspectives
Volume
105 Suppl 5
Publish Date
1997
Start Page
1209
End Page
1213
DOI
10.1289/ehp.97105s51209

Chronic inhalation study of fiber glass and amosite asbestos in hamsters: twelve-month preliminary results.

The effects of chronic inhalation of glass fibers and amosite asbestos are currently under study in hamsters. The study includes 18 months of inhalation exposure followed by lifetime recovery. Syrian golden hamsters are exposed, nose only, for 6 hr/day, 5 day/week to size-selected test fibers: MMVF10a (Schuller 901 insulation glass); MMVF33 (Schuller 475 durable glass); amosite asbestos (three doses); or to filtered air (controls). Here we report interim results on airborne fiber characterization, lung fiber burden, and pathology (preliminary) through 12 months. Aerosolized test fibers averaged 15 to 20 microns in length and 0.5 to 1 micron in diameter. Target aerosol concentrations of World Health Organization (WHO) fibers (longer than 5 microns) were 250 fibers/cc for MMVF10a and MMVF33, and 25, 125, or 250 fibers/cc for amosite. WHO fiber lung burdens showed time-dependent and (for amosite) dose-dependent increases. After a 12-month exposure, lung burdens of fibers longer than 20 microns were greatest with amosite high and mid doses, similar for low-dose amosite and MMVF33, and smaller for MMVF10a. Biological responses of animals exposed for 12 months to MMVF10a were limited to nonspecific pulmonary inflammation. However, exposures to MMVF33 and each of three doses of amosite were associated with lung fibrosis and possible mesotheliomas (1 with MMVF33 and 2, 3, and 1 with amosite low, mid, and high doses, respectively). Pulmonary and pleural changes associated with amosite were qualitatively and quantitatively more severe than those associated with MMVF33. As of the 12-month time point, this study demonstrates that two different fiber glass compositions with similar fiber dimensions but different durabilities can have distinctly different effects on the hamster lung and pleura after inhalation exposure. (Preliminary tumor data through 18 months of exposure and 6 weeks of postexposure recovery became available as this manuscript went to press: No tumors were observed in the control or MMVF10a groups, and no additional tumors were observed in the MMVF33 group; however, a number of additional mesotheliomas were observed in the amosite groups.

Authors
Hesterberg, TW; Axten, C; McConnell, EE; Oberdörster, G; Everitt, J; Miiller, WC; Chevalier, J; Chase, GR; Thevenaz, P
MLA Citation
Hesterberg, TW, Axten, C, McConnell, EE, Oberdörster, G, Everitt, J, Miiller, WC, Chevalier, J, Chase, GR, and Thevenaz, P. "Chronic inhalation study of fiber glass and amosite asbestos in hamsters: twelve-month preliminary results." Environmental health perspectives 105 Suppl 5 (September 1997): 1223-1229.
PMID
9400728
Source
epmc
Published In
Environmental health perspectives
Volume
105 Suppl 5
Publish Date
1997
Start Page
1223
End Page
1229
DOI
10.1289/ehp.97105s51223

Effects of immobilization restraint on Syrian golden hamsters.

Rodent nose-only inhalation toxicology systems comprise whole-body immobilization in plastic restraint tubes. This method of restraint is known to have a variety of effects on animals. In the studies reported here, two independent toxicology laboratories examined the effects of inhalation tube restraint in Syrian golden hamsters, a species that has recently gained importance in inhalation studies of fibrous particulates. Body weight, food and water consumption, core body temperature, and plasma cortisol and corticosterone concentrations were assessed in animals immobilized in nose-only inhalation tubes, and the results were compared with those from unrestrained cage-control animals. Animals were immobilized for either 6 h/ day, 5 days/week for 13 weeks (subchronic), or 4 h/day for 14 consecutive days (subacute), mimicking exposure conditions commonly used in nose-only inhalation studies. Tube restraint was found to induce a marked decrease in body weight, which increased in response to cessation of restraint. The body weight decrement was associated with significant differences in food and water consumption between the restrained and control groups in the subacute study and only food consumption in the subchronic study. During the restraint period, core body temperature in the immobilized animals increased slightly but not above the normal range for this species. Plasma cortisol and corticosterone concentrations were not significantly increased with use of restraint, compared with values in controls. Immobilization-associated body weight depression in Syrian golden hamsters is important for the evaluation of nose-only inhalation study results because many normal physiologic parameters, as well as toxicant-induced effects, are associated with body weight status.

Authors
King-Herbert, AP; Hesterburg, TW; Thevenaz, PP; Hamm, TE; Moss, OR; Janszen, DB; Everitt, JI
MLA Citation
King-Herbert, AP, Hesterburg, TW, Thevenaz, PP, Hamm, TE, Moss, OR, Janszen, DB, and Everitt, JI. "Effects of immobilization restraint on Syrian golden hamsters." Laboratory animal science 47.4 (August 1997): 362-366.
PMID
9306309
Source
epmc
Published In
Comparative Medicine (Memphis)
Volume
47
Issue
4
Publish Date
1997
Start Page
362
End Page
366

Altered expression of transforming growth factor-α: An early event in renal cell carcinoma development

Authors
Everitt, JI; Walker, CL; Goldsworthy, TW; Wolf, DC
MLA Citation
Everitt, JI, Walker, CL, Goldsworthy, TW, and Wolf, DC. "Altered expression of transforming growth factor-α: An early event in renal cell carcinoma development." Molecular Carcinogenesis 19.3 (July 1997): 213-219.
Source
crossref
Published In
Molecular Carcinogenesis
Volume
19
Issue
3
Publish Date
1997
Start Page
213
End Page
219
DOI
10.1002/(SICI)1098-2744(199707)19:3<213::AID-MC9>3.0.CO;2-E

Altered expression of transforming growth factor-alpha: an early event in renal cell carcinoma development.

Transforming growth factor-alpha (TGF-alpha) is a multifunctional cell regulatory protein with a wide range of effects on cell growth and differentiation and has been implicated in the neoplastic transformation of a variety of cell types. Altered expression of TGF-alpha and its cognate receptor (epidermal growth factor receptor) is enhanced in human and rat renal cell carcinomas. The objective of the study reported here was to determine whether altered TGF-alpha expression is an early or late event in renal tubular oncogenesis. The immunohistochemical expression of TGF-alpha was studied in preneoplastic renal tubular lesions in a rat model of hereditary renal cell carcinoma. Strong TGF-alpha immunoreactivity was present at all stages of renal cell tumor development, including the earliest detectable dysplasias. In contrast, the non-neoplastic regenerating tubular epithelium of rat degenerative nephropathy did not stain for TGF-alpha, although this tissue exhibited a proliferative capacity similar to that observed in the dysplastic and neoplastic lesions. This study indicated that altered TGF-alpha expression was detectable early in the development of renal cell tumors and may be an important feature of the transformed phenotype.

Authors
Everitt, JI; Walker, CL; Goldsworthy, TW; Wolf, DC
MLA Citation
Everitt, JI, Walker, CL, Goldsworthy, TW, and Wolf, DC. "Altered expression of transforming growth factor-alpha: an early event in renal cell carcinoma development." Molecular carcinogenesis 19.3 (July 1997): 213-219.
PMID
9254888
Source
epmc
Published In
Molecular Carcinogenesis
Volume
19
Issue
3
Publish Date
1997
Start Page
213
End Page
219
DOI
10.1002/(sici)1098-2744(199707)19:3<213::aid-mc9>3.3.co;2-w

Pharmacokinetics of methanol and formate in female cynomolgus monkeys exposed to methanol vapors.

The 1990 Clean Air Act Amendments contain mandates for reduced automotive emissions and add new requirements for the use of alternative fuels such as methanol to reduce certain automotive pollutants. Methanol is acutely toxic in humans at relatively low doses, and the potential for exposure to methanol will be increased if it is used in automotive fuel. Formate is the metabolite responsible for neurotoxic effects of acute methanol exposure. Since formate metabolism is dependent on folate, potentially sensitive folate-deficient subpopulations, such as pregnant women, may accumulate formate and be at higher risk from low-level methanol exposure. Our objective was to determine the pharmacokinetics of 14C-methanol and 14C-formate in normal and folate-deficient monkeys after exposure to 14C-methanol vapors at environmentally relevant concentrations: below the threshold limit value (TLV), at the TLV of 200 parts per million (ppm), and above the TLV. Four normal adult female cynomolgus monkeys were individually anesthetized with isoflurane, and each was exposed by endotracheal intubation to 10, 45, 200, or 900 ppm 14C-methanol for 2 hours. Concentrations of the inhaled and exhaled 14C-methanol, blood concentrations of 14C-methanol and 14C-formate, exhaled 14C-carbon dioxide (14CO2), and respiratory parameters were measured during exposure. After exposure, 14C-methanol and 14CO2 exhaled, 14C-methanol and 14C-formate excreted in urine, and 14C-methanol and 14C-formate in blood were quantified. The amounts of exhaled 14C-methanol and 14CO2, blood concentrations of 14C-methanol and 14C-formate, and 14C-methanol and 14C-formate excreted in urine were linearly related to methanol exposure concentration. For all exposures, blood concentrations of 14C-methanol-derived formate were 10 to 1000 times lower than endogenous blood formate concentrations (100 to 200 mM) reported for monkeys and were several orders of magnitude lower than levels of formate known to be toxic. Since the metabolism of formate in primates depends on the availability of tetrahydrofolate, the same four monkeys were next placed on a folate-deficient diet until folate concentrations in red blood cells consistent with moderate folate deficiency (29 to 107 ng/mL) were achieved. Monkeys were then reexposed to the highest exposure concentration, 900 ppm 14C-methanol, for a similar 2-hour period, and again the pharmacokinetic data described above were obtained. Even with a reduced folate status, monkeys exposed to 900 ppm methanol for 2 hours had peak concentrations of methanol-derived formate that were well below the endogenous levels of formate. Although these results represent only a single exposure and therefore preclude broad generalizations, they do suggest the body contains sufficient folate stores to effectively detoxify small doses of methanol-derived formate from exogenous sources, such as those that might occur during normal use of automotive fuel.

Authors
Medinsky, MA; Dorman, DC; Bond, JA; Moss, OR; Janszen, DB; Everitt, JI
MLA Citation
Medinsky, MA, Dorman, DC, Bond, JA, Moss, OR, Janszen, DB, and Everitt, JI. "Pharmacokinetics of methanol and formate in female cynomolgus monkeys exposed to methanol vapors." Research report (Health Effects Institute) 77 (June 1997): 1-30.
PMID
9223214
Source
epmc
Published In
Research report (Health Effects Institute)
Issue
77
Publish Date
1997
Start Page
1
End Page
30

Chrysotile asbestos and H2O2 increase permeability of alveolar epithelium.

The alveolar epithelium contains tight junctions and provides a barrier to passage of potentially injurious substances into the pulmonary interstitium. Alveolar epithelial injury is hypothesized to be an important early event in the pathogenesis of asbestosis. Mechanisms that may contribute to alveolar epithelial cell injury following asbestos exposure include the physicochemical interactions between asbestos fibers and cells, and the generation of reactive oxygen species such as hydrogen peroxide (H2O2). The present study examined changes in transepithelial resistance (Rt) (a measure of barrier function) and permeability of alveolar epithelium after chrysotile asbestos and H2O2 exposure. Alveolar epithelial cell monolayers, obtained from isolation of rat alveolar type II cells and grown on porous supports, were exposed to chrysotile asbestos or polystyrene beads (control) at concentrations of 5, 10, and 25 micrograms/cm2 for 24 h. In separate experiments, monolayers were exposed to H2O2 at concentrations of 50, 75, and 100 microM for 1 h Rt was measured using a voltohmmeter. Prior to treatment, monolayers had a high Rt (> 2000 ohms.cm2). Permeability was assessed by measuring flux of [3H]sucrose from apical to basolateral compartments. Cytotoxicity was evaluated by lactate dehydrogenase (LDH) and preincorporated [14C]adenine release. The morphological integrity of the monolayers was evaluated by scanning electron microscopy. Chrysotile asbestos and H2O2 exposure resulted in dose-dependent decrease in alveolar epithelial Rt and increases in permeability under conditions that did not result in over cytotoxicity. These results demonstrate that both chrysotile asbestos and H2O2 have effects on alveolar epithelial Rt and permeability and suggest a potential role for the alveolar epithelium in mediation of asbestos-induced pulmonary interstitial disease.

Authors
Gardner, SY; Brody, AR; Mangum, JB; Everitt, JI
MLA Citation
Gardner, SY, Brody, AR, Mangum, JB, and Everitt, JI. "Chrysotile asbestos and H2O2 increase permeability of alveolar epithelium." Experimental lung research 23.1 (January 1997): 1-16.
PMID
9028796
Source
epmc
Published In
Experimental Lung Research (Informa)
Volume
23
Issue
1
Publish Date
1997
Start Page
1
End Page
16
DOI
10.3109/01902149709046044

Rodent model of reproductive tract leiomyomata: characterization and use in preclinical therapeutic studies.

Authors
Howe, SR; Everitt, JL; Gottardis, MM; Walker, C
MLA Citation
Howe, SR, Everitt, JL, Gottardis, MM, and Walker, C. "Rodent model of reproductive tract leiomyomata: characterization and use in preclinical therapeutic studies." Progress in clinical and biological research 396 (January 1997): 205-215. (Review)
PMID
9108599
Source
epmc
Published In
Progress in Clinical and Biological Research
Volume
396
Publish Date
1997
Start Page
205
End Page
215

Pulmonary and pleural leukocytes from F344 rats produce elevated levels of fibronectin following inhalation of refractory ceramic fibers.

Authors
Gelzleichter, TR; Mangum, JB; Bermudez, E; Wong, BA; Moss, OR; Everitt, JI
MLA Citation
Gelzleichter, TR, Mangum, JB, Bermudez, E, Wong, BA, Moss, OR, and Everitt, JI. "Pulmonary and pleural leukocytes from F344 rats produce elevated levels of fibronectin following inhalation of refractory ceramic fibers." Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 48.6 (November 1996): 487-489.
PMID
8954328
Source
epmc
Published In
Experimental and Toxicologic Pathology
Volume
48
Issue
6
Publish Date
1996
Start Page
487
End Page
489

Use of lung toxicity and lung particle clearance to estimate the maximum tolerated dose (MTD) for a fiber glass chronic inhalation study in the rat.

