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

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) 400 mu g FA/d (400FA; n = 153), c) 800 mu g FA/d (800FA; n = 151), d) 3 g creatine/d (creatine; n = 101), or e) 3 g creatine + 400 mu g of FA/d (creatine + 400FA; n = 103) for 12 wk. For the following 12 wk, half of the FA participants were ran-domly 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 +/- 1.89 mu g/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) con-centrations 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 signifi-cantly 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 supple-mentation 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