The Impact of Arsenic Exposure on Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults

Abstract

Background: Arsenic exposure affects >200 million people worldwide, including ~56 million in Bangladesh. Arsenic exposure increases the risk of chronic disease, and one potential mechanism of arsenic toxicity is epigenetic dysregulation of DNA methylation.Objective: We assessed associations between arsenic exposure and genome-wide DNA methylation among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS), who were exposed by drinking naturally-contaminated well water.Methods: Methylation in whole blood DNA was measured at ~850,000 CpGs using the Illumina EPIC array. To assess associations between arsenic exposure and CpG methylation, we used multivariate linear regression models adjusted for covariates and surrogate variables (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent set of 400 exposed Bangladeshi adults with data on ~450,000 CpGs.Results: We identified nine CpGs associated with urine arsenic exposure (Bonferroni-corrected threshold p<6.5x10-8). Four of these CpGs annotated to the 450K array and all robustly replicated (p<10-3). The top two CpGs annotated upstream of ABR (cg01912040, cg10003262). All urine arsenic-associated CpGs were also associated with arsenic measured in drinking water (p<0.05). Meta-analysis (n=796) identified 33 urine arsenic-associated CpGs (Bonferroni-corrected threshold p<1.3x10-7). Among meta-analysis arsenic associated CpGs, gene-specific expression and methylation was associated for six CpGs (p<0.05) and associated CpGs annotated to three genes (EFNA1, SPSB1, SQSTM1) in the TNFα signaling via NFκB pathway (enrichment p=7.7x10-4).Conclusions: The robust associations between arsenic exposure and DNA methylation observed in this work suggest that epigenetic alterations may be important mediators in arsenic toxicity and could be further investigated as biomarkers of exposure and effect in exposed populations.