BACKGROUND: Several studies employing cell culture and animal models suggest that arsenic (As) exposure induces global DNA hypomethylation. However, As has been associated with global DNA hypermethylation in human study populations. It has been hypothesized that this discrepancy may reflect a non-linear relationship between As dose and DNA methylation.
OBJECTIVE: The objective of this study was to examine the dose-response relationship between As and global methylation of peripheral blood mononuclear cell (PBMC) DNA in apparently healthy Bangladeshi adults chronically exposed to a wide range of As concentrations in drinking water.
METHODS: Global PBMC DNA methylation, plasma folate, blood S-adenosylmethionine (SAM), and concentrations of As in drinking water, blood, and urine were measured in 320 adults. DNA methylation was measured using the [(3)H]-methyl incorporation assay, which provides disintegration per minute (DPM) values that are negatively associated with global DNA methylation.
RESULTS: Water, blood, and urinary As were positively correlated with global PBMC DNA methylation (P < 0.05). In multivariable adjusted models, 1-µg/L increases in water and urinary As were associated with 27.6 unit (95% CI, 6.3 to 49.0) and 22.1 unit (95% CI, 0.5 to 43.8) decreases in DPM per µg DNA, respectively. Categorical models indicated that estimated mean levels of PBMC DNA methylation were highest in participants with the highest As exposures.
CONCLUSIONS: These results suggest that As is positively associated with global methylation of PBMC DNA over a wide range of drinking water As concentrations. Further research is necessary to elucidate underlying mechanisms and physiologic implications.