# Project 2: Arsenic- Obesity- Diabetes Interactions

> **NIH NIH P42** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $324,944

## Abstract

ABSTRACT: PROJECT 2
Inorganic arsenic (iAs) is a ubiquitous, naturally-occurring environmental toxicant that affects over 200 million
people worldwide. Chronic exposure to iAs is associated with numerous human diseases, including type 2
diabetes (T2D). Results of epidemiological studies suggest that efficiency of iAs metabolism, which depends in
part on polymorphisms in iAs-methyltransferase (AS3MT) and on other genetic factors, affects the risk of T2D
risk in iAs-exposed populations. Obesity, the number 1 risk factor for T2D, has also been shown to modify iAs
metabolism and a recent study found that obese individuals are at higher risk of developing T2D when exposed
to iAs. In addition, our preliminary studies show that obesity exacerbates T2D phenotype in iAs-exposed mice in
a sex-dependent manner, and that the responses to the diabetogenic effects iAs exposure differ between
genetically diverse mouse strains. Project 2 addresses a fundamental gap in understanding the interaction
between iAs exposure, iAs metabolism, genetics, obesity and sex in the context of type T2D etiology. Our goal
is to determine the relative contributions of these five critical factors to T2D risk, using genetically diverse male
and female mice with different capacities to metabolize iAs. We hypothesize that there is an interaction
between iAs exposure, iAs metabolism and obesity that increases the risk of T2D, and that the outcome
depends on genetic background and sex. We plan to use a unique mouse population, the Collaborative Cross,
to test our hypothesis. Four key findings underlie our hypothesis: (1) Polymorphisms in AS3MT are linked to both
the differences in the capacity to metabolize (methylate) iAs and to T2D risk in populations exposed to iAs; (2)
methylated metabolites of iAs are more potent than iAs as inhibitors of beta cell function and insulin signaling in
laboratory models; (3) obesity affects iAs metabolism and increases T2D risk in humans, and exacerbates
diabetic phenotype in mice exposed to iAs; finally (4) genetics, which is known to influence metabolic health in
obese individuals, has also been shown to affect susceptibility to the diabetogenic effects of iAs exposure in both
mice and humans. This project is led by a strong team (Drs. Pardo-Manuel de Villena, Styblo, Fry and Zou) with
complimentary expertise in genetics, molecular biology, iAs toxicology and metabolism, iAs-induced T2D and
statistics. We use the unique Collaborative Cross population, state of the art techniques and carefully controlled
experimental design to characterize the interaction between iAs exposure, iAs metabolism and obesity that
increases the risk of T2D, and will establish the influence of genetic background and sex. The project is aligned
with the theme of the UNC-SRP “Identifying novel methods to reduce iAs exposure and elucidating mechanisms
underlying iAs-induced metabolic dysfunction with a vision for disease prevention.” New mechanistic
understanding of the role o...

## Key facts

- **NIH application ID:** 10112264
- **Project number:** 5P42ES031007-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Fernando Pardo-Manuel de Villena
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $324,944
- **Award type:** 5
- **Project period:** 2020-02-20 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112264

## Citation

> US National Institutes of Health, RePORTER application 10112264, Project 2: Arsenic- Obesity- Diabetes Interactions (5P42ES031007-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112264. Licensed CC0.

---

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