Superfund Research Program

Nutritional Influences on Blood Arsenic, Arsenic Methylation and Cognitive Function in Children

Project Leader: Mary V. Gamble
Co-Investigators: Joseph H. Graziano, Ana Navas-Acien
Grant Number: P42ES010349
Funding Period: 2006-2021

Project-Specific Links

Final Progress Reports

Year:   2020  2016  2010 

Nutritional status may account for some of the considerable variability in progression from arsenic (As) exposure to manifestations of disease. Methylation of ingested inorganic As (InAs) to methylarsonic- (MMA) and dimethylarsinic acids (DMA) relies on folate-dependent one-carbon metabolism and facilitates urinary As elimination. Dr. Mary Gamble's SRP project builds upon her Nutritional Influences on As Toxicity (NIAT) studies, which demonstrated that folic acid supplementation increases As methylation and lowers blood As and blood MMA concentrations.

The first aim utilized the repository of biological samples to conduct a nested case-control study. Researchers tested the hypothesis that at the time of enrollment, participants who subsequently developed As-induced skin lesions (SLs) had lower folate and/or higher homocysteine as compared to non-skin lesion controls; they also analyzed genomic methylation of leukocyte DNA. The odds ratios (95 C.I.s) for subsequent development of SLs for participants who had low folate, high Hcys, or hypomethylated PBL-DNA were 1.6 (1.05 – 2.5; p = 0.005), 1.7 (1.1 - 2.6; p = 0.01), and 1.7 (1.1 – 2.7; p = 0.008), respectively, indicating that folate deficiency, hyperhomocysteinemia, and hypomethylation of genomic DNA are risk factors for As-induced skin lesions.

The research group also proposed to analyze biomarkers of oxidative stress. Analyses of urinary 8-oxo-2'-deoxyguanosine suggest that this biomarker is not associated with risk for skin lesions. Additional biomarkers were to include malondialdehyde (MDA) and protein carbonyls. However, the results from Aim 3 (a dose-response study of arsenic-induced oxidative stress) did not find arsenic exposure to be associated with increased MDA. The researchers therefore made an executive decision not to waste precious biological samples and funds to repeat the analysis of MDA for this aim.

For the second aim, the researchers proposed to examine the extent to which urinary As metabolites reflect As metabolites in blood in Bangladeshi adults. The Spearman correlations between As in blood and urine ranged from 0.68 to 0.81 (p < 0.0001 for all metabolites). However, when expressed as a percentage of total As, the correlations were less strong (0.32 – 0.44; p < 0.001). Most striking were the differences in MMA (13 in urine vs. 40 in blood) and DMA (72 in urine vs. 34 in blood), consistent with a short circulating half-life of DMA which is rapidly excreted in urine (Gamble et al., AJCN, 2007).

For the dose-response study of the third aim, 375 participants were enrolled, and biological samples have been analyzed for reduced and oxidized glutathione, reduced and oxidized cysteine, MDA and protein carbonyls. The analyses suggest that As exposure is associated with decreased concentrations of reduced glutathione (GSH) in whole blood and reduced concentrations of both reduced and oxidized cysteine in plasma, consistent with the hypothesis that As exposure is associated with depletion of glutathione. Since GSH is the body's primary antioxidant, this would be expected to be associated with increased oxidative stress. However, arsenic exposure is not significantly associated with other markers of oxidative stress including oxidized GSH, oxidized cysteine, plasma MDA or protein carbonyls. The final measure of oxidative stress currently being evaluated for this aim is urinary 8-oxodG.