{"doi":"10.1289/ehp11270","title":"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","journal":"Environmental Health Perspectives","year":2023,"id":342471,"datarank":0.5350647627878857,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.1288572326225542,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.1288572326225542,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":10,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT01050556"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":338908,"name":"Anne K. Bozack","orcid":"0000-0003-0046-5767","position":1,"is_corresponding":false},{"id":288772,"name":"Ana Navas‐Acién","orcid":"0000-0001-9824-7797","position":2,"is_corresponding":false},{"id":347736,"name":"Jeff Goldsmith","orcid":"0000-0002-6150-8997","position":3,"is_corresponding":false},{"id":302213,"name":"Xinhua Liu","orcid":"0000-0002-7797-6699","position":4,"is_corresponding":false},{"id":1079418,"name":"Megan N. Hall","orcid":null,"position":5,"is_corresponding":false},{"id":425438,"name":"Vesna Ilievski","orcid":null,"position":6,"is_corresponding":false},{"id":694502,"name":"Angela M. Lomax-Luu","orcid":null,"position":7,"is_corresponding":false},{"id":373570,"name":"Faruque Parvez","orcid":"0000-0002-5079-3825","position":8,"is_corresponding":false},{"id":693860,"name":"Hasan Shahriar","orcid":"0000-0002-1625-0229","position":9,"is_corresponding":false},{"id":693861,"name":"Mohammad Nasir Uddin","orcid":"0000-0003-0223-9763","position":10,"is_corresponding":false},{"id":373572,"name":"Tariqul Islam","orcid":"0000-0003-1623-5210","position":11,"is_corresponding":false},{"id":425143,"name":"Joseph H. Graziano","orcid":null,"position":12,"is_corresponding":false},{"id":606805,"name":"Mary V. Gamble","orcid":"0000-0003-4169-1162","position":13,"is_corresponding":false},{"id":693857,"name":"Ahlam Abuawad","orcid":"0000-0002-7241-4574","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:11:12.506815Z","pmid":"36976258","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}