Short-term toxicity and lung clearance were assessed in rats exposed by inhalation to size-selected fibrous glass (FG) for 13 weeks. Results from this study and from a recent FG chronic inhalation study are presented here as guidelines for the selection of a maximum tolerated dose (MTD) for chronic inhalation studies of fibers. Fischer 344 rats were exposed using nose-only inhalation chambers, 6 hr/day, 5 days/week, for 13 weeks to one of five concentrations of FG (36, 206, 316, 552, or 714 fibers/cc; expressed gravimetrically, 3, 16, 30, 45, or 60 mg/m3) or to filtered air. Rats were then held for an additional 10 weeks of postexposure recovery. Test fiber was size-selected from glass wool having a chemical composition representative of building insulation. Rats were terminated at 7, 13, 19, and 23 weeks after the onset of exposure to evaluate pulmonary pathology, lung epithelium cell proliferation, lung fiber burden, and lung lavage cells and chemistry. The effect of fiber inhalation on lung clearance of innocuous microspheres was also evaluated: following fiber exposure, six rats/group were exposed to 85Sr-labeled 3.0-microns polystyrene microspheres by intratracheal inhalation and then monitored for whole-body radioactivity during the 10-week recovery period. Data from the short-term study support the choice of 30 mg/m3 as the MTD for the previous chronic FG study and also provide indicators of long-term lung toxicity and functional impairment that can be used to estimate the MTD for future chronic fiber inhalation studies.

Authors
Hesterberg, TW; McConnel, EE; Miiller, WC; Chevalier, J; Everitt, J; Thevenaz, P; Fleissner, H; Oberdörster, G
MLA Citation
Hesterberg, TW, McConnel, EE, Miiller, WC, Chevalier, J, Everitt, J, Thevenaz, P, Fleissner, H, and Oberdörster, G. "Use of lung toxicity and lung particle clearance to estimate the maximum tolerated dose (MTD) for a fiber glass chronic inhalation study in the rat." Fundamental and applied toxicology : official journal of the Society of Toxicology 32.1 (July 1996): 31-44.
PMID
8812213
Source
epmc
Published In
Fundamental and Applied Toxicology
Volume
32
Issue
1
Publish Date
1996
Start Page
31
End Page
44
DOI
10.1006/faat.1996.0104

Pulmonary and pleural responses in Fischer 344 rats following short-term inhalation of a synthetic vitreous fiber. I. Quantitation of lung and pleural fiber burdens.

The pleura is an important target tissue of fiber-induced disease, although it is not known whether fibers must be in direct contact with pleural cells to exert pathologic effects. In the present study, we determined the kinetics of fiber movement into pleural tissues of rats following inhalation of RCF-1, a ceramic fiber previously shown to induce neoplasms in the lung and pleura of rats. Male Fischer 344 rats were exposed by nose-only inhalation to RCF-1 at 89 mg/m3 (2645 WHO fibers/cc), 6 hr/day for 5 consecutive days. On Days 5 and 32, thoracic tissues were analyzed to determine pulmonary and pleural fiber burdens. Mean fiber counts were 22 x 10(6)/lung (25 x 10(3)/pleura) at Day 5 and 18 x 10(6)/lung (16 x 10(3)/pleura) at Day 32. Similar geometric mean lengths (GML) and diameters (GMD) of pulmonary fiber burdens were observed at both time points. Values were 5 microns for GML (geometric standard deviation GSD approximately 2.3) and 0.3 micron for GMD (GSD approximately 1.9), with correlations between length and diameter (tau) of 0.2-0.3. Size distributions of pleural fiber burdens at both time points were approximately 1.5 microns GML (GSD approximately 2.0) and 0.09 micron GMD (GSD approximately 1.5; tau approximately 0.2-0.5). Few fibers longer than 5 microns were observed at either time point. These findings demonstrate that fibers can rapidly translocate to pleural tissues. However, only short, thin (< 5 microns in length) fibers could be detected over the 32-day time course of the experiment.

Authors
Gelzleichter, TR; Bermudez, E; Mangum, JB; Wong, BA; Everitt, JI; Moss, OR
MLA Citation
Gelzleichter, TR, Bermudez, E, Mangum, JB, Wong, BA, Everitt, JI, and Moss, OR. "Pulmonary and pleural responses in Fischer 344 rats following short-term inhalation of a synthetic vitreous fiber. I. Quantitation of lung and pleural fiber burdens." Fundamental and applied toxicology : official journal of the Society of Toxicology 30.1 (March 1996): 31-38.
PMID
8812215
Source
epmc
Published In
Fundamental and Applied Toxicology
Volume
30
Issue
1
Publish Date
1996
Start Page
31
End Page
38
DOI
10.1006/faat.1996.0040

Pulmonary and pleural responses in Fischer 344 rats following short-term inhalation of a synthetic vitreous fiber. II. Pathobiologic responses.

The pleura is a target site for toxic effects induced by a variety of fibrous particulates, including both natural mineral and man-made vitreous fibers. We examined selected cytological and biochemical indicators of inflammation in both the pleural compartment and pulmonary parenchyma in F344 rats following inhalation of RCF-1, a kaolin-based ceramic fiber. Male F344 rats were exposed by inhalation to 89 mg/m3 (2645 WHO fibers/cc) RCF-1 6 hr/day for 5 consecutive days. In lung parenchyma, cytological and biochemical inflammatory responses occurred rapidly following exposure. In contrast, pleural responses were delayed in onset and of a much smaller magnitude than those observed in lung. At both Day 1 and Day 28 postexposure, increased quantities of lactate dehydrogenase, N-acetyl glucosaminidase, alkaline phosphatase, albumin, and neutrophils were present in bronchoalveolar lavage fluid. These responses were attenuated at the latter time point. No significant responses were detected in pleural lavage fluid until 28 days following exposure, at which time elevated numbers of macrophages and eosinophils, but not neutrophils, were observed. Increased albumin and fibronectin were also observed in PLF at this latter time point. These findings demonstrate that the onset of pleural and pulmonary responses following inhalation of RCF-1 are temporally separated and that pleural injury may increase in severity with time following exposure. The increase in severity of pleural inflammation found in the postexposure period cannot be readily explained by fiber translocation.

Authors
Gelzleichter, TR; Bermudez, E; Mangum, JB; Wong, BA; Moss, OR; Everitt, JI
MLA Citation
Gelzleichter, TR, Bermudez, E, Mangum, JB, Wong, BA, Moss, OR, and Everitt, JI. "Pulmonary and pleural responses in Fischer 344 rats following short-term inhalation of a synthetic vitreous fiber. II. Pathobiologic responses." Fundamental and applied toxicology : official journal of the Society of Toxicology 30.1 (March 1996): 39-46.
PMID
8812217
Source
epmc
Published In
Fundamental and Applied Toxicology
Volume
30
Issue
1
Publish Date
1996
Start Page
39
End Page
46
DOI
10.1006/faat.1996.0041

Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus.

Germline alterations of the human von Hippel-Lindau (VHL) tumor suppressor gene predispose to renal cell carcinoma and a constellation of other tumor types found in VHL disease. This gene is also mutated or deleted in a high proportion of sporadic nonpapillary renal cell carcinomas. In the Eker rat model, spontaneous renal cell carcinoma develops with a high frequency. We therefore investigated the role of this tumor suppressor gene in the development of these hereditary rat tumors. By using reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis, the sequence of the rat VHL gene was determined over the portion of the gene homologous to regions where most mutations in the human VHL gene occur. The sequence homology was 90% and the amino-acid identity 99% between the rat and human genes. A developmental and tumor-specific pattern of expression for the VHL gene was found; a ubiquitous 3.2-kb transcript was expressed in all rat tissues examined (neonatal kidney, lung, liver, brain, heart, kidney, spleen, testis, and stomach), and an additional 4.5-kb transcript was expressed in neonatal kidney and cell lines derived from Eker rat renal cell carcinomas (ERC cell lines). To determine whether mutations in the VHL gene were involved in tumor development in the Eker model, RT-PCR, single-strand conformation polymorphism (SSCP) analysis, and direct sequencing were used to search for alterations in this gene in the ERC cell lines. Alterations in the VHL gene were not detected by SSCP, and these data were confirmed by direct sequencing. Transformed rat kidney epithelial cell lines derived from Fisher rats also expressed the VHL gene but like the ERC cell lines did not contain mutations in the VHL gene. These data indicate that in the rat, transformation of kidney epithelial cells and the development of solid, nonpapillary renal cell carcinoma can occur via pathways that are independent of alterations at the VHL gene locus.

Authors
Walker, C; Ahn, YT; Everitt, J; Yuan, X
MLA Citation
Walker, C, Ahn, YT, Everitt, J, and Yuan, X. "Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus." Molecular carcinogenesis 15.2 (February 1996): 154-161.
PMID
8599582
Source
epmc
Published In
Molecular Carcinogenesis
Volume
15
Issue
2
Publish Date
1996
Start Page
154
End Page
161
DOI
10.1002/(sici)1098-2744(199602)15:2<154::aid-mc8>3.0.co;2-j

Pulmonary and Pleural Responses in Fischer 344 Rats Following Short-Term Inhalation of a Synthetic Vitreous Fiber

Authors
GELZLEICHTER, THOMASR; BERMUDEZ, EDILBERTO; MANGUM, JAMESB; WONG, BRAINA; EVERITT, JEFFREYI; MOSS, OWENR
MLA Citation
GELZLEICHTER, THOMASR, BERMUDEZ, EDILBERTO, MANGUM, JAMESB, WONG, BRAINA, EVERITT, JEFFREYI, and MOSS, OWENR. "Pulmonary and Pleural Responses in Fischer 344 Rats Following Short-Term Inhalation of a Synthetic Vitreous Fiber." Toxicological Sciences 30.1 (1996): 31-38.
Source
crossref
Published In
Toxicological Sciences (Elsevier)
Volume
30
Issue
1
Publish Date
1996
Start Page
31
End Page
38
DOI
10.1093/toxsci/30.1.31

Pulmonary and Pleural Responses in Fischer 344 Rats Following Short-Term Inhalation of a Synthetic Vitreous Fiber

Authors
GELZLEICHTER, THOMASR; BERMUDEZ, EDILBERTO; MANGUM, JAMESB; WONG, BRAINA; MOSS, OWENR; EVERITT, JEFFREYI
MLA Citation
GELZLEICHTER, THOMASR, BERMUDEZ, EDILBERTO, MANGUM, JAMESB, WONG, BRAINA, MOSS, OWENR, and EVERITT, JEFFREYI. "Pulmonary and Pleural Responses in Fischer 344 Rats Following Short-Term Inhalation of a Synthetic Vitreous Fiber." Toxicological Sciences 30.1 (1996): 39-46.
Source
crossref
Published In
Toxicological Sciences (Elsevier)
Volume
30
Issue
1
Publish Date
1996
Start Page
39
End Page
46
DOI
10.1093/toxsci/30.1.39

Hereditary renal cell carcinoma in the Eker rat: a unique animal model for the study of cancer susceptibility.

A class of genes, the so-called tumor suppressor genes or anti-oncogenes, was originally identified as being responsible for germ-line transmission of cancer susceptibility in humans. Tumor suppressor genes are recessive at the cellular level with respect to oncogenesis but often manifest as dominantly inherited familial cancer syndromes. This type of cancer syndrome arises in the Eker rat due to a genetic defect in the tuberous sclerosis 2 (Tsc2) gene. The Eker rat familial cancer syndrome serves as a unique animal model in which to study the molecular pathways of renal tubular epithelial carcinogenesis as well as a valuable tool for studies that examine how chemical carcinogens interact with cancer susceptibility genes.

Authors
Everitt, JI; Goldsworthy, TL; Wolf, DC; Walker, CL
MLA Citation
Everitt, JI, Goldsworthy, TL, Wolf, DC, and Walker, CL. "Hereditary renal cell carcinoma in the Eker rat: a unique animal model for the study of cancer susceptibility." Toxicology letters 82-83 (December 1995): 621-625.
PMID
8597118
Source
epmc
Published In
Toxicology Letters
Volume
82-83
Publish Date
1995
Start Page
621
End Page
625
DOI
10.1016/0378-4274(95)03506-0

Estrogen stimulation and tamoxifen inhibition of leiomyoma cell growth in vitro and in vivo.

Uterine leiomyomas (fibroids) are the most common gynecological neoplasms and may be associated with significant morbidity. Recently, we described a rat model (Eker rat) of fibroid development in which reproductive tract leiomyomas develop spontaneously with high frequency. The present studies describe the estrogen and antiestrogen responsiveness of an Eker rat leiomyoma-derived cell line in vitro and a nude mouse xenograft system in vivo. In this cell line, estradiol stimulated growth in estrogen-depleted medium, whereas the nonsteroidal antiestrogen tamoxifen maximally inhibited cell proliferation in medium containing 10% charcoal-stripped serum. Proliferation was also decreased by the biologically active tamoxifen metabolite 4-hydroxytamoxifen; the metabolite was more effective than the parent compound in exerting this growth inhibition. Compared to placebo-treated controls, estradiol increased the size of tumors that developed in a nude mouse xenograft system, whereas tamoxifen increased tumor latency and decreased tumor size. This study of leiomyoma cells in a well defined system suggests that antiestrogens may prove efficacious in the treatment of this clinically important neoplasm.

Authors
Howe, SR; Gottardis, MM; Everitt, JI; Walker, C
MLA Citation
Howe, SR, Gottardis, MM, Everitt, JI, and Walker, C. "Estrogen stimulation and tamoxifen inhibition of leiomyoma cell growth in vitro and in vivo." Endocrinology 136.11 (November 1995): 4996-5003.
PMID
7588234
Source
epmc
Published In
Endocrinology
Volume
136
Issue
11
Publish Date
1995
Start Page
4996
End Page
5003
DOI
10.1210/endo.136.11.7588234

Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat.

Somatic events leading to the inactivation of tumor suppressor genes often involve chromosomal alterations that can be detected as loss of heterozygosity (LOH). In the Eker rat, spontaneous tumors of the kidney, uterus, and spleen develop as a result of a germline mutation of the tuberous sclerosis 2 (Tsc2) gene. We examined the pattern and frequency of LOH at the predisposing locus in 77 primary tumors and cell lines to gain an understanding of the role of Tsc2 allelic loss in the pathogenesis of Eker-derived tumors. Although most renal and uterine tumors (primary and cell lines) displayed LOH, splenic hemangiosarcomas did not. Although the presence of normal tissue may account for some of this difference, the possibility exists that an alternative mechanism, such as subtle mutation or gene dosage effects, may be involved during splenic tumorigenesis. Northern analysis confirmed that LOH resulted in loss of the wild-type transcripts for the Tsc2 gene. Thus, the inactivation of both alleles plays an important role in renal and uterine tumor development, in keeping with Knudson's two-hit hypothesis. In addition, renal tumors that retained the wild-type allele also did not express the normal transcript, suggesting that the remaining Tsc2 alleles had acquired subtle mutations resulting in loss of gene function.

