Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults.

BACKGROUND: Arsenic exposure affects >200 million people worldwide, including >50 million in Bangladesh. Arsenic exposure increases the risk of cancer and other chronic diseases, and one potential mechanism of arsenic toxicity is epigenetic dysregulation. OBJECTIVE: We assessed associations between arsenic exposure and genome-wide DNA methylation measured at baseline 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 similar to 850,000 CpGs using the Illumina IniiniumMethylationEPIC (EPIC) array. To assess associations between arsenic exposure and CpG methylation, we used linear regression models adjusted for covariates and surrogate variables (S Vs) (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent dataset of 450,000 CpGs from 400 Bangladeshi individuals with arsenical skin lesions. RESULTS: We identified 34 CpGs associated with log(2)-transformed creatinine-adjusted urinary arsenic [false discovery rate (UDR) < 0.05]. Sixteen of these CpGs annotated to the 450K array, and 10 associations were replicated (p < 0.05). The top two CpGs annotated upstream of the ABR gene (cg01912040, cg10003262). All urinary arsenic associated CpGs were also associated with arsenic concentration measured in drinking water (p < 0.05). Meta-analysis (n = 796 samples) identified 221 urinary arsenic associated CpGs (FDR <0.05). The arsenic-associated CpGs from the meta-analysis were enriched in non-CpG islands and shores (p = 7.9 x 10(-8)) and depleted in promoter regions (p = 1.1 x 10(-3)). Among the arsenic associated CpGs (FDR < 0.05), we observed significant enrichment of genes annotating to the reactive oxygen species pathway, inflammatory response, and tumor necrosis factor alpha. (TNF alpha.) signaling via nuclear factor kappa-B (NF kappa B) hallmarks (p <0.05). CONCLUSIONS: The novel and replicable associations between arsenic exposure and DNA methylation at specific CpGs observed in this work suggest that epigenetic alterations should be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations.