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<sup>III</sup>], arsenate [InAs<sup>V</sup>], 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<sup>V</sup>), 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.
Authors
- Faruque Parvez (ORCID: https://orcid.org/0000-0002-5079-3825)
- Mary V. Gamble (ORCID: https://orcid.org/0000-0003-4169-1162)
- Olgica Balac
- Irene Martinez‐Morata (ORCID: https://orcid.org/0000-0003-3165-4931)
- Mohammad Nasir Uddin (ORCID: https://orcid.org/0000-0003-0223-9763)
- Abu Bakkar Siddique (ORCID: https://orcid.org/0000-0002-1484-0823)
- Teodoro Bottiglieri (ORCID: https://orcid.org/0000-0002-4199-7551)
- Vesna Ilievski
- Wending Li (ORCID: https://orcid.org/0000-0001-5405-8708)
- Ronald A. Glabonjat (ORCID: https://orcid.org/0000-0003-3104-1940)
- Douglas I. Walker (ORCID: https://orcid.org/0000-0003-2912-398X)
- Megan M. Niedzwiecki (ORCID: https://orcid.org/0000-0001-6647-141X)
- Brandon L. Pierce (ORCID: https://orcid.org/0000-0002-7829-952X)
- Brismar Pinto‐Pacheco (ORCID: https://orcid.org/0000-0002-0111-5825)
- Haotian Wu (ORCID: https://orcid.org/0000-0002-6271-0249)
- Tariqul Islam (ORCID: https://orcid.org/0000-0003-1623-5210)
- Vesna Slavkovich (ORCID: https://orcid.org/0000-0002-5155-2847)
- Xiangping Lin (ORCID: https://orcid.org/0000-0001-6045-4459)
- Ana Navas-Acien (ORCID: https://orcid.org/0000-0001-9824-7797)
- Jeff Goldsmith
- Joseph H. Graziano
- Marianthi-Anna Kioumourtzoglou
- Gabriela L. Jackson
Institutions
- Emory University (US)
- Chicago Department of Public Health (US)
- University of Dhaka (BD)
- University of Chicago (US)
- Netherlands Metabolomics Centre (NL)
- Baylor Medical Center at Garland (US)
- Comprehensive Blood & Cancer Center (US)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
- Baylor Scott & White Health (US)
- U-M Rogel Cancer Center (US)
- Columbia University (US)
- Stanford University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Environmental Science & Technology
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1021/acs.est.5c01597
- Citations
- 1
- Primary Topic
- Arsenic contamination and mitigation
- Type
- article
- Field-Weighted Citation Impact
- 0.86
Funders
- National Institutes of Health