Authors
Yeung, RS; Xiao, GH; Everitt, JI; Jin, F; Walker, CL
MLA Citation
Yeung, RS, Xiao, GH, Everitt, JI, Jin, F, and Walker, CL. "Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat." Molecular carcinogenesis 14.1 (September 1995): 28-36.
PMID
7546222
Source
epmc
Published In
Molecular Carcinogenesis
Volume
14
Issue
1
Publish Date
1995
Start Page
28
End Page
36
DOI
10.1002/mc.2940140107

Expression of insulin-like growth factor II in spontaneously immortalized rat mesothelial and spontaneous mesothelioma cells: a potential autocrine role of insulin-like growth factor II.

Insulin-like growth factors (IGFs) are polypeptides that play an important role in cellular proliferation and differentiation. The present study examines the role of IGFs in the growth of mesothelial cells. Cell lines derived from normal rat mesothelium as well as lines derived from spontaneous rat mesotheliomas were found to express RNA transcripts for IGF-II. In contrast, cell lines derived from asbestos-induced rat mesotheliomas did not express this growth factor. All cell lines expressed receptors for IGF-I and IGF-II, as well as insulin receptors. Coexpression of IGF-II and its cognate receptor suggested that IGF-II was acting as an autocrine growth factor in the spontaneously immortalized cells and the cells derived from the spontaneous tumors. The biological activity of IGF-II secreted by the cell lines into conditioned medium could be neutralized using an IGF-II-specific antibody. Growth was inhibited in a dose-dependent manner; at the highest antibody concentration used (100 micrograms anti-IGF-II/ml), cell growth was decreased to 47% of control values. This inhibition was partially reversible by treatment of the cultures with IGF-II (91% of the control). These data suggest that IGF-II expression may be involved in the spontaneous alteration of rat mesothelial cells and may function as an autocrine or paracrine growth factor to modulate the growth of these cells in vitro and in vivo. Ubiquitous expression of IGF-II by cells that have not been exposed to asbestos and the lack of IGF-II expression by asbestos-transformed cells suggest that the mechanisms of changes in growth factor expression differ in mesothelial cells transformed by different pathways.

Authors
Rutten, AA; Bermudez, E; Stewart, W; Everitt, JI; Walker, CL
MLA Citation
Rutten, AA, Bermudez, E, Stewart, W, Everitt, JI, and Walker, CL. "Expression of insulin-like growth factor II in spontaneously immortalized rat mesothelial and spontaneous mesothelioma cells: a potential autocrine role of insulin-like growth factor II." Cancer research 55.16 (August 1995): 3634-3639.
PMID
7627973
Source
epmc
Published In
Cancer Research
Volume
55
Issue
16
Publish Date
1995
Start Page
3634
End Page
3639

Preneoplastic and neoplastic lesions of rat hereditary renal cell tumors express markers of proximal and distal nephron.

Long-Evans (Eker) rats carry a mutation that predisposes them to develop spontaneous renal cell tumors of two morphologic patterns: solid chromophilic masses or cystic lesions lined by eosinophilic cells. Previous studies have suggested that these tumors arise from the proximal tubules. In the present study, lectin-binding characteristics and cytokeratin expression of various stages of hereditary rat renal epithelial neoplasia were examined to localize the portion of the nephron from which tumors arise. Lectin-binding histochemistry has been used as a marker of cell surface glycoprotein expression, thought to be important in the differentiation of benign from malignant epithelial lesions and in the determination of their cell of origin. The presence or absence of keratin intermediate filaments in the rat nephron has been used to identify nephron segments. The polyclonal antibody to high- and low-molecular-weight cytokeratin stained the cells of the collecting ducts but not the proximal or distal tubules. Binding to the proximal tubules by the lectins Conavalia ensiformis (Con A), Dolichas biflorus, Ricinus communis (RCA-1), and Triticum vulgare and to the distal tubules by Con A, RCA-1, Arachis hypogaea (PNA) with and without neuraminidase, and the antibody for cytokeratins was demonstrated. The lectin binding and cytokeratin staining patterns of rat hereditary renal cell carcinoma, adenoma and the preneoplastic lesions of atypical tubules and hyperplasias suggest that cystic adenomas arise from the distal nephron, principally the collecting duct, whereas the solid atypical tubules, hyperplasias, and adenomas arise from the proximal nephron, principally the proximal tubule.

Authors
Wolf, DC; Whiteley, HE; Everitt, JI
MLA Citation
Wolf, DC, Whiteley, HE, and Everitt, JI. "Preneoplastic and neoplastic lesions of rat hereditary renal cell tumors express markers of proximal and distal nephron." Veterinary pathology 32.4 (July 1995): 379-386.
PMID
7483212
Source
epmc
Published In
Veterinary pathology
Volume
32
Issue
4
Publish Date
1995
Start Page
379
End Page
386
DOI
10.1177/030098589503200406

Estrogen/antiestrogen responsiveness in an in vivo/in vitro model for myometrial tumorigenesis.

Authors
Howe, SR; Everitt, JI; Gottardis, MM; Walker, C
MLA Citation
Howe, SR, Everitt, JI, Gottardis, MM, and Walker, C. "Estrogen/antiestrogen responsiveness in an in vivo/in vitro model for myometrial tumorigenesis." Annals of the New York Academy of Sciences 761 (June 1995): 373-375.
PMID
7625739
Source
epmc
Published In
Annals of the New York Academy of Sciences
Volume
761
Publish Date
1995
Start Page
373
End Page
375
DOI
10.1111/j.1749-6632.1995.tb31396.x

Rodent model of reproductive tract leiomyomata. Clinical and pathological features.

Mesenchymal tumors of the lower reproductive tract of women are poorly understood at the molecular level as a result in part of the lack of relevant animal models. The present study describes a novel model of gynecological smooth muscle tumors in which these neoplasms arise in Eker rats as part of a familial cancer syndrome. The tumors develop as a result of a germline mutation in the tuberous sclerosis 2 (TSC2) gene, and predisposition to tumor development is inherited in an autosomal dominant fashion. Uterine and/or cervical tumors arise spontaneously as single or multicentric neoplasms and increase in incidence with increasing age. The tumors were classified into three phenotypic variants of leiomyoma/leiomyosarcoma and into stromal cervicovaginal tumors on the basis of cytological and histological features and immunostaining patterns for smooth muscle actin and desmin. Tumors histologically identical to the typical human myometrial leiomyoma arose, as did a subset of atypical leiomyomas having an epithelioid phenotype. Eker rats were found to develop both benign and malignant smooth muscle tumors. The high spontaneous incidence of smooth muscle tumors of uterus and cervix in this rodent model provides a unique opportunity to study the molecular mechanisms underlying the development of these clinically important gynecological neoplasms.

Authors
Everitt, JI; Wolf, DC; Howe, SR; Goldsworthy, TL; Walker, C
MLA Citation
Everitt, JI, Wolf, DC, Howe, SR, Goldsworthy, TL, and Walker, C. "Rodent model of reproductive tract leiomyomata. Clinical and pathological features." The American Journal of Pathology 146.6 (June 1995): 1556-1567.
PMID
7778693
Source
epmc
Published In
The American journal of pathology
Volume
146
Issue
6
Publish Date
1995
Start Page
1556
End Page
1567

Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines.

Uterine myometrial tumors are the most commonly found gynecological neoplasm in women. The underlying causes of uterine leiomyomata are poorly understood, a result in part of the absence of a good animal model system in which to study these tumors. This report describes a novel rat model (Eker rat) in which spontaneous gynecological smooth muscle tumors arise with a high frequency. Leiomyomas are the predominant reproductive tract tumor that arise in these animals, although leiomyosarcomas have also been observed. Cell lines have been established from both the benign and malignant lesions. All of the lines express smooth muscle-specific actin, and leiomyoma-derived cell lines express desmin. Two of the cell lines are tumorigenic in nude mice, and the lines are variable for expression of estrogen and progesterone receptors. These lines are the first rodent tumor-derived lines to be established from leiomyomata and are the only lines available from a hereditary form of these tumors. Together with Eker rats that spontaneously develop leiomyomata, they constitute an in vitro/in vivo model system for gaining insights into the mechanism of transformation of uterine smooth muscle cells and the role of steroid hormones and hormone receptors in myometrial tumorigenesis.

Authors
Howe, SR; Gottardis, MM; Everitt, JI; Goldsworthy, TL; Wolf, DC; Walker, C
MLA Citation
Howe, SR, Gottardis, MM, Everitt, JI, Goldsworthy, TL, Wolf, DC, and Walker, C. "Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines." The American Journal of Pathology 146.6 (June 1995): 1568-1579.
PMID
7539981
Source
epmc
Published In
The American journal of pathology
Volume
146
Issue
6
Publish Date
1995
Start Page
1568
End Page
1579

Proposed IACUC guidelines for the review of rodent toxicology studies.

Authors
Everitt, J; Griffin, W
MLA Citation
Everitt, J, and Griffin, W. "Proposed IACUC guidelines for the review of rodent toxicology studies." Contemporary topics in laboratory animal science 34.3 (May 1995): 72-74.
PMID
16457557
Source
epmc
Published In
Contemporary topics in laboratory animal science / American Association for Laboratory Animal Science
Volume
34
Issue
3
Publish Date
1995
Start Page
72
End Page
74

p53 status in spontaneous and dimethylnitrosamine-induced renal cell tumors from rats.

Rats carrying the Eker tumor-susceptibility mutation (Eker rats) are predisposed to developing renal cell carcinoma. Rats heterozygous for the Eker mutation develop spontaneous multiple bilateral renal cell tumors by the age of 1 yr. In a previous study, Eker-mutation carrier and noncarrier rats were exposed to the renal carcinogen dimethylnitrosamine (DMN), and male rats carrying the Eker mutation exhibited a 70-fold increase in the induction of renal adenomas and carcinomas when compared with noncarrier rats. In this study, spontaneous and DMN-induced rat renal cell tumors (adenomas and carcinomas) were analyzed for mutations of the p53 gene by direct sequencing of cDNA polymerase chain reaction products. There were no mutations in p53 cDNA derived from renal tumors from six untreated rats. Mutations were found in one of 15 of the DMN-induced tumors: a transition at codon 140, CCT-->CTT, in a renal adenoma. Additionally, seven cell lines derived from spontaneous renal cell tumors did not contain mutations in p53. The low frequency of p53 mutations (one of 21 renal cell tumors and none of seven cell lines derived from renal cell tumors) indicates that the development of both spontaneous and carcinogen-induced renal tumors involved a non-p53-dependent pathway. As p53 is infrequently mutated in human renal cell carcinomas and in rat renal mesenchymal tumors, it is likely that a tumor suppressor gene or genes other than p53 are involved in the development of renal cancer.

Authors
Horesovsky, G; Recio, L; Everitt, J; Goldsworthy, T; Wolf, DC; Walker, C
MLA Citation
Horesovsky, G, Recio, L, Everitt, J, Goldsworthy, T, Wolf, DC, and Walker, C. "p53 status in spontaneous and dimethylnitrosamine-induced renal cell tumors from rats." Molecular carcinogenesis 12.4 (April 1995): 236-240.
PMID
7727045
Source
epmc
Published In
Molecular Carcinogenesis
Volume
12
Issue
4
Publish Date
1995
Start Page
236
End Page
240
DOI
10.1002/mc.2940120408

Autocrine growth stimulation by transforming growth factor alpha in asbestos-transformed rat mesothelial cells.

Although the association between asbestos exposure and mesothelioma development has been established for decades, very little is known regarding the molecular mechanism(s) by which asbestos fibers induce this disease. In this series of experiments, the potential for transforming growth factor alpha (TGF-alpha) to act as an autocrine growth factor in transformed mesothelial cells was examined in rats, a model system frequently used to assess the tumorigenic potential of fibrous particulates. Both asbestos-transformed cells and spontaneously transformed cells expressed functional EGF receptors, although only the asbestos-transformed cells expressed TGF-alpha. Expression of TGF-alpha transcripts was correlated with secretion of picogram amounts of growth factor into conditioned medium by the asbestos-transformed cells. In addition, whereas TGF-alpha inhibited the growth of spontaneously transformed mesothelial cells, it stimulated the growth of asbestos-transformed cells. Neutralizing antibody that recognized TGF-alpha secreted by the asbestos-transformed cells was able to inhibit the growth of these cells. Taken together, these data indicate that TGF-alpha acts as an autocrine growth factor for asbestos-transformed rat mesothelial cells. Therefore, in asbestos-transformed mesothelial cells, altered production and responsiveness to TGF-alpha distinguish these cells from spontaneously transformed mesothelial cells. These data suggest that differences in mesothelioma etiology may be reflected in differences in the molecular alterations present in these tumors.

Authors
Walker, C; Everitt, J; Ferriola, PC; Stewart, W; Mangum, J; Bermudez, E
MLA Citation
Walker, C, Everitt, J, Ferriola, PC, Stewart, W, Mangum, J, and Bermudez, E. "Autocrine growth stimulation by transforming growth factor alpha in asbestos-transformed rat mesothelial cells." Cancer research 55.3 (February 1995): 530-536.
PMID
7530596
Source
epmc
Published In
Cancer Research
Volume
55
Issue
3
Publish Date
1995
Start Page
530
End Page
536

Mechanisms of fiber-induced diseases: implications for the safety evaluation of synthetic vitreous fibers.

Inhalation of certain natural mineral fibers, such as amphibole asbestos, is associated with the development of inflammatory, fibroproliferative, and neoplastic diseases in the lung and pleura of man and experimental animals. The mechanisms by which fibers induce fibrosis and cancer are largely unknown, but are thought to be modulated by reactive oxygen species and altered growth factor pathways. Studies in rats using intracavitary implantation and instillation of fiber preparations led to the belief that all fibers with certain dimensional characteristics had similar toxic potential. It is now known that different fiber types of similar dimension can vary substantially in biological activity. A variety of physicochemical properties govern fiber toxicity and carcinogenicity, including: size and shape; surface chemistry; solubility and biopersistence; and chemical composition. Although the molecular event(s) that translate fiber-induced cellular injury into a pathologic state are unknown, there is strong evidence in man and laboratory animals to suggest both dose dependency and thresholds for effects.

Authors
Everitt, JI
MLA Citation
Everitt, JI. "Mechanisms of fiber-induced diseases: implications for the safety evaluation of synthetic vitreous fibers." Regulatory toxicology and pharmacology : RTP 20.3 Pt 2 (December 1994): S68-S75. (Review)
PMID
7724857
Source
epmc
Published In
Regulatory Toxicology and Pharmacology
Volume
20
Issue
3 Pt 2
Publish Date
1994
Start Page
S68
End Page
S75

Increased susceptibility to in vitro transformation of cells carrying the Eker tumor susceptibility mutation.

