Fate of arsenicals in mice carrying the human AS3MT gene exposed to environmentally relevant levels of arsenite in drinking water

Abstract

Although mice are widely used to study adverse effects of inorganic arsenic (iAs), higher rates of iAs methylation in mice than in humans may limit their utility as a model organism. A recently created 129S6 mouse strain in which the Borcs7/As3mt locus replaces the human BORCS7/AS3MT locus exhibits a human-like pattern of iAs metabolism. Here, we evaluate dosage dependency of iAs metabolism in humanized (Hs) mice. We determined tissue and urinary concentrations and proportions of iAs, methylarsenic (MAs), and dimethylarsenic (DMAs) in male and female Hs and wild-type (WT) mice that received 25- or 400-ppb iAs in drinking water. At both exposure levels, Hs mice excrete less total arsenic (tAs) in urine and retain more tAs in tissues than WT mice. Tissue tAs levels are higher in Hs females than in Hs males, particularly after exposure to 400-ppb iAs. Tissue and urinary fractions of tAs present as iAs and MAs are significantly greater in Hs mice than in WT mice. Notably, tissue tAs dosimetry in Hs mice resembles human tissue dosimetry predicted by a physiologically based pharmacokinetic model. These data provide additional support for use of Hs mice in laboratory studies examining effects of iAs exposure in target tissues or cells.

Effects of Early Life Oral Arsenic Exposure on Intestinal Tract Development and Lipid Homeostasis in Neonatal Mice: Implications for NAFLD Development

“…In addition, mice are known to have a significantly higher tolerance for detoxifying iAs than humans owing to the high activity of arsenite methyltransferase (AS3MT), which catalyzes arsenic methylation. 88 , 89 Therefore, the use of doses up to for long-term iAs treatments have been reported in experimental mouse studies. 90 – 93 Taking all of the above factors into consideration, together with a correction factor ( K M ) of 12.3 based on body surface area, 94 a single dose of BW iAs via oral gavage was applied in this study.…”

Atomic spectrometry update: review of advances in elemental speciation

“…The applicability of the developed method was demonstrated by determining As in 13 homeopathic products available on the Polish market. The fate of arsenicals in mice carrying the human AS3MT gene exposed to environmentally relevant levels of As III in drinking water has been reported by Douillet et al 74 Although mice are widely used to study adverse effects of iAs, the higher rates of iAs methylation in mice when compared to humans may limit their utility as a model organism. A recently created 129S6 mouse strain in which the Borcs7/As3mt locus replaces the human BORCS7/AS3MT locus and exhibits a human-like pattern of iAs metabolism was used in this study.…”

Invited Perspective: Humanized Mice for Arsenic Metabolism—A Better Model for Investigating Arsenic-Induced Diseases?

“…The AS3MT humanized mouse model, which was developed by researchers at the University of North Carolina at Chapel Hill, 16 is a big step toward equalizing arsenic distribution, metabolism, and excretion between mice and humans and may be a great advance toward resolving mouse-to-human comparisons. However, there may still be species- and strain-specific differences in cellular arsenic transport mechanisms.…”