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
[InAsIII], arsenate [InAsV], 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 AsV), 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