Rats carrying the Eker tumor susceptibility mutation are genetically predisposed to renal cell carcinoma. Rats heterozygous for the Eker mutation (Eker carriers) develop multiple bilateral renal cell carcinomas by the age of 1 year. Using an in vitro rat kidney epithelial (RKE) transformation assay developed in our laboratory, proximal tubule cells derived from known Eker rat carriers (+/ek) and non-carriers (+/+) were exposed to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), to determine if cells derived from Eker carriers were more susceptible to in vitro transformation than cells derived from non-carrier animals. The percent transformation frequency following MNNG treatment was 7.5-fold higher in cells derived from carrier animals when compared to cells from non-carrier animals. This increased susceptibility to transformation due to inheritance of the Eker mutation is consistent with a predisposition resulting from inactivation of a tumor suppressor gene. The increased susceptibility of kidney epithelial cells carrying the Eker mutation may prove useful in the further development of the RKE transformation assay as a sensitive tool to identify potential renal carcinogens. In addition, because transformation frequency in the RKE assay measures a very early step in multistage transformation, these results also suggest that alterations (by Loss of Heterozygosity or mutation) at the Eker tumor susceptibility locus are an early event in the development of renal tumors in the rat.

Authors
Horesovsky, G; Ginsler, J; Everitt, J; Walker, C
MLA Citation
Horesovsky, G, Ginsler, J, Everitt, J, and Walker, C. "Increased susceptibility to in vitro transformation of cells carrying the Eker tumor susceptibility mutation." Carcinogenesis 15.10 (October 1994): 2183-2187.
PMID
7955051
Source
epmc
Published In
Carcinogenesis
Volume
15
Issue
10
Publish Date
1994
Start Page
2183
End Page
2187
DOI
10.1093/carcin/15.10.2183

Atypical tubule hyperplasia and renal tubule tumors in conventional rats on 90-day toxicity studies.

Bilateral, multicentric renal tubule tumors were found in 4 rats at the termination of 3 separate 90-day toxicity studies during the safety evaluation of 3 unrelated chemicals. The 3 studies were conducted at 2 separate locations, but the rats used were obtained from the same commercial source. The rat strains were Fischer-344 (1 male and 1 female case) and Sprague-Dawley (2 female cases). Three of the renal tumor cases were from either the high-dose or mid-dose treatment groups, and 1 case was an untreated control. The tumors were accompanied by multiple foci of atypical tubule hyperplasia but only in the tumor-bearing rats. There were no lesions associated with renal tumor pathogenesis in any of the remaining treated or untreated animals in the 3 studies. In addition, there was no indication of nephrotoxicity in the treated or untreated animals. Tumor morphology was characterized by a generally vacuolated appearance, eosinophilia, cytoplasmic and nuclear pleomorphism, and conspicuously hypertrophied nucleoli. The renal tubule tumors in these 90-day studies were compared to hereditary renal tubule tumors occurring in the Eker rat, a Long-Evans derivative with a genetic predisposition to this tumor type. The multiplicity of renal tubule tumors, early age of onset, and tumor morphology described in the cases from the 90-day studies were very similar to those characterizing the hereditary renal tumor model.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Hard, GC; Long, PH; Crissman, JW; Everitt, JI; Yano, BL; Bertram, TA
MLA Citation
Hard, GC, Long, PH, Crissman, JW, Everitt, JI, Yano, BL, and Bertram, TA. "Atypical tubule hyperplasia and renal tubule tumors in conventional rats on 90-day toxicity studies." Toxicologic pathology 22.5 (September 1994): 489-496.
PMID
7899777
Source
epmc
Published In
Toxicologic Pathology (Sage)
Volume
22
Issue
5
Publish Date
1994
Start Page
489
End Page
496
DOI
10.1177/019262339402200503

Mesothelial cell proliferation induced by intrapleural instillation of man-made fibers in rats and hamsters.

Long-term inhalation exposure to a biopersistent man-made ceramic fiber (RCF 1) results in a high incidence of pleural mesotheliomas in Syrian golden hamsters but not in identically exposed rats. To understand better the mechanisms involved in the intraspecies pathobiology of fiber-exposed mesothelium, the ability of the two different man-made fibers to induce cell proliferation in hamster and rat pleural mesothelial cells was investigated. Three dose levels of either glass fibers (MMVF 10) or ceramic fibers (RCF 1) were instilled intrapleurally into male Fischer 344 rats and male Syrian Golden hamsters. Rats and hamsters were exposed to approximately equal numbers of long thin fibers per kilogram of body weight using a single intrapleural instillation. Bromodeoxyuridine (BrdU) was administered via an implanted osmotic pump, and mesothelial cell proliferation was assessed at 7 and 28 days postinstillation (PI) using immunocytochemical visualization of labeled S-phase cells. Both rats and hamsters exhibited dose-dependent increases in proliferation of pleural mesothelial cells following exposure to both fiber types. Interspecies differences in mesothelial cell proliferation were noted for fiber type and pleural site. At 28 days PI, RCF-induced mesothelial cell proliferation was found to be more pronounced in hamsters than in rats in the caudal visceral pleural. Comparing both fibers either by equal mass or by equal fiber numbers, mesothelial cell proliferation in RCF 1-treated animals was higher than in animals exposed to MMVF 10, especially in hamsters, and may be a factor in the difference in mesothelioma induced by the two fibers. The higher sustained (28 day) mesothelial cell proliferation in the visceral pleural of hamsters exposed to RCF may contribute to the species-specific differences in mesothelioma incidence found in long-term rodent inhalation studies.

Authors
Rutten, AA; Bermudez, E; Mangum, JB; Wong, BA; Moss, OR; Everitt, JI
MLA Citation
Rutten, AA, Bermudez, E, Mangum, JB, Wong, BA, Moss, OR, and Everitt, JI. "Mesothelial cell proliferation induced by intrapleural instillation of man-made fibers in rats and hamsters." Fundamental and applied toxicology : official journal of the Society of Toxicology 23.1 (July 1994): 107-116.
PMID
7958554
Source
epmc
Published In
Fundamental and Applied Toxicology
Volume
23
Issue
1
Publish Date
1994
Start Page
107
End Page
116
DOI
10.1006/faat.1994.1086

Wilms' tumor suppressor gene expression in rat and human mesothelioma.

Induction of mesothelioma in the rat is an important animal model for assessing the carcinogenic potential of fibers and for understanding the molecular basis underlying the development of these tumors. Mesotheliomas and nephroblastoma (Wilms' tumor) have many developmental, biochemical, and histological similarities; however, the expression of the Wilms' tumor suppressor gene, WT-1, has not been well characterized in the rat, and its expression pattern in rat or human mesothelioma has not been described. We report that WT-1 transcripts (3.2 kilobases) could be detected by Northern analysis in adult rat testis, spleen, kidney, lung, heart, and glomerular mesangial cells. Normal adult mesothelial cells also expressed this gene. Rat mesothelioma cell lines expressed WT-1 transcripts of 3.2 kilobases and an additional 2.8-kilobase transcript, previously only reported to be expressed in the testis. Normal and transformed rat mesothelial cells expressed all four of the WT-1 splice variants, except testis, which only expressed WT-1 splice variants containing exon 5. Seven of seven human mesothelioma cell lines examined also expressed WT-1 transcripts, suggesting that expression of this gene may be useful in the diagnosis of these tumors.

Authors
Walker, C; Rutten, F; Yuan, X; Pass, H; Mew, DM; Everitt, J
MLA Citation
Walker, C, Rutten, F, Yuan, X, Pass, H, Mew, DM, and Everitt, J. "Wilms' tumor suppressor gene expression in rat and human mesothelioma." Cancer research 54.12 (June 1994): 3101-3106.
PMID
8205524
Source
epmc
Published In
Cancer Research
Volume
54
Issue
12
Publish Date
1994
Start Page
3101
End Page
3106

Pleural lesions in Syrian golden hamsters and Fischer-344 rats following intrapleural instillation of man-made ceramic or glass fibers.

The mesothelium is a target of the toxic and carcinogenic effects of certain natural mineral and man-made fibers. Long-term inhalation of a ceramic fiber (RCF-1) results in a high incidence of pleural mesotheliomas in Syrian golden hamsters but not in identically exposed Fischer-344 rats. The present study compared the histopathology of the early pleural response in rats and hamsters instilled with artificial fibers. Groups of Syrian golden hamsters and Fischer-344 rats were instilled with ceramic (RCF-1) or glass (MMVF-10) fibers directly into the pleural space. Each species received approximately equal numbers of long, thin fibers per g body weight. Fiber-induced lesions were compared 7 and 28 days postinstillation. Both hamsters and rats developed qualitatively similar dose-dependent inflammatory lesions that were not fiber-type specific. Both species developed fibrosis in conjunction with inflammation in the visceral pleura, but a striking interspecies difference was noted in the pattern of mesothelial cell response. Hamsters developed greater surface mesothelial cell proliferation and had focal aggregates of mesothelial cells embedded deep within regions of visceral pleural fibrosis. It is hypothesized from the present study that the marked fiber-induced proliferative mesothelial cell response of the hamster visceral pleura may explain the high number of pleural mesotheliomas found in long-term fiber studies in this species.

Authors
Everitt, JI; Bermudez, E; Mangum, JB; Wong, B; Moss, OR; Janszen, D; Rutten, AA
MLA Citation
Everitt, JI, Bermudez, E, Mangum, JB, Wong, B, Moss, OR, Janszen, D, and Rutten, AA. "Pleural lesions in Syrian golden hamsters and Fischer-344 rats following intrapleural instillation of man-made ceramic or glass fibers." Toxicologic pathology 22.3 (May 1994): 229-236.
PMID
7817114
Source
epmc
Published In
Toxicologic Pathology (Sage)
Volume
22
Issue
3
Publish Date
1994
Start Page
229
End Page
236

Carcinogenicity and toxicity of inhaled nitrobenzene in B6C3F1 mice and F344 and CD rats.

The potential carcinogenicity and toxicity of inhaled nitrobenzene were evaluated following chronic (2-year) exposure in mice and rats. Male and female B6C3F1 mice were exposed to 0, 5, 25, or 50 ppm nitrobenzene, while male and female F344 rats and male CD rats were exposed to 0, 1, 5, or 25 ppm nitrobenzene. All exposures were for 6 hr/day, 5 days/week excluding holidays, for a total of 505 days over 2 years. Survival was not adversely affected by nitrobenzene exposure, and only mild exposure-related decreases in body weights (< 10% of control) were occasionally noted. Nitrobenzene exposure resulted in increased incidence of neoplasia in male B6C3F1 mice (pulmonary alveolar/bronchiolar and thyroid follicular cell neoplasms), female B6C3F1 mice (mammary gland neoplasms), male F344 rats (hepatocellular and renal neoplasms), female F344 rats (endometrial stromal neoplasms), and male CD rats (hepatocellular neoplasms). In addition, there were marginal increases in the incidence of hepatocellular neoplasia in female B6C3F1 mice and thyroid follicular neoplasia in male F344 rats. Groups of nitrobenzene-exposed mice and rats with increased incidence of renal and thyroid neoplasia also had increased incidences of hyperplasia in these tissues. Toxicity resulting from chronic inhalation of nitrobenzene was manifested by methemoglobinemia, anemia, and adaptive or degenerative changes in the nose, liver, and testis. The results indicate that inhaled nitrobenzene is carcinogenic and toxic in mice and rats, and that the spectrum of these responses in animals is dependent on species, sex, and genetic background.

Authors
Cattley, RC; Everitt, JI; Gross, EA; Moss, OR; Hamm, TE; Popp, JA
MLA Citation
Cattley, RC, Everitt, JI, Gross, EA, Moss, OR, Hamm, TE, and Popp, JA. "Carcinogenicity and toxicity of inhaled nitrobenzene in B6C3F1 mice and F344 and CD rats." Fundamental and applied toxicology : official journal of the Society of Toxicology 22.3 (April 1994): 328-340.
PMID
8050629
Source
epmc
Published In
Fundamental and Applied Toxicology
Volume
22
Issue
3
Publish Date
1994
Start Page
328
End Page
340
DOI
10.1006/faat.1994.1039

Carcinogenicity and Toxicity of Inhaled Nitrobenzene in B6C3F1 Mice and F344 and CD Rats

Authors
Cattley, R
MLA Citation
Cattley, R. "Carcinogenicity and Toxicity of Inhaled Nitrobenzene in B6C3F1 Mice and F344 and CD Rats." Fundamental and Applied Toxicology 22.3 (April 1994): 328-340.
Source
crossref
Published In
Fundamental and Applied Toxicology
Volume
22
Issue
3
Publish Date
1994
Start Page
328
End Page
340
DOI
10.1006/faat.1994.1039

Carcinogenicity of inhaled benzene in CBA mice.

This study investigated benzene-induced neoplasia in CBA/Ca mice, with special emphasis on hematopoietic tissues. Ten-week-old male CBA/Ca mice were exposed to 300 ppm benzene via inhalation for 6 hr/day, 5 days/week, for 16 weeks and held 18 months after the last exposure. There were 125 benzene-exposed and 125 sham-exposed mice. Malignant lymphoma was a statistically significant cause of early mortality in the benzene-exposed mice. Fourteen benzene-exposed mice developed lymphoma (lymphoblastic, lymphocytic, or mixed) as compared to only 2 sham-exposed mice. Benzene-exposed mice also developed preputial gland squamous cell carcinomas (60% in benzene-exposed vs 0% in sham-exposed) and had an increased incidence of lung adenomas (36% vs 14%). Moderate to marked granulocytic hyperplasia was present in benzene-exposed animals, with a 36% incidence in the bone marrow and 6% in the spleen, as compared to the sham-exposed with 8 and 0%, respectively. Interpretation of the granulocytic response as a direct effect of benzene was complicated by the presence of inflammation in the mice. Although inhaled benzene was clearly carcinogenic in CBA mice, it did not induce granulocytic leukemia.

Authors
Farris, GM; Everitt, JI; Irons, RD; Popp, JA
MLA Citation
Farris, GM, Everitt, JI, Irons, RD, and Popp, JA. "Carcinogenicity of inhaled benzene in CBA mice." Fundamental and applied toxicology : official journal of the Society of Toxicology 20.4 (May 1993): 503-507.
PMID
8314465
Source
epmc
Published In
Fundamental and Applied Toxicology
Volume
20
Issue
4
Publish Date
1993
Start Page
503
End Page
507
DOI
10.1006/faat.1993.1061

Carcinogenicity of Inhaled Benzene in CBA Mice

Authors
Farris, G
MLA Citation
Farris, G. "Carcinogenicity of Inhaled Benzene in CBA Mice." Fundamental and Applied Toxicology 20.4 (May 1993): 503-507.
Source
crossref
Published In
Fundamental and Applied Toxicology
Volume
20
Issue
4
Publish Date
1993
Start Page
503
End Page
507
DOI
10.1006/faat.1993.1061

Suppression of tumorigenicity of A549 lung adenocarcinoma cells by human chromosomes 3 and 11 introduced via microcell-mediated chromosome transfer.

