Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh

Background: Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethylarsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. Objective: This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. Design: In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 mu g per day), 3 g creatine per day, 400 mu g FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo. Results: Among groups receiving FA, the mean decrease in ln(% InAs) and % MMAs and increase in % DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in % MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in % InAs or % DMAs. The decrease in % MMAs at wk 6 and 12 was larger in the 800 mu g FA than in the 400 mu g FA group (P = 0.034). There were no differences in treatment effects between the 400 mu g FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(% InAs) and % DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation. Conclusions: The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.