Joel Meyer

Overview:

Dr. Meyer studies the effects of toxic agents and stressors on human and wildlife health. He is particularly interested in understanding the mechanisms by which environmental agents cause DNA damage, the molecular processes that organisms employ to protect prevent and repair DNA damage, and genetic differences that may lead to increased or decreased sensitivity to DNA damage. Mitochondrial DNA damage and repair, as well as mitochondrial function in general, are a particular focus. He studies these effects in the nematode Caenorhabditis elegans, in cell culture, and collaboratively in other laboratory model organisms as well as in human populations in the USA and globally.

Positions:

Associate Professor of Environmental Genomics in the Division of Environmental Sciences and Policy

Environmental Sciences and Policy
Nicholas School of the Environment

Faculty Network Member of The Energy Initiative

Nicholas Institute-Energy Initiative
Institutes and Provost's Academic Units

Affiliate, Duke Global Health Institute

Duke Global Health Institute
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1992

Juniata College

Ph.D. 2003

Duke University

Grants:

Center for Environmental Implications of Nanotechnology

Administered By
Pratt School of Engineering
Awarded By
National Science Foundation
Role
Investigator
Start Date
End Date

Fluoride and human health: Assessing novel biomarkers in detecting bone disorder

Administered By
Earth and Climate Sciences
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

COPAS BIOSORT Worm Sorter

Administered By
Neurology, Headache and Pain
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Are mitochondria a major target of antimicrobial silver nanoparticles?

Administered By
Environmental Sciences and Policy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

GW150184 Mitochondrial dysfunction and Gulf War Illness

Administered By
Environmental Sciences and Policy
Awarded By
United States Army Medical Research Acquisition Activity
Role
Principal Investigator
Start Date
End Date

Publications:

Calcium/Calmodulin Dependent Protein Kinase Kinase 2 Regulates the Expansion of Tumor-Induced Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy.
Authors
Huang, W; Liu, Y; Luz, A; Berrong, M; Meyer, JN; Zou, Y; Swann, E; Sundaramoorthy, P; Kang, Y; Jauhari, S; Lento, W; Chao, N; Racioppi, L
MLA Citation
Huang, Wei, et al. “Calcium/Calmodulin Dependent Protein Kinase Kinase 2 Regulates the Expansion of Tumor-Induced Myeloid-Derived Suppressor Cells.Front Immunol, vol. 12, 2021, p. 754083. Pubmed, doi:10.3389/fimmu.2021.754083.
URI
https://scholars.duke.edu/individual/pub1500529
PMID
34712241
Source
pubmed
Published In
Frontiers in Immunology
Volume
12
Published Date
Start Page
754083
DOI
10.3389/fimmu.2021.754083

Risk of lead exposure from wild game consumption from cross-sectional studies in Madre de Dios, Peru

Background: Studies have shown elevated blood lead levels (BLL) in residents of remote communities in the Amazon, yet sources of lead exposure are not fully understood, such as lead ammunition consumed in wild game. Methods: Data was collected during two cross-sectional studies that enrolled 307 individuals in 26 communities. Regression models with community random effects were used to evaluate risk factors for BLLs, including diet, water source, smoking, sex, age, and indigenous status. The All-Ages Lead Model (AALM) from the Environmental Protection Agency (EPA) was used to estimate background and dose from wild game consumption. Findings: Indigenous status and wild game consumption were associated with increased BLLs. Indigenous participants had 2.52 µg/dL (95% CI: 1.95–3.24) higher BLLs compared to non-indigenous. Eating wild game was associated with a 1.41 µg/dL (95% CI: 1.20–1.70) increase in BLLs. Two or more portions per serving were associated with increased BLLs of 1.66 µg/dL (95% CI: 1.10–2.57), compared to smaller servings. Using the AALM, we estimate background lead exposures to be 20 µg/day with consumption of wild game contributing 500 µg/meal. Lastly, we found a strong association between BLLs and mercury exposure. Interpretation: Consumption of wild game hunted with lead ammunition may pose a common source of lead exposure in the Amazon. Communities that rely on wild game and wild fish may face a dual burden of exposure to lead and mercury, respectively. Funding: Duke Bass Connections, Duke Superfund Centre funded by the National Institute of Environmental Health Sciences (P42ES010356), Duke Global Health Doctoral Scholar's Program, and Hunt Oil provided funding.
Authors
Berky, AJ; Robie, E; Chipa, SN; Ortiz, EJ; Palmer, EJ; Rivera, NA; Avalos, AMM; Meyer, JN; Hsu-Kim, H; Pan, WK
MLA Citation
Berky, A. J., et al. “Risk of lead exposure from wild game consumption from cross-sectional studies in Madre de Dios, Peru.” The Lancet Regional Health  Americas, vol. 12, Aug. 2022. Scopus, doi:10.1016/j.lana.2022.100266.
URI
https://scholars.duke.edu/individual/pub1521460
Source
scopus
Published In
The Lancet Regional Health Americas
Volume
12
Published Date
DOI
10.1016/j.lana.2022.100266

Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans.

Complex-I-deficiency represents the most frequent pathogenetic cause of human mitochondriopathies. Therapeutic options for these neurodevelopmental life-threating disorders do not exist, partly due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a genetically tractable model organism widely used to investigate neuronal pathologies. Here, we generate C. elegans models for mitochondriopathies and show that depletion of complex I subunits recapitulates biochemical, cellular and neurodevelopmental aspects of the human diseases. We exploit two models, nuo-5/NDUFS1- and lpd-5/NDUFS4-depleted animals, for a suppressor screening that identifies lutein for its ability to rescue animals' neurodevelopmental deficits. We uncover overexpression of synaptic neuroligin as an evolutionarily conserved consequence of mitochondrial dysfunction, which we find to mediate an early cholinergic defect in C. elegans. We show lutein exerts its beneficial effects by restoring neuroligin expression independently from its antioxidant activity, thus pointing to a possible novel pathogenetic target for the human disease.
Authors
Maglioni, S; Schiavi, A; Melcher, M; Brinkmann, V; Luo, Z; Laromaine, A; Raimundo, N; Meyer, JN; Distelmaier, F; Ventura, N
MLA Citation
Maglioni, Silvia, et al. “Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans.Nature Communications, vol. 13, no. 1, May 2022, p. 2620. Epmc, doi:10.1038/s41467-022-29972-4.
URI
https://scholars.duke.edu/individual/pub1520742
PMID
35551180
Source
epmc
Published In
Nature Communications
Volume
13
Published Date
Start Page
2620
DOI
10.1038/s41467-022-29972-4

Sex-specific DNA methylation and associations with in utero tobacco smoke exposure at nuclear-encoded mitochondrial genes.

Sex-linked differences in mitochondrial ATP production, enzyme activities, and reactive oxygen species generation have been reported in multiple tissue and cell types. While the effects of reproductive hormones underlie many of these differences, regulation of sexually dimorphic mitochondrial function has not been fully characterized. We hypothesized that sex-specific DNA methylation contributes to sex-specific expression of nuclear genes that influence mitochondrial function. Herein, we analysed DNA methylation data specifically focused on nuclear-encoded mitochondrial genes in 191 males and 190 females. We found 596 differentially methylated sites (DMSs) (FDR p < 0.05), corresponding to 324 genes, with at least a 1% difference in methylation between sexes. To investigate the potential functional significance, we utilized gene expression microarray data. Of the 324 genes containing DMSs, 17 showed differences in gene expression by sex. Particularly striking was that ATP5G2, encoding subunit C of ATP synthase, contains seven DMSs and exhibits a sex difference in expression (p = 0.04). Finally, we also found that alterations in DNA methylation associated with in utero tobacco smoke exposure were sex-specific in these nuclear-encoded mitochondrial genes. Interestingly, the level of sex differences in DNA methylation at nuclear-encoded mitochondrial genes and the level of methylation changes associated with smoke exposure were less prominent than that of other genes. This suggests more conservative regulation of DNA methylation at these nuclear-encoded mitochondrial genes as compared to others. Overall, our findings suggest that sex-specific DNA methylation may help establish sex differences in expression and function and that sex-specific alterations in DNA methylation in response to exposures could contribute to sex-variable toxicological responses.
Authors
King, DE; Sparling, AC; Lloyd, D; Satusky, MJ; Martinez, M; Grenier, C; Bergemann, CM; Maguire, R; Hoyo, C; Meyer, JN; Murphy, SK
MLA Citation
King, Dillon E., et al. “Sex-specific DNA methylation and associations with in utero tobacco smoke exposure at nuclear-encoded mitochondrial genes.Epigenetics, Mar. 2022, pp. 1–17. Pubmed, doi:10.1080/15592294.2022.2043591.
URI
https://scholars.duke.edu/individual/pub1511878
PMID
35238269
Source
pubmed
Published In
Epigenetics : Official Journal of the Dna Methylation Society
Published Date
Start Page
1
End Page
17
DOI
10.1080/15592294.2022.2043591