To map tumor suppressor genes for lung adenocarcinomas, we introduced normal human chromosomes 3, 7, and 11 into the A549 tumor cell line by microcell-mediated chromosome transfer to test which chromosomes had the ability to suppress tumorigenicity. These human chromosomes, which contain the neomycin gene as a selectable marker, were transferred into A549 lung adenocarcinoma cells at frequencies of 0.3-1.8 x 10(-6). Two microcell hybrid clones with an introduced chromosome 3, two with an introduced chromosome 7, and six with an introduced chromosome 11 were isolated and examined for their growth properties and tumorigenicity in nude mice. Whereas parental A549 cells formed tumors with an average latency of 68 d, both microcell hybrids with an introduced chromosome 3 failed to form tumors for over 360 d. Similar tumorigenicity results were obtained when the clones were implanted into denuded tracheas, a more orthotopic transplantation site. The two clones with an introduced chromosome 7 were still tumorigenic; they formed tumors within 100-123 d after injection and grew progressively, although the tumors grew slightly slower than the parental cells did. Among the six clones with an introduced chromosome 11, one clone was still highly tumorigenic but did not contain an extra copy of an intact introduced chromosome 11. Three clones with a single intact copy of introduced chromosome 11 formed tumors with latency periods significantly longer than those of the parental cells. Two clones had two copies of the introduced chromosome 11, and both failed to form tumors within 1 yr of injection. These results indicate that chromosomes 3 and 11 can suppress the tumorigenicity of A549 lung adenocarcinoma cells.

Authors
Satoh, H; Lamb, PW; Dong, JT; Everitt, J; Boreiko, C; Oshimura, M; Barrett, JC
MLA Citation
Satoh, H, Lamb, PW, Dong, JT, Everitt, J, Boreiko, C, Oshimura, M, and Barrett, JC. "Suppression of tumorigenicity of A549 lung adenocarcinoma cells by human chromosomes 3 and 11 introduced via microcell-mediated chromosome transfer." Molecular carcinogenesis 7.3 (January 1993): 157-164.
PMID
8098218
Source
epmc
Published In
Molecular Carcinogenesis
Volume
7
Issue
3
Publish Date
1993
Start Page
157
End Page
164
DOI
10.1002/mc.2940070306

Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome.

A rodent model of hereditary cancer in which a single gene mutation predisposes rats to bilateral multicentric renal cell carcinoma (RCC) is described. This rat hereditary cancer syndrome shares certain similarities with von Hippel-Lindau disease (VHLD). In addition to the early development of renal epithelial tumors with morphologic similarity to human RCC, rats which bear the RCC gene are predisposed to the development of secondary primary cancers later in life. Splenic vascular proliferative lesions, including hemangiosarcoma, were seen in 23% of 14-month-old rats of both sexes that had renal tumors. At fourteen months of age, 62% of female rats with renal cell tumors had sarcomas of the lower reproductive tract of probable smooth muscle origin. Non-carrier siblings of affected animals did not have renal, reproductive, or splenic neoplasia. The finding of a specific constellation of familial neoplasms, including multicentric bilateral renal cell carcinoma, in this autosomal dominant disorder of rats suggests that this syndrome is analogous to human VHLD. In addition to its usefulness for studies of the biochemical and molecular mechanisms of renal carcinogenesis, this animal model will provide a unique tool to investigate how cancer susceptibility genes interact with environmental risk factors such as chemical carcinogens.

Authors
Everitt, JI; Goldsworthy, TL; Wolf, DC; Walker, CL
MLA Citation
Everitt, JI, Goldsworthy, TL, Wolf, DC, and Walker, CL. "Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome." The Journal of urology 148.6 (December 1992): 1932-1936.
PMID
1433648
Source
epmc
Published In
The Journal of Urology
Volume
148
Issue
6
Publish Date
1992
Start Page
1932
End Page
1936
DOI
10.1016/s0022-5347(17)37087-8

Antioxidant defense mechanisms in cultured pleural mesothelial cells.

The role of different antioxidant pathways in cultured rat pleural mesothelial cells was studied by exposing the cells to various hydrogen peroxide (H2O2) concentrations and by measuring H2O2 cell cytotoxicity and the capacity of the cells to scavenge H2O2. The antioxidant enzymes, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and catalase were analyzed biochemically. Catalase and CuZn superoxide dismutase were localized by immunocytochemistry. To enable investigation of the glutathione redox cycle and catalase pathways, glutathione reductase was inactivated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and catalase was inactivated with aminotriazole. When the cells were exposed to a low, sublethal (0.030 mM) H2O2 concentration, glutathione reductase but not catalase inactivation resulted in a decreased capacity to remove H2O2 from the extracellular medium. When the cells were exposed to a high (0.25 mM) H2O2 concentration, H2O2-scavenging capacity decreased remarkably when catalase was inactivated. When the cells were exposed to 0.1 to 0.5 mM H2O2, cell cytotoxicity (lactate dehydrogenase release) increased significantly if glutathione reductase was inactivated; catalase inactivation resulted in a significant cytotoxicity only at high (greater than or equal to 0.25 mM) H2O2 concentrations. Immunocytochemical studies showed that the cells, both in situ and in vitro, contained low amounts of catalase. This suggests that the results of the catalase-inhibition studies are probably not due to a change in the characteristics of the cells in culture. 3-Aminobenzamide is a compound that is known to prevent NAD depletion through inhibition of poly(ADP-ribose) polymerase during oxidant stress. When intact cells were treated with different antioxidants and exposed to 0.5 mM H2O2, both catalase and 3-aminobenzamide protected the cells completely.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Kinnula, VL; Everitt, JI; Mangum, JB; Chang, LY; Crapo, JD
MLA Citation
Kinnula, VL, Everitt, JI, Mangum, JB, Chang, LY, and Crapo, JD. "Antioxidant defense mechanisms in cultured pleural mesothelial cells." American journal of respiratory cell and molecular biology 7.1 (July 1992): 95-103.
PMID
1627338
Source
epmc
Published In
American journal of respiratory cell and molecular biology
Volume
7
Issue
1
Publish Date
1992
Start Page
95
End Page
103
DOI
10.1165/ajrcmb/7.1.95

Predisposition to renal cell carcinoma due to alteration of a cancer susceptibility gene.

A single germ line gene mutation at a tumor susceptibility locus in a rodent model of hereditary human renal cancer caused a 70-fold increase in susceptibility to chemical carcinogenesis. A carcinogen that targeted both renal epithelial and mesenchymal cells caused an increase in tumors of epithelial origin in susceptible animals; the number of carcinogen-induced mesenchymal tumors was unaffected by the presence of the mutation at the susceptibility locus. Thus, this mutation defines a genetic locus for susceptibility to carcinogen-induced tumors and modulation of carcinogen susceptibility by this locus exhibits cell-type specificity.

Authors
Walker, C; Goldsworthy, TL; Wolf, DC; Everitt, J
MLA Citation
Walker, C, Goldsworthy, TL, Wolf, DC, and Everitt, J. "Predisposition to renal cell carcinoma due to alteration of a cancer susceptibility gene." Science (New York, N.Y.) 255.5052 (March 1992): 1693-1695.
PMID
1553556
Source
epmc
Published In
Science
Volume
255
Issue
5052
Publish Date
1992
Start Page
1693
End Page
1695
DOI
10.1126/science.1553556

Oxidants and antioxidants in alveolar epithelial type II cells: in situ, freshly isolated, and cultured cells.

Antioxidant enzyme activities, H2O2 clearance, and H2O2 generation by rat alveolar epithelial type II cells were compared between in situ, freshly isolated (6 h ex vivo), and cultured cells (48 h ex vivo). Immunocytochemical studies did not show changes in catalase, Mn superoxide dismutase, or CuZn superoxide dismutase labeling density in cytoplasm, peroxisomes, or mitochondria. Numbers of peroxisomes and mitochondria per cell decreased in cultured cells. Biochemical studies showed that cell culture resulted in a significant decrease in activities of catalase (49%), glutathione reductase (50%), glutathione peroxidase (74%), and in the capacity of the cells to scavenge extracellular H2O2. Addition of the specific catalase inhibitor, aminotriazole, decreased the rate of consumption of exogenously added H2O2 in freshly isolated cells but not in cultured cells. Neither aminotriazole nor 1,3-bis (2-chloroethyl)-1-nitrosourea, which inactivates glutathione reductase, altered H2O2 consumption by cultured cells. The rate of extracellular H2O2 release in both freshly isolated and cultured cells was 0.71 nmol.min-1.mg protein-1. It can be concluded that levels of some antioxidant enzymes fall in cultured alveolar epithelial type II cells, and that, although catalase likely plays a significant role in protection of freshly isolated cells against oxidant stress, this pathway may be less important after culture.

Authors
Kinnula, VL; Chang, L; Everitt, JI; Crapo, JD
MLA Citation
Kinnula, VL, Chang, L, Everitt, JI, and Crapo, JD. "Oxidants and antioxidants in alveolar epithelial type II cells: in situ, freshly isolated, and cultured cells." The American journal of physiology 262.1 Pt 1 (January 1992): L69-L77.
PMID
1733283
Source
epmc
Published In
The American journal of physiology
Volume
262
Issue
1 Pt 1
Publish Date
1992
Start Page
L69
End Page
L77

Cytochrome P-450- and glutathione-associated enzyme activities in freshly isolated enriched lung cell fractions from beta-naphthoflavone-treated male F344 rats.

Xenobiotics metabolized in rat pulmonary tissue are often selectively cytotoxic to individual lung cell populations. A non-homogeneous distribution of xenobiotic biotransformation enzymes, e.g., cytochrome P-450 (P-450)- and glutathione (GSH)-associated enzymes, in rat lung tissue may underlie this observed cell-selective pneumotoxicity. To evaluate this hypothesis, the relative activities of P-450- and GSH-associated enzymes were measured in sonicated, freshly isolated preparations containing enriched complements of individual toxicant-sensitive lung cell types, including non-ciliated bronchiolar epithelial (Clara) cells (24% pure), alveolar type II cells (86% pure) and pulmonary endothelial cells (identified by membrane-associated angiotensin converting enzyme activity). Lung cell fractions were isolated by centrifugal elutriation from male F344 rats that 48 h earlier received a single i.p. injection of either P-450-inducer beta-naphthoflavone (50 mg beta-NF/kg body weight) or corn oil vehicle. The enriched Clara cell fraction possessed (per 10(6) cells) greater P-450 and reduced GSH contents and higher enzyme activities (i.e., NADPH- and NADH cytochrome c reductases, benzyloxy (BROD)-, pentoxy (PROD)- and etoxyresorufin (EROD)-O-dealkylases, GSH transferase, GSH peroxidase, GSH reductase and NADPH quinone oxidoreductase) than either the enriched type II cell or endothelial cell preparations. However, the relative biochemical activities for the enriched fractions (Clara greater than type II greater than endothelial) generally reflected respective sonicate cellular protein content. Treatment of rats with beta-NF resulted in: (a) an induction in EROD activity in the enriched preparations of type II cells, Clara cells and endothelial cells (125-, 89- and 35-fold, respectively); (b) higher NADPH quinone oxidoreductase activities, which were increased to the greatest degree (3-fold) in the enriched type II cell fraction and (c) a small elevation in GSH transferase activity measured in the enriched Clara cell fraction. Although the enriched rat lung cell preparations possessed unique biochemical profiles for constitutive and beta-NF-inducible P-450- and GSH-associated enzymes, additional studies with higher purity preparations (e.g., Clara cells) will be required to more fully evaluate the relationship between relative cellular complements of xenobiotic biotransformation enzymes and pneumotoxicant susceptibility.

Authors
Lacy, SA; Mangum, JB; Everitt, JI
MLA Citation
Lacy, SA, Mangum, JB, and Everitt, JI. "Cytochrome P-450- and glutathione-associated enzyme activities in freshly isolated enriched lung cell fractions from beta-naphthoflavone-treated male F344 rats." Toxicology 73.2 (January 1992): 147-160.
PMID
1609425
Source
epmc
Published In
TOXICOLOGY
Volume
73
Issue
2
Publish Date
1992
Start Page
147
End Page
160
DOI
10.1016/0300-483x(92)90098-y

Possible cellular and molecular mechanisms for asbestos carcinogenicity.

Asbestos fibers may exert their carcinogenic effects on mesothelial cells and bronchial epithelial cells by direct and indirect mechanisms. Direct effects can occur following the physical interaction of fibers with target cells or by the generation of free radicals from the fiber surface; indirect effects, following the interaction of fibers with inflammatory cells can result in the production of cellular mediators such as cytokines and various reactive oxygen species. As a result, target cells may be induced to proliferate and/or sustain genetic alterations, which lead to tumor development.

Authors
Walker, C; Everitt, J; Barrett, JC
MLA Citation
Walker, C, Everitt, J, and Barrett, JC. "Possible cellular and molecular mechanisms for asbestos carcinogenicity." American journal of industrial medicine 21.2 (January 1992): 253-273. (Review)
PMID
1536158
Source
epmc
Published In
American Journal of Industrial Medicine
Volume
21
Issue
2
Publish Date
1992
Start Page
253
End Page
273
DOI
10.1002/ajim.4700210214

Characterization of platelet-derived growth factor and platelet-derived growth factor receptor expression in asbestos-induced rat mesothelioma.

Although altered expression of platelet-derived growth factor (PDGF) is a hallmark of human mesothelioma, expression of PDGF receptors has not been characterized in this cell type. In addition, the expression of this growth factor and its cognate receptor in rodent mesothelioma has not been investigated. In this study, examination of transformed mesothelial cells derived from asbestos-induced rat mesotheliomas revealed that these cells expressed high affinity PDGF receptors (Kd = 0.5 nM) and receptor number was 1.6 x 10(5)/cell. Western analysis using antibodies specific for either the alpha-type or beta-type PDGF receptor and Northern analysis using probes specific for alpha- and beta-type receptor RNA transcripts indicated that these cells expressed beta-type PDGF receptors but that alpha-type receptors could not be detected. However, when the mesothelioma-derived cells were examined for the expression of PDGF, no expression of this growth factor could be detected. The transformed cells expressed no detectable A- or B-chain PDGF RNA transcripts; and using a competitive enzyme immunoassay specific for isoforms containing the B chain of PDGF and a sandwich enzyme-linked immunosorbent assay specific for A-chain-containing isoforms, neither AA, nor AB, nor BB isoforms of this growth factor could be detected in medium conditioned by these cells. The absence of alterations in PDGF expression in rat mesothelioma, in contrast to the data for the human disease, suggests that the production of this growth factor by transformed mesothelial cells may be species specific.

