Genornic methylation of peripheral blood leukocyte DNA: influences of arsenic and folate in Bangladeshi adults

Background: Studies in cell culture and animal models indicate that arsenic exposure induces modifications in DNA methylation, including genome-wide DNA hypomethylation. It is not known whether arsenic exposure influences genomic DNA methylation in human populations chronically exposed to arsenic-contaminated drinking water. Objective: The objective of this study was to determine whether arsenic is associated with genomic hypomethylation of peripheral blood leukocyte (PBL) DNA in Bangladeshi adults who are chronically exposed to arsenic. We also investigated whether arsenic-induced alterations in DNA methylation may be influenced by folate nutritional status. Design: PBL DNA methylation and concentrations of plasma folate, plasma arsenic, and urinary arsenic were assessed in 294 adults in Araihazar, Bangladesh. Genomic PBL DNA methylation was measured by using a [H-3]-methyl incorporation assay. Results: Urinary arsenic, plasma arsenic, and plasma folate were positively associated with the methylation of PBL DNA (P = 0.009, 0.03, and 0.03, respectively). Stratification of participants by folate nutritional status [<9 nmol/L (n = 190) or :9 nmol/L (n = 104)] showed that the associations between arsenic exposure and methylation of PBL DNA were restricted to persons with folate concentrations >= 9 nmol/L. Conclusions: Contrary to our a priori hypothesis, arsenic exposure was positively associated with genomic PBL DNA methylation in a dose-dependent manner. This effect is modified by folate, which suggests that arsenic-induced increases in DNA methylation cannot occur in the absence of adequate folate. The underlying mechanisms and physiologic implications of increased genomic DNA methylation are unclear, and they warrant further study.