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Epigenetic biomarkers of autoimmune risk and protective antioxidant signaling in methylmercury-exposed adults

Caren Weinhouse, Luiza Perez, Ian Ryde, Jaclyn M. Goodrich, View ORCID ProfileJ. Jaime Miranda, Heileen Hsu-Kim, Susan K. Murphy, Joel N. Meyer, William K. Pan
doi: https://doi.org/10.1101/2022.07.05.498896
Caren Weinhouse
1Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon
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  • For correspondence: weinhous@ohsu.edu william.pan@duke.edu
Luiza Perez
2Duke Global Health Institute, Duke University, Durham, North Carolina
3Environmental Science and Policy, Nicholas School of the Environment, Duke University, Durham, North Carolina
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Ian Ryde
3Environmental Science and Policy, Nicholas School of the Environment, Duke University, Durham, North Carolina
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Jaclyn M. Goodrich
4Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan
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J. Jaime Miranda
5CRONICAS Center of Excellence in Chronic Diseases, Universidad Peruana Cayetano Heredia, Lima, Peru
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  • ORCID record for J. Jaime Miranda
Heileen Hsu-Kim
6Department of Civil and Environmental Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina
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Susan K. Murphy
3Environmental Science and Policy, Nicholas School of the Environment, Duke University, Durham, North Carolina
7Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
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Joel N. Meyer
2Duke Global Health Institute, Duke University, Durham, North Carolina
3Environmental Science and Policy, Nicholas School of the Environment, Duke University, Durham, North Carolina
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William K. Pan
2Duke Global Health Institute, Duke University, Durham, North Carolina
3Environmental Science and Policy, Nicholas School of the Environment, Duke University, Durham, North Carolina
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  • For correspondence: weinhous@ohsu.edu william.pan@duke.edu
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I. Abstract

Background Methylmercury (MeHg) is an environmental pollutant of global public health concern. MeHg is associated with immune dysfunction but the underlying mechanisms are unclear. The most common route of MeHg exposure is through consumption of fatty fish that contain beneficial n-3 polyunsaturated fatty acids (PUFA) that may protect against MeHg toxicity.

Objectives To better inform individual costs and benefits of fish consumption, we aimed to identify candidate epigenetic biomarkers of biological responses that reflect MeHg toxicity and PUFA protection.

Methods We profiled genome-wide DNA methylation using Illumina Infinium MethylationEPIC BeadChip in whole blood from N=32 individuals from Madre de Dios, Peru. Madre de Dios has high artisanal and small-scale gold mining activity, which results in high MeHg exposure to nearby residents. We compared DNA methylation in N=16 individuals with high (>10 µg/g) vs. N=16 individuals with low (<1 µg/g) total hair mercury (a proxy for methylmercury exposure), matched on age and sex.

Results We identified hypomethylated (i.e., likely activated) genes and promoters in high vs. low MeHg-exposed participants linked to Th1/Th2 immune imbalance, decreased IL-7 signaling, and increased marginal zone B cells. These three pathways are feasible mechanisms for MeHg-induced autoimmunity. In addition, we identified candidate epigenetic biomarkers of PUFA-mediated protection: hypomethylated enhancer binding sites for retinoid X receptor (RXR) and retinoic acid receptor α (RARα). Last, we observed hypomethylated enhancer and promoter binding sites for glucocorticoid receptor (GR), which is associated with developmental neurotoxicity, and transcription factor 7-like 2 (TCF7L2), which is associated with type 2 diabetes (T2D) risk.

Discussion Here, we identify a set of candidate epigenetic biomarkers for assessing individualized risk of autoimmune response and protection against neurotoxicity due to MeHg exposure and fish consumption. In addition, our results may inform surrogate tissue biomarkers of early MeHg exposure-related neurotoxicity and T2D risk.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflicts of Interest. The authors declare that they have nothing to disclose.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 06, 2022.
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Epigenetic biomarkers of autoimmune risk and protective antioxidant signaling in methylmercury-exposed adults
Caren Weinhouse, Luiza Perez, Ian Ryde, Jaclyn M. Goodrich, J. Jaime Miranda, Heileen Hsu-Kim, Susan K. Murphy, Joel N. Meyer, William K. Pan
bioRxiv 2022.07.05.498896; doi: https://doi.org/10.1101/2022.07.05.498896
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Epigenetic biomarkers of autoimmune risk and protective antioxidant signaling in methylmercury-exposed adults
Caren Weinhouse, Luiza Perez, Ian Ryde, Jaclyn M. Goodrich, J. Jaime Miranda, Heileen Hsu-Kim, Susan K. Murphy, Joel N. Meyer, William K. Pan
bioRxiv 2022.07.05.498896; doi: https://doi.org/10.1101/2022.07.05.498896

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