Authors
Walker, C; Bermudez, E; Stewart, W; Bonner, J; Molloy, CJ; Everitt, J
MLA Citation
Walker, C, Bermudez, E, Stewart, W, Bonner, J, Molloy, CJ, and Everitt, J. "Characterization of platelet-derived growth factor and platelet-derived growth factor receptor expression in asbestos-induced rat mesothelioma." Cancer research 52.2 (January 1992): 301-306.
PMID
1309438
Source
epmc
Published In
Cancer Research
Volume
52
Issue
2
Publish Date
1992
Start Page
301
End Page
306

Cytogenetic and molecular correlates between rodent and human renal cell carcinoma.

In man, RCC makes up the largest proportion of primary kidney cancers, comprising approximately 85% of renal tumors and accounting for approximately 2% of the cancer deaths each year (Richie and Skinner 1981). As shown in Table 2, there are many similarities between spontaneous rat RCC and human RCC. Therefore, rat RCC and the Eker rat model in particular appear to be well suited to investigations into the mechanisms by which this disease occurs. In addition, animal models such as the Eker rat may also be valuable as human surrogates for developing and testing new approaches for treatment of human renal cancer.

Authors
Walker, C; Recio, L; Funaki, K; Everitt, J
MLA Citation
Walker, C, Recio, L, Funaki, K, and Everitt, J. "Cytogenetic and molecular correlates between rodent and human renal cell carcinoma." Progress in clinical and biological research 376 (January 1992): 289-302. (Review)
PMID
1528923
Source
epmc
Published In
Progress in Clinical and Biological Research
Volume
376
Publish Date
1992
Start Page
289
End Page
302

Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: pharmacokinetics, rat-to-monkey interspecies scaling, and extrapolation to man.

DNA-protein cross-links were formed in the respiratory tract of rhesus monkeys exposed to [14C]formaldehyde (0.7, 2, or 6 ppm; 6 hr). Concentrations of cross-links (pmol/mg DNA) were highest in the mucosa of the middle turbinates; lower concentrations were produced in the anterior lateral wall/septum and nasopharynx. Very low concentrations were found in the larynx/trachea/carina and in the proximal portions of the major bronchi of some monkeys exposed to 6 ppm but not to 0.7 ppm. No cross-links were detected in the maxillary sinuses or lung parenchyma. The pharmacokinetics of cross-link formation in the nose were interpreted using a model in which the rate of formation is proportional to the tissue concentration of formaldehyde. The model includes both saturable and nonsaturable elimination pathways and describes regional differences in DNA binding as having an anatomical rather than a biochemical basis. Using this model, the concentration of cross-links formed in corresponding tissues of different species can be predicted by scaling the pharmacokinetic parameter that depends on minute volume (V) and quantity of nasal mucosal DNA (MDNA). The concentration-response curve for the average rate of cross-link formation in the turbinates, lateral wall, and septum of rhesus monkeys was predicted from that of F-344 rats exposed under similar conditions. There was significant overlap between predicted and fitted curves, implying that V and MDNA are major determinants of the rate of cross-link formation in the nasal mucosa of different species. Concentrations of cross-links that may be produced in the nasal mucosa of adult men were predicted based on experimental data in rats and monkeys. The results suggest that formaldehyde would generate lower concentrations of cross-links in the nasal mucosa of humans than of monkeys, and much lower concentrations in humans than in rats. The rate of formation of DNA-protein cross-links can be regarded as a surrogate for the delivered concentration of formaldehyde. Use of this surrogate should decrease the uncertainty of human cancer risk estimates derived by interspecies extrapolation by providing a more realistic measure of the delivered concentration at critical target sites.

Authors
Casanova, M; Morgan, KT; Steinhagen, WH; Everitt, JI; Popp, JA; Heck, HD
MLA Citation
Casanova, M, Morgan, KT, Steinhagen, WH, Everitt, JI, Popp, JA, and Heck, HD. "Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: pharmacokinetics, rat-to-monkey interspecies scaling, and extrapolation to man." Fundamental and applied toxicology : official journal of the Society of Toxicology 17.2 (August 1991): 409-428.
PMID
1765228
Source
epmc
Published In
Fundamental and Applied Toxicology
Volume
17
Issue
2
Publish Date
1991
Start Page
409
End Page
428
DOI
10.1016/0272-0590(91)90230-2

Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: Pharmacolinetics, rat-to-monkey interspecies scaling, and extrapolation to man

Authors
CASANOVA, M
MLA Citation
CASANOVA, M. "Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: Pharmacolinetics, rat-to-monkey interspecies scaling, and extrapolation to man." Fundamental and Applied Toxicology 17.2 (August 1991): 409-428.
Source
crossref
Published In
Fundamental and Applied Toxicology
Volume
17
Issue
2
Publish Date
1991
Start Page
409
End Page
428
DOI
10.1016/0272-0590(91)90230-2

Trisomy of rat chromosome 1 associated with mesothelial cell transformation.

Identification of specific chromosomal aberrations in transformed mesothelial cells is an important step in elucidating the mechanism of transformation of these cells which are targets for occupational and environmental carcinogens, such as asbestos fibers. Cytogenetic analysis of normal rat mesothelial cell lines revealed that at late passage (p20-p34), trisomy of chromosome 1 was present in greater than 80% of the cells in four spontaneously immortalized lines examined, whereas at early passage (p8-p10), only 15-44% of the cells had trisomy 1. Trisomy of chromosome 1 had increased in the population as a function of passage, suggesting that cells with trisomy 1 had a selective growth advantage under in vitro culture conditions and that this alteration was associated with transformation. A commercially available rat mesothelial cell line (4/4 RM4, ATCC), was also found to have a duplication of a portion of the long arm of chromosome 1. To determine if chromosome 1 alterations have relevance to the transformed phenotype in vivo, a neoplastic cell line was established from a spontaneous rat mesothelioma. At passage 15, trisomy of chromosome 1 was observed in 26% of the metaphases in this line. However, when these cells were injected into nude mice, 99% of the cells from the resulting tumor contained an additional copy of chromosome 1. Therefore, trisomy 1 also conferred a selective growth advantage in vivo and/or was associated with the malignant subpopulation in the tumor derived cell line. These studies suggest that chromosome 1 contains a gene(s) involved in transformation of rat mesothelial cells.

Authors
Funaki, K; Everitt, J; Bermudez, E; Walker, C
MLA Citation
Funaki, K, Everitt, J, Bermudez, E, and Walker, C. "Trisomy of rat chromosome 1 associated with mesothelial cell transformation." Cancer research 51.15 (August 1991): 4059-4066.
PMID
1855220
Source
epmc
Published In
Cancer Research
Volume
51
Issue
15
Publish Date
1991
Start Page
4059
End Page
4066

Hydrogen peroxide production by alveolar type II cells, alveolar macrophages, and endothelial cells.

Extracellular H2O2 release and intracellular H2O2 production were determined in rat lung alveolar macrophages, rat alveolar type II cells, and cultured bovine aortic endothelial cells. Isolated macrophages (5 h ex vivo) released 3.1 +/- 0.09 nmol H2O2.min-1.mg cell protein-1, freshly isolated (5 h ex vivo) type II cells released 0.7 +/- 0.07 nmol H2O2.min-1.mg protein-1, and cultured endothelial cells released 0.06 +/- 0.005 nmol H2O2.min-1.mg protein-1. The rate of extracellular H2O2 release decreased rapidly over time in both fresh macrophages and freshly isolated type II cells. When the measurements were repeated at different times ex vivo, the decrease was greater than 20%/h, and H2O2 release was almost undetectable 12 h ex vivo. The decrease occurred while lactate dehydrogenase release, catalase activity, and intracellular H2O2 production remained unchanged. Catalase activity was 59.3 +/- 4.9 nmol O2 produced.min-1.mg protein-1 in type II cells, 13.2 +/- 1.8 in macrophages, and 11.4 +/- 2.7 in endothelial cells. Aminotriazole is a compound that inhibits catalase in the presence of H2O2 at a rate that is proportional to the rate of intracellular H2O2 production in or near peroxisomes. Incubation of the cells with aminotriazole led to a rapid inhibition of catalase. In 15 min the reduction of catalase activity was 69% in type II cells, 53% in macrophages, and 37% in endothelial cells. When freshly isolated type II cells were exposed to hyperoxia (95% O2) for 30 min, no changes in the rate of either intracellular H2O2 production or extracellular H2O2 release were seen.

Authors
Kinnula, VL; Everitt, JI; Whorton, AR; Crapo, JD
MLA Citation
Kinnula, VL, Everitt, JI, Whorton, AR, and Crapo, JD. "Hydrogen peroxide production by alveolar type II cells, alveolar macrophages, and endothelial cells." The American journal of physiology 261.2 Pt 1 (August 1991): L84-L91.
PMID
1872419
Source
epmc
Published In
The American journal of physiology
Volume
261
Issue
2 Pt 1
Publish Date
1991
Start Page
L84
End Page
L91

Altered expression of transforming growth factor-alpha in hereditary rat renal cell carcinoma.

A hereditary form of renal cell carcinoma exists in rats that results from a single gene mutation and is histologically similar to that described in humans. Cell lines derived from these rat tumors were shown to express abundant transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF)-receptor RNA transcripts, but no EGF mRNA. In contrast, normal kidney expressed EGF and EGF-receptor transcripts, but TGF-alpha transcripts were barely detectable. Other kidney epithelial cell lines examined (NRK 52E, MDCK, and LLCPK) were negative for expression of both TGF-alpha and EGF transcripts, but expressed EGF receptors. In addition, the renal cell carcinoma-derived lines secreted TGF-alpha into the media. Immunohistochemistry of normal kidney with a TGF-alpha specific antibody revealed a characteristic pattern of staining of collecting ducts and, to a lesser degree, proximal tubules. In the neoplastic kidney tissue, both the cystic and solid portions of the tumors displayed intense immunoreactivity, indicating that altered expression of this growth factor by the transformed cells occurred in situ. These results suggest that altered TGF-alpha expression is an important aspect of the neoplastic phenotype in rodent as well as human renal cell carcinoma, and support the use of this hereditary rodent tumor model for studying the pathogenesis of this disease.

Authors
Walker, C; Everitt, J; Freed, JJ; Knudson, AG; Whiteley, LO
MLA Citation
Walker, C, Everitt, J, Freed, JJ, Knudson, AG, and Whiteley, LO. "Altered expression of transforming growth factor-alpha in hereditary rat renal cell carcinoma." Cancer research 51.11 (June 1991): 2973-2978.
PMID
2032234
Source
epmc
Published In
Cancer Research
Volume
51
Issue
11
Publish Date
1991
Start Page
2973
End Page
2978

Primary optic nerve meningiomas in F344 rats.

Authors
Yoshitomi, K; Everitt, JI; Boorman, GA
MLA Citation
Yoshitomi, K, Everitt, JI, and Boorman, GA. "Primary optic nerve meningiomas in F344 rats." Veterinary pathology 28.1 (January 1991): 79-81.
PMID
2017830
Source
epmc
Published In
Veterinary pathology
Volume
28
Issue
1
Publish Date
1991
Start Page
79
End Page
81
DOI
10.1177/030098589102800111

Co-culture of primary pulmonary cells to model alveolar injury and translocation of proteins.

Primary rat alveolar type II cells and early passage rat lung fibroblasts were co-cultured on opposite sides of a collagen-coated polycarbonate filter. This is an approach to "model", in part, an alveolar wall to study mechanisms of cytotoxicity and translocation of bioactive materials from the alveolar space to the lung interstitium. Type II cells were recovered from adult rat (Fischer 344) lungs by enzyme digestion and "panning". Lung fibroblasts were separated from the same species, cultured initially in 10% fetal bovine serum and used in the co-culture system at early passage. The type II cells formed a monolayer of dedifferentiated epithelium which provided a barrier on the upper side of the collagen (human type IV)-coated filter. The fibroblasts on the bottom of the filter replicated logarithmically in the presence of serum, could be rendered quiescent in defined medium and then returned to rapid growth phase with the reintroduction of serum. The intact epithelial monolayer excluded trypan blue, albumin, platelet-derived growth factor, and alpha2-macroglobulin from the lower compartment of the culture chamber. Altering the integrity of the monolayer by a variety of means allowed translocation of these materials through the collagen-coated filters. Particularly interesting was the effect of taurine chloramine which caused subtle changes in the alveolar epithelium and allowed subsequent translocation of albumin. In addition, we showed that rat alveolar macrophages remain viable with some spreading on the surface of the epithelial monolayer. This co-culture system will have future application in the study of how reactive oxygen species might affect the epithelial barrier, and whether macrophage-derived growth factors can influence fibroblast proliferation if the monolayer is intact or injured.

Authors
Mangum, JB; Everitt, JI; Bonner, JC; Moore, LR; Brody, AR
MLA Citation
Mangum, JB, Everitt, JI, Bonner, JC, Moore, LR, and Brody, AR. "Co-culture of primary pulmonary cells to model alveolar injury and translocation of proteins." In vitro cellular & developmental biology : journal of the Tissue Culture Association 26.12 (December 1990): 1135-1143.
PMID
1706697
Source
epmc
Published In
In vitro cellular & developmental biology : journal of the Tissue Culture Association
Volume
26
Issue
12
Publish Date
1990
Start Page
1135
End Page
1143
DOI
10.1007/bf02623690

Expression of growth factor and growth factor receptor RNA in rat pleural mesothelial cells in culture.

Mineral fiber-induced pleural mesothelioma in the rat is a suitable model for asbestos-induced mesothelioma in humans. A proposed mechanism for the genesis of mesotheliomas is the initiation of an autocrine pathway leading to unregulated growth of the mesothelium. To understand if changes in the expression of mRNA of critical growth factors and receptors occur in target mesothelial cells, it is first necessary to characterize the pattern of expression of these genes in normal mesothelial cells. Rat mesothelial cells were isolated from the parietal pleura and strains of these cells were propagated in vitro. The cells were diploid, had epithelial gross morphology and ultrastructure, and coexpressed keratins and vimentin. Northern blot analysis demonstrated that the cells expressed transforming growth factor beta 1 and fibroblast growth factor. Transcripts for transforming growth factor alpha, platelet-derived growth factor A-chain, and platelet-derived growth factor B-chain were not detected. Receptors for platelet-derived growth factor, epidermal growth factor, and insulin were detected. Although normal mesothelial cells express receptors for these growth factors, no production of their corresponding ligands by these cells could be detected, suggesting that autocrine stimulation of growth via the production of such factors may be specific to transformed mesothelial cells.

Authors
Bermudez, E; Everitt, J; Walker, C
MLA Citation
Bermudez, E, Everitt, J, and Walker, C. "Expression of growth factor and growth factor receptor RNA in rat pleural mesothelial cells in culture." Experimental cell research 190.1 (September 1990): 91-98.
PMID
1974862
Source
epmc
Published In
Experimental Cell Research
Volume
190
Issue
1
Publish Date
1990
Start Page
91
End Page
98
DOI
10.1016/0014-4827(90)90148-4

Infectious diseases of the upper respiratory tract: implications for toxicology studies.

