A Dose-response Study of Arsenic Exposure, Folate, and Genomic Methylation of Peripheral Blood Mononuclear Cell DNA in Bangladesh

Abstract

S-29B7-3 Background/Aims: Chronic arsenic exposure is associated with increased risk for cancers of the skin, lung, liver, and bladder; however, the mechanism(s) underlying arsenic-induced carcinogenesis are poorly understood. Animal and in vitro data suggest that chronic arsenic exposure induces genomic hypomethylation of DNA. In contrast, our previous study in adults chronically exposed to arsenic-contaminated drinking water in Bangladesh suggested that arsenic exposure is associated with increased genomic methylation of total leukocyte DNA, and that this association is contingent on adequate folate. Methods: We undertook a cross-sectional study specifically designed to evaluate the dose-response relationship between arsenic exposure and genomic methylation of peripheral blood mononuclear cell DNA. We recruited 375 participants between 30 and 65 years of age, including 75 for each of 5 categories of water arsenic: 0–50, 51–100, 101–200, 201–300, and >300 μg/L. Genomic DNA methylation was measured using the [3]-methyl incorporation assay; results of this assay are inversely related to DNA methylation. Results: Water arsenic was associated with increased DNA methylation, and this association was influenced by folate nutritional status (Spearman correlations −0.24, P = 0.007, and −0.08, P = 0.2 for folate-sufficient and folate-deficient respectively). Mean DPM values (in thousands) by increasing categories of water As for folate-sufficient participants were 172, 169, 154, 145, and 139, P for trend = 0.001; a statistically significant (P = 0.02) but weaker trend was observed for folate-deficient participants. The results were unchanged after further adjustment for age and other covariates. Conclusion: Arsenic exposure is associated with dose-dependent increases in peripheral blood mononuclear cell DNA methylation, and this association is somewhat stronger among folate sufficient participants. Differences between experimental studies and our work may be related to the dose and duration of arsenic exposure. The implications of increases in genomic DNA methylation are unclear; we propose this may be an adaptive response to an upstream event. Additional studies are underway to identify potential mechanisms underlying these observations.