Metabolic Signature of Arsenic Exposure and Metabolism: The Folic Acid and Creatine Trial

Arsenic exposure remains a leading public health concern. Folic acid (FA) supplementation enhances one-carbon metabolism (OCM), thus promoting arsenic methylation and facilitating urinary arsenic elimination. Here, we investigate the metabolic profiles linked to arsenic exposure and metabolism based on a FA clinical trial. Arsenic exposure was assessed by the concentrations of blood arsenic (bAs) species: arsenite [InAs^III], arsenate [InAs^V], monomethyl- [MMA], and dimethyl- [DMA] arsenicals. Arsenic metabolism was assessed by the relative distribution (%) of these arsenicals in urine. Nontargeted metabolomic profiling was analyzed by LC-HRMS. OCM-related metabolites were analyzed by HPLC/MS/MS. Metabolomic profiling identified 8 unique metabolites and 812 metabolomic features (FDR < 0.05) associated with bAs (predominantly As^V), and 66 metabolites and 285 metabolomic features with %uAs (predominantly %uInAs). Metabolic pathways enriched for bAs and %uAs were similar, highlighting phenylalanine, tyrosine, and tryptophan biosynthesis. A FA-induced %uInAs change was associated with four metabolites, three of which share links to acetyl-CoA metabolism. Of 11 measured OCM metabolites, cystathionine was positively associated with all bAs species. Methionine, S-adenosylmethionine, S-adenosylhomocysteine, cysteine, choline, betaine, and dimethylglycine were associated with increased As methylation profiles in urine (FDR < 0.05). Collectively, these findings may aid in the discovery of mechanisms underlying arsenic-induced health outcomes and potential targeted interventions. This trial was registered with clinicaltrials.gov: NCT01050556.