The consequences of adventitious infectious agents upon the interpretation of toxicology studies performed in rats and mice are incompletely understood. Several prevalent murine pathogens cause alterations of the respiratory system that can confuse the assessment of chemically induced airway injury. In some instances the pathogenesis of infection with these agents has been relatively well studied in the lower respiratory tract. However, there are few well-controlled studies that have examined the upper respiratory region, which result in interpretive problems for toxicologic pathologists. The conduct and interpretation of both short-term and chronic rodent bioassays can be compromised by both the clinical and subclinical manifestations of infectious diseases. This paper reviews several important infectious diseases of the upper airway of rats and mice and discusses the potential influence of these conditions on the results of toxicology studies.

Authors
Everitt, JI; Richter, CB
MLA Citation
Everitt, JI, and Richter, CB. "Infectious diseases of the upper respiratory tract: implications for toxicology studies." Environmental Health Perspectives 85 (April 1990): 239-247. (Review)
PMID
2200664
Source
epmc
Published In
Environmental health perspectives
Volume
85
Publish Date
1990
Start Page
239
End Page
247
DOI
10.2307/3430687

The use of tracheal implants in toxicology and carcinogenesis research.

Tracheal implants have served as an important experimental pathology tool with which to study the toxic and/or carcinogenic effects of chemicals upon upper respiratory tract epithelium. Initial studies with this method utilized heterotopic rat tracheal transplants which were exposed to compounds of interest, and assessed for toxic and/or carcinogenic endpoints. Grafts containing rodent tissue have proved useful for studying the cellular and biochemical features of neoplastic progression at different time intervals following in vivo exposure to carcinogens. More recent studies have utilized epithelial denuded tracheal implants inoculated with respiratory cell populations, and xenografted into immunodeficient nu/nu mice. This technique permits the study of airway epithelium from a variety of species, including man. The advent of molecular pathology techniques such as in situ hybridization will further expand the uses of tracheal implant technology for studies with xenografted human tissues. Such implants should prove useful for the examination of species- and tissue-specific characteristics of growth and differentiation by providing a bridge between cell culture and whole animal studies.

Authors
Everitt, JI; Hesterberg, TW; Boreiko, CJ
MLA Citation
Everitt, JI, Hesterberg, TW, and Boreiko, CJ. "The use of tracheal implants in toxicology and carcinogenesis research." Toxicology 60.1-2 (January 1990): 27-40. (Review)
PMID
2180131
Source
epmc
Published In
TOXICOLOGY
Volume
60
Issue
1-2
Publish Date
1990
Start Page
27
End Page
40
DOI
10.1016/0300-483x(90)90160-i

Clinical and morphologic features of post-traumatic ocular sarcomas in cats.

Authors
Dubielzig, RR; Everitt, J; Shadduck, JA; Albert, DM
MLA Citation
Dubielzig, RR, Everitt, J, Shadduck, JA, and Albert, DM. "Clinical and morphologic features of post-traumatic ocular sarcomas in cats." Veterinary pathology 27.1 (January 1990): 62-65.
PMID
2309385
Source
epmc
Published In
Veterinary pathology
Volume
27
Issue
1
Publish Date
1990
Start Page
62
End Page
65
DOI
10.1177/030098589002700111

Effects of formaldehyde gas on the respiratory tract of rhesus monkeys. Pathology and cell proliferation.

Formaldehyde is a nasal carcinogen in rats but it remains to be determined what cancer risk this chemical poses in humans. Molecular dosimetry studies of formaldehyde and cellular proliferative responses to formaldehyde-induced cytotoxicity have been studied in the rodent and are important components of the authors' ongoing research, which has now been extended to nonhuman primates, a species more analogous to humans. The present study was designed to characterize formaldehyde injury in the respiratory tract of nonhuman primates to provide a direct comparison to the toxic effects of formaldehyde in rodents. Groups of three rhesus monkeys were exposed to room air, or 6 ppm formaldehyde for 5 days per week for 1 or 6 weeks, and the respiratory tract was assessed for nature and extent of histologic responses, and changes in epithelial cell proliferation rate. Lesions were characterized by mild degeneration and early squamous metaplasia confined to specific regions of the transitional and respiratory epithelia of the nasal passages and the respiratory epithelium of the trachea and major bronchi. There was minimal progression of histologic changes between 1 and 6 weeks; however, the percent of nasal surface area affected significantly increased in the 6-week exposure group. Formaldehyde-induced lesions were associated with increases in cell proliferation rates up to 18-fold over controls, which remained significantly elevated after 6 weeks of exposure. Histologic lesions and increases in cell proliferation were most extensive in the nasal passages and were minimal in the lower airways, whereas the maxillary sinuses exhibited no evidence of a response to formaldehyde exposure. Based on the extent of lesions and cell proliferation data, it appears that the monkey is more sensitive than the rat to the acute and subacute effects of formaldehyde at 6 ppm. The absence of response in the maxillary sinuses in the monkey suggests that combining tumors of the nasal cavity and sinuses in epidemiologic studies may not be appropriate for formaldehyde cancer risk assessment. Results of this study also have provided important information for tissue sample site selection in the monkey respiratory tract for ongoing molecular dosimetry studies.

Authors
Monticello, TM; Morgan, KT; Everitt, JI; Popp, JA
MLA Citation
Monticello, TM, Morgan, KT, Everitt, JI, and Popp, JA. "Effects of formaldehyde gas on the respiratory tract of rhesus monkeys. Pathology and cell proliferation." The American journal of pathology 134.3 (March 1989): 515-527.
PMID
2923182
Source
epmc
Published In
The American journal of pathology
Volume
134
Issue
3
Publish Date
1989
Start Page
515
End Page
527

Development of a tracheal implant xenograft model to expose human bronchial epithelial cells to toxic gases.

A tracheal implant model was developed which enabled exposure of differentiated normal human bronchial epithelial cells (NHBE) to a single exposure of a model toxic gas (formaldehyde). NHBE cells were grown in vitro in explant culture under defined serum-free conditions from previously frozen bronchial segments, harvested, and used to repopulate de-epithelialized rabbit tracheas. Rabbit tracheal segments repopulated with NHBE cells were implanted into the subcutis of congenitally athymic nude mice. Following graft vascularization, the xenografted NHBE cells differentiated and formed a mucociliary epithelial surface which lined approximately 50% of the surface of the implant lumen. Eight weeks post-implantation both ends of the implanted grafts were cannulated, and formaldehyde (HCHO) vapor (0, 6, or 15 ppm) in humidified air was passed through the tracheal lumens. Representative epithelial surfaces were examined by light and scanning electronmicroscopy, and autoradiography prior to, immediately after, and 48 hr following a 1-hr exposure to the test vapors. Light microscopic examination of implant sections immediately following exposure to 6 and 15 ppm HCHO detected cessation of ciliary activity, which recovered by 48 hr post-exposure. Scanning electron microscopic examination of the epithelial surface demonstrated mild morphologic changes, restricted to those implants exposed to 15 ppm. Findings immediately following HCHO exposure included swelling and exfoliation of individual cells, deciliation, and mucus release. Changes present after 48 hr included presence of flattened cells with few short microvilli and focal increase in the number of S-phase nuclei in the basal epithelium. These results demonstrate the utility of tracheal implants for single short-term exposure of differentiated human bronchial epithelial cells to gaseous agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Everitt, JI; Boreiko, CJ; Mangum, JB; Martin, JT; Iglehart, JD; Hesterberg, TW
MLA Citation
Everitt, JI, Boreiko, CJ, Mangum, JB, Martin, JT, Iglehart, JD, and Hesterberg, TW. "Development of a tracheal implant xenograft model to expose human bronchial epithelial cells to toxic gases." Toxicologic pathology 17.3 (January 1989): 465-473.
PMID
2814223
Source
epmc
Published In
Toxicologic Pathology (Sage)
Volume
17
Issue
3
Publish Date
1989
Start Page
465
End Page
473
DOI
10.1177/019262338901700301

Urologic syndrome associated with wire caging in AKR mice.

Individually housed male AKR/NCrlBR mice used in a chronic inhalation experiment were noted to develop a severe obstructive genitourinary condition. The mouse urologic syndrome (MUS) had one or more of the following features: bladder distension; peripreputial urine staining, alopecia, and edema; paraphimosis; urethral blockage; ulcerative balanophosthitis; hydronephrosis; pyelonephritis; rectal prolapse; and perineal ulcerative dermatitis. MUS was less severe and less prevalent in similarly housed B6C3F1/CrlBR and NIH-Swiss mice used in the same experiment. Epidemiologic evidence within the animal facility restricted the syndrome to the inhalation toxicology area. The effects of intermittent water deprivation as well as wire caging on the development of MUS were studied because these conditions were only utilized in the inhalation facility. Male AKR/NCrlBR mice, caged individually in suspended wire caging or kept isolated in polystyrene shoebox style cages containing wire floorwalk bottoms, all developed MUS within 16 weeks. Mice which were housed directly on hardwood bedding in identical plastic caging remained free of the syndrome, as did castrated males which were kept in suspended wire cages. Water deprivation was not found to be a major contributing factor to the development of the condition, but was found to augment its severity. We concluded that although MUS is probably multifactorial in etiology, housing susceptible animals on wire bottom caging may exacerbate the incidence and severity of the condition in certain strains of male mice.

Authors
Everitt, JI; Ross, PW; Davis, TW
MLA Citation
Everitt, JI, Ross, PW, and Davis, TW. "Urologic syndrome associated with wire caging in AKR mice." Laboratory animal science 38.5 (October 1988): 609-611.
PMID
3193755
Source
epmc
Published In
Comparative Medicine (Memphis)
Volume
38
Issue
5
Publish Date
1988
Start Page
609
End Page
611

Formaldehyde concentrations in the blood of rhesus monkeys after inhalation exposure.

The effect of subchronic exposure to formaldehyde (HCHO; 6 ppm; 6 hr/day, 5 days/wk for 4 wk) on the HCHO concentration in the blood of three rhesus monkeys was investigated. Immediately after the final exposure, the monkeys were sedated, and blood samples were withdrawn 7 min after the end of exposure. The HCHO concentration in the blood, determined by gas chromatography-mass spectrometry was 1.84 +/- 0.15 micrograms/g blood and did not differ significantly after a further 45 hr without exposure to HCHO (2.04 +/- 0.40 micrograms/g blood). The average concentration of HCHO in the blood of exposed monkeys was also not significantly different from that of three unexposed controls (2.42 +/- 0.09 micrograms/g blood). However, individual monkeys differed significantly from one another with respect to their blood concentrations of HCHO. These results indicate that subchronic inhalation exposure of non-human primates to HCHO has no significant effect on the HCHO concentration in the blood, and that the average concentration of HCHO in the blood of monkeys is similar to that in the blood of humans.

Authors
Casanova, M; Heck, HD; Everitt, JI; Harrington, WW; Popp, JA
MLA Citation
Casanova, M, Heck, HD, Everitt, JI, Harrington, WW, and Popp, JA. "Formaldehyde concentrations in the blood of rhesus monkeys after inhalation exposure." Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 26.8 (August 1988): 715-716.
PMID
3198038
Source
epmc
Published In
Food and Chemical Toxicology
Volume
26
Issue
8
Publish Date
1988
Start Page
715
End Page
716
DOI
10.1016/0278-6915(88)90071-3

Effect of a purified diet on dystrophic cardiac calcinosis in mice.

Male and female C3H/HeNCrl mice were divided into test groups and fed either a purified diet (AIN-76A) or a natural ingredient diet (NIH-07). Lesions of dystrophic cardiac calcinosis (DCC) were found to be more prevalent and more severe in mice fed the purified diet. The cardiac changes, which were similar in nature in both groups of mice, consisted of randomly distributed foci of myocardial mineralization and fibrosis. These lesions were not associated with clinical disease or significant alterations in serum calcium, lactic dehydrogenase, aspartate aminotransferase, alkaline phosphatase or creatine kinase levels. We conclude that AIN-76A purified diet should be utilized with caution in toxicology studies which use mice as experimental subjects, especially if the heart is a potential target organ.

Authors
Everitt, JI; Ross, PW; Neptun, DA; Mangum, JB
MLA Citation
Everitt, JI, Ross, PW, Neptun, DA, and Mangum, JB. "Effect of a purified diet on dystrophic cardiac calcinosis in mice." Laboratory animal science 38.4 (August 1988): 426-429.
PMID
3184851
Source
epmc
Published In
Comparative Medicine (Memphis)
Volume
38
Issue
4
Publish Date
1988
Start Page
426
End Page
429

A nylon ball device for primate environmental enrichment.

Authors
Ross, PW; Everitt, JI
MLA Citation
Ross, PW, and Everitt, JI. "A nylon ball device for primate environmental enrichment." Laboratory animal science 38.4 (August 1988): 481-483.
PMID
3184864
Source
epmc
Published In
Comparative Medicine (Memphis)
Volume
38
Issue
4
Publish Date
1988
Start Page
481
End Page
483

Carcinogen-induced unscheduled DNA synthesis in xenotransplanted human tracheobronchial epithelium: comparison with rat tracheal epithelium.

Extrapolation from rodent genotoxicity data to humans is complicated by variables such as interspecies differences in carcinogen metabolism and DNA repair. A xenograft system containing human bronchial epithelial cells was used to assess the induction of unscheduled DNA synthesis (UDS) by carcinogens and to compare the response with that of rat tracheal epithelium. Cells from human bronchus were grown in explant culture, inoculated into de-epithelialized rat tracheas and implanted subcutaneously into nude mice. Within six weeks, a differentiated mucociliary epithelium lined the xenografted tracheas. Fresh rat tracheas and human xenografts were cut into rings and incubated in media containing [3H]thymidine and either the direct-acting carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 3-1000 microM), or a carcinogen requiring metabolic activation, 4-nitroquinoline-1-oxide (4-NQO, 3-100 microM). Tissues were then fixed, sectioned, processed for autoradiography and the number of nuclear grains (NG) determined for 100 epithelial cells lining the trachea in each section. A time- and concentration-dependent increase in NG was observed in both human xenografts and rat tracheas after treatment with MNNG or 4-NQO, indicating induction of UDS by these agents. The UDS response to MNNG in the human xenografts was similar to that observed in the rat tracheas, whereas the response to 4-NQO was greater in rat tracheas. These studies indicate that the human xenograft system should have applications for the study of carcinogen-induced damage in normal bronchial epithelial cells.

