A dose-response study of arsenic exposure and markers of oxidative damage in Bangladesh.

OBJECTIVE: To evaluate the dose-response relationship between arsenic (As) exposure and markers of oxidative damage in Bangladeshi adults. METHODS: We recruited 378 participants drinking water from wells assigned to five water As exposure categories; the distribution of subjects was as follows: (1) less than 10 µg/L (n=76); (2) 10 to 100 µg/L (n=104); (3) 101 to 200 µg/L (n=86); (4) 201 to 300 µg/L (n=67); and (5) more than 300 µg/L (n=45). Arsenic concentrations were measured in well water, as well as in urine and blood. Urinary 8-oxo-2'-deoxyguanosine and plasma protein carbonyls were measured to assess oxidative damage. RESULTS: None of our measures of As exposure were significantly associated with protein carbonyl or 8-oxo-2'-deoxyguanosine levels. CONCLUSIONS: We found no evidence to support a significant relationship between long-term exposure to As-contaminated drinking water and biomarkers of oxidative damage among Bangladeshi adults.

A dose-response study of arsenic exposure and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults.

BACKGROUND: Several studies employing cell culture and animal models have suggested that arsenic (As) exposure induces global DNA hypomethylation. However, As has been associated with global DNA hypermethylation in human study populations. We hypothesized that this discrepancy may reflect a nonlinear 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 [3H]-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, 49.0) and 22.1-unit (95% CI: 0.5, 43.8) decreases in DPM per microgram 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.

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults.

Oxidative stress and DNA methylation are metabolically linked through the relationship between one-carbon metabolism and the transsulfuration pathway, but possible modulating effects of oxidative stress on DNA methylation have not been extensively studied in humans. Enzymes involved in DNA methylation, including DNA methyltransferases and histone deacetylases, may show altered activity under oxidized cellular conditions. Additionally, in vitro studies suggest that glutathione (GSH) depletion leads to global DNA hypomethylation, possibly through the depletion of S-adenosylmethionine (SAM). We tested the hypothesis that a more oxidized blood GSH redox status is associated with decreased global peripheral blood mononuclear cell (PBMC) DNA methylation in a sample of Bangladeshi adults. Global PBMC DNA methylation and whole blood GSH, glutathione disulfide (GSSG), and SAM concentrations were measured in 320 adults. DNA methylation was measured by using the [ (3)H]-methyl incorporation assay; values are inversely related to global DNA methylation. Whole blood GSH redox status (Eh) was calculated using the Nernst equation. We found that a more oxidized blood GSH Eh was associated with decreased global DNA methylation (B ± SE, 271 ± 103, p = 0.009). Blood SAM and blood GSH were associated with global DNA methylation, but these relationships did not achieve statistical significance. Our findings support the hypothesis that a more oxidized blood GSH redox status is associated with decreased global methylation of PBMC DNA. Furthermore, blood SAM does not appear to mediate this association. Future research should explore mechanisms through which cellular redox might influence global DNA methylation.