Arsenic methylation capacity is associated with locus-specific DNA methylation: an epigenome-wide association study among adults with low-to-moderate arsenic exposure in the United States

Abstract

Background/Aims: Chronic Arsenic (As) exposure remains a global health problem. Adverse health effects persist decades after arsenic exposure has ended, suggesting a role for epigenetic dysregulation. Methylation of inorganic arsenic (iAs) to monomethylarsonate (MMA) and dimethylarsinate (DMA) by arsenic(III) methyltransferase (AS3MT) decreases toxicity and facilitates urinary excretion. Whether arsenic methylation is associated with DNA methylation is unknown. Methods: We measured DNA methylation at >850,000 loci in 2,325 participants in the Strong Heart Study, a population-based study of American Indian adults exposed to low-moderate levels of arsenic in drinking water. Arsenic methylation was measured as the proportion of arsenic metabolites in urine: iAs%, MMA%, and DMA%. Blood DNA differentially methylated positions (DMPs) associated with each arsenic metabolite were tested using linear models. Gene ontology (GO) analysis was conducted using GOmeth adjusting for array coverage. Models were adjusted for estimated cell type proportions, age, sex, BMI, smoking, education, estimated glomerular filtration rate, and study site. Results: In adjusted models, we identified 84 and 13, 46 and 22, and 112 and 25 CpGs associated with iAs%, MMA%, and DMA% at PFDR < 0.05 / PBonferroni < 0.05, respectively. Seventeen FDR-significant CpGs were common between arsenic metabolites, including 4 CpGs annotated to AS3MT and 13 CpGs located within 650 kilobase pairs up- or downstream of the AS3MT gene and annotated to CNNM2, WBP1L, C10orf95, NT5C2, CALHM1, and TRIM8. Top GO terms overrepresented among genes containing iAs% DMPs were related to muscle hypertrophy; top GO terms associated with MMA% and %DMA% were related to response to tumor cells and regulation of protein catabolic processes. Conclusions: In an epigenome-wide association study, we identified CpGs associated with % arsenic metabolites within a gene region covering AS3MT. Further research is needed to understand the relationship between DNA methylation of AS3MT, gene expression, arsenic methylation capacity and health.