Authors
Hesterberg, TW; Boreiko, CJ; Maness, SC; Iglehart, JD; Mangum, JB; Everitt, JI
MLA Citation
Hesterberg, TW, Boreiko, CJ, Maness, SC, Iglehart, JD, Mangum, JB, and Everitt, JI. "Carcinogen-induced unscheduled DNA synthesis in xenotransplanted human tracheobronchial epithelium: comparison with rat tracheal epithelium." Carcinogenesis 9.3 (March 1988): 467-472.
PMID
3125997
Source
epmc
Published In
Carcinogenesis
Volume
9
Issue
3
Publish Date
1988
Start Page
467
End Page
472
DOI
10.1093/carcin/9.3.467

High mortality with severe dystrophic cardiac calcinosis in C3H/OUJ mice fed high fat purified diets.

Severe degenerative myocardial disease occurred in female C3H/OUJ mice fed purified diets for 36 weeks; the diet contained 5% or 20% fat as non-hydrogenated soybean oil. Deaths of lactating females of this group (17/35 high fat diet and 7/35 low fat diet animals) were due to sudden cardiovascular collapse. Cardiomegaly with marked atrial and ventricular myocardial mineralization was seen at necropsy. Histologically, the random, myopathic foci were characterized by severe myocardial degeneration, mineralization, and fibrosis. Mural thrombosis, pulmonary arteriosclerosis, and mild myocardial inflammatory cell infiltrates were also present. Pathological changes were similar to those of dystrophic cardiac calcinosis, an incidental necropsy finding in certain mouse strains.

Authors
Everitt, JI; Olson, LM; Mangum, JB; Visek, WJ
MLA Citation
Everitt, JI, Olson, LM, Mangum, JB, and Visek, WJ. "High mortality with severe dystrophic cardiac calcinosis in C3H/OUJ mice fed high fat purified diets." Veterinary pathology 25.2 (March 1988): 113-118.
PMID
3363788
Source
epmc
Published In
Veterinary pathology
Volume
25
Issue
2
Publish Date
1988
Start Page
113
End Page
118
DOI
10.1177/030098588802500202

Pathologic changes associated with fatal Plasmodium falciparum infection in the Bolivian squirrel monkey (Saimiri sciureus boliviensis).

Fatal cases of experimental Plasmodium falciparum (Indochina I) in Bolivian squirrel monkeys (Saimiri sciureus boliviensis) were examined by histologic and ultrastructural methods. Gross lesions were characterized by hepatosplenomegaly and interstitial pulmonary changes. Histologically, there was marked diffuse reticuloendothelial hyperplasia, pulmonary alveolar septal thickening, mesangioproliferative glomerulonephropathy, sequestration of parasitized erythrocytes in deep vascular beds, degenerative parenchymal changes in the liver and myocardium, and in one case retinal and cerebral hemorrhage. These data indicate that the Bolivian squirrel monkey is a good model for studying pathologic changes associated with human falciparum malaria.

Authors
Whiteley, HE; Everitt, JI; Kakoma, I; James, MA; Ristic, M
MLA Citation
Whiteley, HE, Everitt, JI, Kakoma, I, James, MA, and Ristic, M. "Pathologic changes associated with fatal Plasmodium falciparum infection in the Bolivian squirrel monkey (Saimiri sciureus boliviensis)." The American journal of tropical medicine and hygiene 37.1 (July 1987): 1-8.
PMID
3300388
Source
epmc
Published In
American Journal of Tropical Medicine and Hygiene
Volume
37
Issue
1
Publish Date
1987
Start Page
1
End Page
8

Lymphocyte activation, cell-mediated cytotoxicity and their relationship to dietary fat-enhanced mammary tumorigenesis in C3H/OUJ mice.

The effects of dietary soybean oil (SBO) concentration (5 vs. 20% by weight) on mammary tumorigenesis, mitogen-induced blastogenesis, cell-mediated cytotoxicity and serum and lymphocyte fatty acid composition were studied in C3H/OUJ female mice. Weanling mice fed 20% SBO for 9 mo had a higher incidence (89 vs. 65%) and greater average size (2.9 vs. 1.9 g) of mammary tumor virus type S breast tumors than mice fed 5% SBO. The response of isolated splenocytes to the T-cell mitogens concanavalin A and phytohemagglutinin was 20-25% lower in mice fed 20% SBO than in mice fed 5% SBO for 20 wk. There was no effect of SBO concentration on the splenocyte response to lipopolysaccharide E55:B5, a B-cell mitogen, or to pokeweed mitogen, and B- and T-cell mitogen. Cell-mediated cytotoxicity to allogenic P815 tumor cells was 20% lower in mice fed 20% SBO than in mice fed 5% SBO for 12 wk. The lower cell-mediated immunity associated with 20% SBO was not due to changes in the fatty acid composition of the two major splenocyte membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine. However, serum levels of linoleic acid were higher in mice fed 20% SBO. Raising dietary SBO from 5 to 20% by weight was associated with increased mammary tumorigenesis, reduced T-cell blastogenesis and lower cell-mediated cytotoxicity.

Authors
Olson, LM; Clinton, SK; Everitt, JI; Johnston, PV; Visek, WJ
MLA Citation
Olson, LM, Clinton, SK, Everitt, JI, Johnston, PV, and Visek, WJ. "Lymphocyte activation, cell-mediated cytotoxicity and their relationship to dietary fat-enhanced mammary tumorigenesis in C3H/OUJ mice." The Journal of nutrition 117.5 (May 1987): 955-963.
PMID
3585550
Source
epmc
Published In
The Journal of nutrition
Volume
117
Issue
5
Publish Date
1987
Start Page
955
End Page
963

Diagnostic exercise: eye lesions in rats.

Authors
Everitt, JI; McLaughlin, SA; Helper, LC
MLA Citation
Everitt, JI, McLaughlin, SA, and Helper, LC. "Diagnostic exercise: eye lesions in rats." Laboratory animal science 37.2 (April 1987): 203-204.
PMID
3599890
Source
epmc
Published In
Comparative Medicine (Memphis)
Volume
37
Issue
2
Publish Date
1987
Start Page
203
End Page
204

Effects of an insecticidal dip containing d-limonene in the cat.

A study was undertaken to determine the effects of a single dermal application of a commercial insecticidal dip containing 78.2% d-limonene in cats. At the manufacturer's recommended concentration of 1.5 oz/gal of water, no clinical signs or lesions of toxicosis were seen. At 5 times the recommended concentration, clinical signs were mild and consisted of hypersalivation of short duration, ataxia, and muscle tremors resembling shivering. At 15 times the recommended concentration, clinical signs included hypersalivation lasting 15 to 30 minutes, moderate-to-severe ataxia lasting 1 to 5 hours, muscle tremors resembling shivering lasting 1 to 4 hours, and severe hypothermia beginning soon after treatment and lasting 5 hours. Gross lesions were confined to excoriation of the scrotal and perineal areas of the treated male cats at the 15 X concentration. No deaths or other lasting effects were seen at any dosage.

Authors
Hooser, SB; Beasley, VR; Everitt, JI
MLA Citation
Hooser, SB, Beasley, VR, and Everitt, JI. "Effects of an insecticidal dip containing d-limonene in the cat." Journal of the American Veterinary Medical Association 189.8 (October 1986): 905-908.
PMID
3771360
Source
epmc
Published In
Journal of the American Veterinary Medical Association
Volume
189
Issue
8
Publish Date
1986
Start Page
905
End Page
908

Diagnostic exercise: lingual growths in rabbits.

Authors
Sundberg, JP; Everitt, JI
MLA Citation
Sundberg, JP, and Everitt, JI. "Diagnostic exercise: lingual growths in rabbits." Laboratory animal science 36.5 (October 1986): 499-500.
PMID
3773460
Source
epmc
Published In
Comparative Medicine (Memphis)
Volume
36
Issue
5
Publish Date
1986
Start Page
499
End Page
500

Experimental Babesia bovis infection in Holstein calves.

One intact and two splenectomized Holstein calves were infected intravenously with a Mexican strain of Babesia bovis and killed following the onset of severe clinical disease. A light and electron microscopic study was conducted on selected tissues to examine the relationship between parasitized erythrocytes and microvascular endothelial cells. The pattern and degree of specific organ sequestration of parasitized erythrocytes was assessed and correlated to lesions. Red blood cells infected with Babesia bovis exhibited stellate membrane protrusions. This morphological change appeared to mediate erythrocyte sequestration in the microvascular and capillary beds of the brain, kidney, and adrenal gland by an as yet unknown mechanism(s).

Authors
Everitt, JI; Shadduck, JA; Steinkamp, C; Clabaugh, G
MLA Citation
Everitt, JI, Shadduck, JA, Steinkamp, C, and Clabaugh, G. "Experimental Babesia bovis infection in Holstein calves." Veterinary pathology 23.5 (September 1986): 556-562.
PMID
3776013
Source
epmc
Published In
Veterinary pathology
Volume
23
Issue
5
Publish Date
1986
Start Page
556
End Page
562
DOI
10.1177/030098588602300503

Multicentric nerve sheath fibrosarcomas of multiple cranial nerve roots in two dogs.

Nerve sheath fibrosarcomas of the left 5th through 8th cranial nerve roots were diagnosed in 1 dog and of the left 4th through 8th cranial nerve roots in another dog. Clinical signs in both dogs included head tilt to the left, circling to the left, left hemiparesis and proprioception deficits, rotary nystagmus, left-sided atrophy of masticatory muscles, and cutaneous hypalgesia of the left side of the face. Cranial nerve roots from both dogs were incorporated in discrete, firm, encapsulated, lobulated, tan masses of various sizes that compressed adjacent brain stem and cranial nerves. There were no regional or distant metastases; however, there was enlargement of nerve roots adjacent to the masses. The masses were composed of bundles and sheets of anaplastic, polymorphic to spindle-shaped cells that infiltrated cranial nerves and ganglia and extended into the brain along nerve roots. Masses contained various amounts of collagen and reticulin fibers, but no mucopolysaccharide ground substance. There was no myelin or S-100 protein associated with neoplastic cells. The tumors appeared to have a multicentric origin from cranial nerve sheaths.

Authors
Zachary, JF; O'Brien, DP; Ingles, BW; Everitt, JI; Parker, AJ
MLA Citation
Zachary, JF, O'Brien, DP, Ingles, BW, Everitt, JI, and Parker, AJ. "Multicentric nerve sheath fibrosarcomas of multiple cranial nerve roots in two dogs." Journal of the American Veterinary Medical Association 188.7 (April 1986): 723-726.
PMID
3700229
Source
epmc
Published In
Journal of the American Veterinary Medical Association
Volume
188
Issue
7
Publish Date
1986
Start Page
723
End Page
726

Sudden death in training and racing Thoroughbred horses.

We reviewed case records, necropsy reports, and histologic sections from 25 Thoroughbred racehorses that died suddenly at 3 Chicago racetracks. These were young horses ranging in age from 2 to 5 years. There were more females (n = 16) than males (n = 9), and the incidence of death increased slightly in the spring and summer. Twenty-one of the 25 horses died while racing or training. Only 8 of the 25 horses (32%) had lesions sufficient to account for the death. In 6 of those 8 cases, death was caused by massive thoracic or abdominal hemorrhage. The site or nature of the vascular defect in these cases could not be determined. One horse died of severe preexisting pulmonary disease, and one died of encephalitis and cardiac papillary muscle fibrosis. The cause of death was undetermined in 17 horses (68%). Nearly all horses had pulmonary edema, congestion, and/or hemorrhage. We postulate that these unexplained deaths were a result of exercise-induced acute cardiovascular failure.

Authors
Gelberg, HB; Zachary, JF; Everitt, JI; Jensen, RC; Smetzer, DL
MLA Citation
Gelberg, HB, Zachary, JF, Everitt, JI, Jensen, RC, and Smetzer, DL. "Sudden death in training and racing Thoroughbred horses." Journal of the American Veterinary Medical Association 187.12 (December 1985): 1354-1356.
PMID
4086352
Source
epmc
Published In
Journal of the American Veterinary Medical Association
Volume
187
Issue
12
Publish Date
1985
Start Page
1354
End Page
1356

Use of in vitro cytotoxicity to rank ocular irritation of six surfactants.

Authors
Shadduck, JA; Everitt, J; Bay, P
MLA Citation
Shadduck, JA, Everitt, J, and Bay, P. "Use of in vitro cytotoxicity to rank ocular irritation of six surfactants." Alternative methods in toxicology. 3 (January 1985): 641-649.
Source
epmc
Volume
3
Publish Date
1985
Start Page
641
End Page
649

Lymphosarcoma as the cause of ataxia in a horse.

Authors
Shamis, LD; Everitt, JI; Baker, GJ
MLA Citation
Shamis, LD, Everitt, JI, and Baker, GJ. "Lymphosarcoma as the cause of ataxia in a horse." Journal of the American Veterinary Medical Association 184.12 (June 1984): 1517-1518.
PMID
6547423
Source
epmc
Published In
Journal of the American Veterinary Medical Association
Volume
184
Issue
12
Publish Date
1984
Start Page
1517
End Page
1518

Porcine necrotizing staphylococcal endometritis.

Authors
Everitt, JI; Fetter, AW; Kenney, RM; Della-Ferra, MA
MLA Citation
Everitt, JI, Fetter, AW, Kenney, RM, and Della-Ferra, MA. "Porcine necrotizing staphylococcal endometritis." Veterinary pathology 18.1 (January 1981): 125-127.
PMID
7467064
Source
epmc
Published In
Veterinary pathology
Volume
18
Issue
1
Publish Date
1981
Start Page
125
End Page
127
DOI
10.1177/030098588101800116

Cutaneous herpes simplex virus infection of guinea pigs as a model for antiviral chemotherapy.

The kinetics of Herpesvirus hominis (Type 1) replication and lesion development in guinea pig skin were determined. The data indicate that lesion scores did not always reflect virus content. Virus replication was detected prior to appearance of lesions and maximum virus content preceded maximum lesion score. Lesions resolved slowly while virus content declined rapidly to an undetectable level. The utility of the guinea pig skin-herpesvirus model for the evaluation of ara-A and kethoxal was studied. Ara-A treatment at three dose levels suppressed lesion development and at the two highest dose levels lesion development was delayed. Lesion virus content, when determined during the period of maximum virus replication, was not affected by treatment. Kethoxal markedly suppressed lesion development and virus growth. Aspects of this experimental model typify cutaneous herpes simplex disease of man. Studies designed to further assess its utility for evaluating antiviral drugs seem warranted.

Authors
Schafer, TW; Lieberman, M; Everitt, J; Came, P
MLA Citation
Schafer, TW, Lieberman, M, Everitt, J, and Came, P. "Cutaneous herpes simplex virus infection of guinea pigs as a model for antiviral chemotherapy." Annals of the New York Academy of Sciences 284 (March 1977): 624-631.
PMID
280151
Source
epmc
Published In
Annals of the New York Academy of Sciences
Volume
284
Publish Date
1977
Start Page
624
End Page
631
DOI
10.1111/j.1749-6632.1977.tb21996.x
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