# Humanized mouse models for arsenic toxicology

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $418,152

## Abstract

PROJECT SUMMARY
Contamination of drinking water and foods with inorganic arsenic (iAs) represents a major public health risk in
the U.S. and worldwide. Exposure to iAs has been linked to cancer, diabetes, cardiovascular, respiratory and
neurological diseases.
Humans and most other mammalian species have developed mechanism for detoxification of iAs, which involves
a two-step conversion of iAs to methyl-As (MAs) and dimethyl-As (DMAs) and excretion of the methylated
metabolites in urine. In mammals, iAs methylation is catalyzed by orthologs of a single enzyme, arsenic
methyltransferase (AS3MT). An impaired capacity to methylate iAs, e.g., due to AS3MT polymorphism, has
been linked to increased risk of diseases associated with iAs exposure.
Mechanisms underlying the adverse effects of iAs exposure have been extensively studied using laboratory
models. However, laboratory research has been hindered by substantial differences between laboratory animals
and humans in their capacity to metabolize iAs. In particular, laboratory mice have been shown to methylate
and detoxify iAs much more efficiently than humans, making it difficult to reproduce in mice some of the adverse
phenotypes reported in population studies, specifically cancer and diabetes. The ultimate goal of the proposed
research is to develop novel mouse models, in which iAs metabolism resembles that in humans and in which
iAs-associated diseases can be studied at environmentally relevant iAs exposure levels.
We have recently generated a new mouse strain in which the Borcs7/As3mt locus was humanized by syntenic
replacement. AS3MT expression in tissues of the humanized (Hs/Hs) mice resembles that in human tissues
and differs from expression of mouse As3mt: AS3MT expression is lower in livers and much higher in adrenals.
Notably, the different pattern of AS3MT expression in tissues of Hs/Hs mice is associated with low efficiency of
iAs detoxification and with the profiles for iAs and its methylated metabolites in tissues and excreta that are
consistent with those reported in humans.
The goals of this project are: (1) To characterize susceptibility of Hs/Hs mice to adverse effects of iAs exposure,
focusing on the diabetogenic effects, (2) to generate a new mouse strain expressing AS3MT haplotype that has
been linked to impaired iAs methylation and risk of iAs-induced diseases in human cohorts, and (3) to explore
association between AS3MT expression in adrenals and adrenal function.
The proposed research will generate and validate unique mouse models for iAs toxicology. These models will
make it possible to study adverse effects of iAs at environmentally relevant exposure levels and in context with
human-like metabolism of iAs and AS3MT polymorphism. Using these models will markedly improve
translatability and impact of laboratory studies focusing on iAs induced diseases.

## Key facts

- **NIH application ID:** 10470377
- **Project number:** 5R01ES032643-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Beverly H Koller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,152
- **Award type:** 5
- **Project period:** 2021-08-17 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470377

## Citation

> US National Institutes of Health, RePORTER application 10470377, Humanized mouse models for arsenic toxicology (5R01ES032643-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10470377. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*