The Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population.

ABSTRACT

BACKGROUND: Chronic arsenic (As) exposure is a global environmental health issue. Inorganic As (InAs) undergoes methylation to monomethyl (MMAs) and dimethyl-arsenical species (DMAs); full methylation to DMAs facilitates urinary excretion and is associated with reduced risk for As-related health outcomes. Nutritional factors, including folate and creatine, influence one-carbon metabolism, the biochemical pathway that provides methyl groups for As methylation. OBJECTIVE: Our aim was to investigate the effects of supplementation with folic acid (FA), creatine, or the two combined on the concentrations of As metabolites and the primary methylation index (PMI MMAs/InAs) and secondary methylation index (SMI DMAs/MMAs) in blood in Bangladeshi adults having a wide range of folate status. METHODS: In a randomized, double-blinded, placebo (PBO)-controlled trial, 622 participants were recruited independent of folate status and assigned to one of five treatment arms a) PBO (n=102), b) 400µg FA/d (400FA; n=153), c) 800µg FA/d (800FA; n=151), d) 3g creatine/d (creatine; n=101), or e) 3g creatine+400µg of FA/d (creatine+400FA; n=103) for 12 wk. For the following 12 wk, half of the FA participants were randomly switched to the PBO while the other half continued FA supplementation. All participants received As-removal water filters at baseline. Blood As (bAs) metabolites were measured at weeks 0, 1, 12, and 24. RESULTS: At baseline, 80.3% (n=489) of participants were folate sufficient (≥9 nmol/L in plasma). In all groups, bAs metabolite concentrations decreased, likely due to filter use; for example, in the PBO group, blood concentrations of MMAs (bMMAs) (geometric mean±geometric standard deviation) decreased from 3.55±1.89µg/L at baseline to 2.73±1.74 at week 1. After 1 wk, the mean within-person increase in SMI for the creatine+400FA group was greater than that of the PBO group (p=0.05). The mean percentage decrease in bMMAs between baseline and week 12 was greater for all treatment groups compared with the PBO group [400FA -10.4 (95% CI -11.9, -8.75), 800FA -9.54 (95% CI -11.1, -7.97), creatine -5.85 (95% CI -8.59, -3.03), creatine+400FA -8.44 (95% CI -9.95, -6.90), PBO -2.02 (95% CI -4.03, 0.04)], and the percentage increase in blood DMAs (bDMAs) concentrations for the FA-treated groups significantly exceeded that of PBO [400FA 12.8 (95% CI 10.5, 15.2), 800FA 11.3 (95% CI 8.95, 13.8), creatine+400FA 7.45 (95% CI 5.23, 9.71), PBO -0.15 (95% CI -2.85, 2.63)]. The mean decrease in PMI and increase in SMI in all FA groups significantly exceeded PBO (p<0.05). Data from week 24 showed evidence of a reversal of treatment effects on As metabolites from week 12 in those who switched from 800FA to PBO, with significant decreases in SMI [-9.0% (95% CI -3.5, -14.8)] and bDMAs [-5.9% (95% CI -1.8, -10.2)], whereas PMI and bMMAs concentrations continued to decline [-7.16% (95% CI -0.48, -14.3) and -3.1% (95% CI -0.1, -6.2), respectively] for those who remained on 800FA supplementation. CONCLUSIONS: FA supplementation lowered bMMAs and increased bDMAs in a sample of primarily folate-replete adults, whereas creatine supplementation lowered bMMAs. Evidence of the reversal of treatment effects on As metabolites following FA cessation suggests short-term benefits of supplementation and underscores the importance of long-term interventions, such as FA fortification. https//doi.org/10.1289/EHP11270.