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

Abstract

I.AbstractBackgroundMethylmercury (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.ObjectivesTo 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.MethodsWe 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.ResultsWe 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.DiscussionHere, 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.