Folate and Cobalamin Modify Associations between S-adenosylmethionine and Methylated Arsenic Metabolites in Arsenic-Exposed Bangladeshi Adults

Abstract

Chronic exposure to inorganic arsenic (InAs) through drinking water is a major problem worldwide. InAs undergoes hepatic methylation to form mono- and dimethyl arsenical species (MMA and DMA, respectively), facilitating arsenic elimination. Both reactions are catalyzed by arsenic (+3 oxidation state) methyltransferase (AS3MT) using S-adenosylmethionine (SAM) as the methyl donor, yielding the methylated product and S-adenosylhomocysteine (SAH), a potent product-inhibitor of AS3MT. SAM biosynthesis depends on folate- and cobalamin-dependent one-carbon metabolism. With the use of samples from 353 participants in the Folate and Oxidative Stress Study, our objective was to test the hypotheses that blood SAM and SAH concentrations are associated with arsenic methylation and that these associations differ by folate and cobalamin nutritional status. Blood SAM and SAH were measured by HPLC. Arsenic metabolites in blood and urine were measured by HPLC coupled to dynamic reaction cell inductively coupled plasma MS. In linear regression analyses, SAH was not associated with any of the arsenic metabolites. However, log(SAM) was negatively associated with log(% urinary InAs) (β: -0.11; 95% CI: -0.19, -0.02; P = 0.01), and folate and cobalamin nutritional status significantly modified associations between SAM and percentage of blood MMA (%bMMA) and percentage of blood DMA (%bDMA) (P = 0.02 and P = 0.01, respectively). In folate- and cobalamin-deficient individuals, log(SAM) was positively associated with %bMMA (β: 6.96; 95% CI: 1.86, 12.05; P < 0.01) and negatively associated with %bDMA (β: -6.19; 95% CI: -12.71, 0.32; P = 0.06). These findings suggest that when exposure to InAs is high, and methyl groups are limiting, SAM is used primarily for MMA synthesis rather than for DMA synthesis, contributing additional evidence that nutritional status may explain some of the interindividual differences in arsenic metabolism and, consequently, susceptibility to arsenic toxicity.

Determinants and Consequences of Arsenic Metabolism Efficiency among 4,794 Individuals: Demographics, Lifestyle, Genetics, and Toxicity

“…This lack of association with PC2 was not evident when examining the association of water arsenic with PMI, iAs%, or MMA% (presumably because these phenotypes are correlated with DMA% and PC1). Previous studies suggest that the second methylation step is inhibited at increased exposure levels (particularly elevated levels of iAs III and MMA III ) both in the experimental setting (63,64) and in human observational studies (65), consistent with the associations observed in this study.…”

Low-level arsenic exposure: Nutritional and dietary predictors in first-grade Uruguayan children

“…Arsenic is methylated in the body by methyltransferases, including As methyltransferase (AS3MT), with SAM as main methyl donor (Marafante 1984). Folate plays an important role in one-carbon metabolism by recruiting methyl groups and is associated with individual variation in arsenic methylation capacity (Howe, Niedzwiecki et al 2014). Although we did not measure folate status, low dietary folate intake (<300 and 200 µg/d) was observed in 15% and 4% of the study children, respectively, suggesting that deficiency is not prevalent.…”

Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment

“…As noted previously (Section 3.2.1), methylation of iAs requires the conversion of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (Howe et al, 2014), which eventually becomes homocysteine (Gamble et al, 2005;States et al, 2009;Zakharyan and Aposhian, 1999). Efficient metabolism of homocysteine requires adequate intake of vitamin B6, B12 and folic acid; thus, considering the findings of Chen et al (2007a), iAs may exert its effect on CVD through the formation of homocysteine, particularly in individuals with insufficient levels of folate and B vitamins .…”