Developmental nicotine exposure and masculinization of the rat preoptic area.

Nicotine is a neuroteratogenic component of tobacco smoke, e-cigarettes, and other products and can exert sex-specific effects in the developing brain, likely mediated through sex hormones. Estradiol modulates expression of nicotinic acetylcholine receptors in rats, and plays critical roles in neurodevelopmental processes, including sexual differentiation of the brain. Here, we examined the effects of developmental nicotine exposure on the sexual differentiation of the preoptic area (POA), a brain region that normally displays robust structural sexual dimorphisms and controls adult mating behavior in rodents. Using a rat model of gestational exposure, developing pups were exposed to nicotine (2 mg/kg/day) via maternal osmotic minipump (subcutaneously, sc) throughout the critical window for brain sexual differentiation. At postnatal day (PND) 4, a subset of offspring was analyzed for epigenetic effects in the POA. At PND40, all offspring were gonadectomized, implanted with a testosterone-releasing capsule (sc), and assessed for male sexual behavior at PND60. Following sexual behavior assessment, the area of the sexually dimorphic nucleus of the POA (SDN-POA) was measured using immunofluorescent staining techniques. In adults, normal sex differences in male sexual behavior and in the SDN-POA area were eliminated in nicotine-treated animals. Using novel analytical approaches to evaluate overall masculinization of the adult POA, we identified significant masculinization of the nicotine-treated female POA. In neonates (PND4), nicotine exposure induced trending alterations in methylation-dependent masculinizing gene expression and DNA methylation levels at sexually-dimorphic differentially methylated regions, suggesting that developmental nicotine exposure is capable of triggering masculinization of the rat POA via epigenetic mechanisms.
Authors
Joglekar, R; Cauley, M; Lipsich, T; Corcoran, DL; Patisaul, HB; Levin, ED; Meyer, JN; McCarthy, MM; Murphy, SK
MLA Citation
Joglekar, Rashmi, et al. “Developmental nicotine exposure and masculinization of the rat preoptic area.Neurotoxicology, vol. 89, Mar. 2022, pp. 41–54. Pubmed, doi:10.1016/j.neuro.2022.01.005.
URI
https://scholars.duke.edu/individual/pub1505860
PMID
35026373
Source
pubmed
Published In
Neurotoxicology
Volume
89
Published Date
Start Page
41
End Page
54
DOI
10.1016/j.neuro.2022.01.005

Research Areas:

Abnormalities, Drug-Induced
Aldehydes
Benzopyrans
Calcium
Calibration
Cell Survival
DNA Replication
Dose-Response Relationship, Drug
Energy Metabolism
Fluorenes
Genotype
Half-Life
HeLa Cells
Heart
Heart Defects, Congenital
Humic Substances
Laboratories
Larva
Molecular Structure
Mutation
Neoplasm Proteins
Phosphorylation
Ponds
Proteolysis
Silver Nitrate
Solubility
Structure-Activity Relationship
Sulfides
Toxicity Tests
Transcriptome