Metabolism of inorganic arsenic in mice carrying the human AS3MT gene and fed folate deficient or folate supplemented diet

Madison Miller; Christelle Douillet; Peter H Cable; Sergey A Krupenko; Bingzhen Shang; Hadley J Hartwell; Fei Zou; Beverly H Koller; Rebecca C Fry; Fernando Pardo-Manuel de Villena; Miroslav Stýblo

doi:10.1016/j.taap.2024.117173

Metabolism of inorganic arsenic in mice carrying the human AS3MT gene and fed folate deficient or folate supplemented diet

Toxicol Appl Pharmacol. 2024 Nov 25:117173. doi: 10.1016/j.taap.2024.117173. Online ahead of print.

Affiliations

¹ Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA.
² Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; The UNC Nutrition Research Institute, Kannapolis, NC 28081, USA.
³ Department of Environmental Sciences and Engineering, CB#7431, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431, USA.
⁴ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7420, USA.
⁵ Department of Genetics, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7264, USA.
⁶ Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA. Electronic address: stylo@med.unc.edu.

PMID: 39603428
DOI: 10.1016/j.taap.2024.117173

Abstract

Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes the S-adenosylmethionine (SAM)-dependent methylation of inorganic arsenic (iAs), yielding monomethyl‑arsenic (MAs) and dimethyl‑arsenic (DMAs) metabolites. The formation of DMAs in this pathway is considered a key mechanism for iAs detoxification. Availability of SAM for iAs methylation depends in part on dietary intake of folate. Results of population studies suggest that supplementation with folate stimulates iAs methylation, increasing DMAs and decreasing iAs and MAs proportions in urine and/or blood. The goal of the present study was to determine if folate intake affects methylation and clearance of iAs in a recently established mouse strain that expresses human AS3MT and exhibits a human-like pattern of iAs metabolism. The humanized male and female mice were fed folate-deficient (FD) or folate-supplemented (FS) diet for 6 weeks, followed by exposure to 0 ppb or 400 ppb iAs in drinking water for 5 weeks, while on the same types of diet. The concentrations and proportions of iAs, MAs and DMAs were determined in urine, liver, kidneys, and spleen. The diet-, sex- and dose-related differences were assessed by t-test or a non-parametric test; Bonferroni test was used to correct for multiple comparisons. In general, proportions of DMAs were greater and proportions of iAs were smaller in urine and tissues of FS mice as compared to FD mice. However, folate supplementation also increased MAs proportions. Notably, the folate intake had no effect on the concentrations of total arsenic either in the urine or the tissues. These results suggest that, similar to humans, folate supplementation stimulates iAs methylation in the humanized mice. However, the stimulation of iAs methylation is not associated with clearance of arsenic from tissues, possibly due to an inefficient conversion of MAs to DMAs.

Keywords: AS3MT; Arsenic methylation efficiency; Dietary folate intake; Humanized mice.