Genomic Methylation of Peripheral Blood Leukocyte DNA: influences of Arsenic and Folate in Bangladeshi Adults

J Richard Pilsner, Xinhua Liu, Habibul Ahsan, Vesna Ilievski, Vesna Slavkovich, Diane Levy, Pam Factor-Litvak, Joseph H Graziano, and Mary V Gamble

Abstract

Background: Studies in cell culture and animal models indicate that arsenic exposure induces modifications in DNA methylation, in- cluding 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 chron- ically 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 mea- sured by using a [3H]-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 methyl- ation of PBL DNA were restricted to persons with folate concentra- tions < 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 methyl-ation are unclear, and they warrant further study.

Key Words: DNA methylation, epigenetics, folate, folic acid, folate deficiency, one-carbon metabolism, S-adenosyl- methionine, SAM, arsenic, arsenicosis, Bangladesh, well water