# Diabetogenic Mine Tailings: Mechanistic Link Between Arsenic, NRF2, Autophagy, and Diabetes

> **NIH NIH P42** · UNIVERSITY OF ARIZONA · 2024 · $269,633

## Abstract

SUMMARY (Project 1: Donna Zhang)
Contamination of soil and water by metal-containing hazardous substances, particularly at sites near mine
tailings and smelters, has led to chronic exposure of nearby communities to toxic metal mixtures, posing a
serious health problem. Based on data from the Agency for Toxic Substances Disease Registry, the number
one contaminant associated with mine tailings at these sites is the toxic metalloid arsenic (As). Epidemiological
studies have demonstrated a positive correlation between chronic As exposure, either through drinking water
or food, with an increased incidence of diabetes. Thus, exposure to As-containing mine tailings, which could
result in inhalation or ingestion of As, may be a significant contributor to enhanced risk of disease in exposed
communities. Importantly, despite the known severity of the health effects, the molecular mechanisms by which
As-containing mine tailings enhance diabetic phenotypes have not yet been elucidated. Previously, we
reported that low, environmentally relevant doses of arsenic block autophagy, a key cellular degradation
pathway critical to maintaining proteostasis. Furthermore, we have shown that autophagic dysfunction results
in prolonged activation of the key antioxidant transcription factor NRF2. Normally maintained at low levels
through KEAP1-mediated ubiquitination and degradation by the 26S proteasome, NRF2 is upregulated at the
protein level via oxidative modification of KEAP1 (KEAP1-C151 dependent, canonical) or sequestration of
Keap1 into autophagosomes during As-induced autophagy dysfunction (p62-dependent, non-canonical). While
controlled Nrf2 activation through the Keap1-C151 dependent canonical mechanism is protective, prolonged
p62-dependent non-canonical activation of NRF2 during As exposure causes cellular dysfunction and tissue
damage, indicative of a “dark side” to NRF2. We hypothesize that As-containing mine tailings promote
diabetes through p62-dependent, prolonged activation of Nrf2. This hypothesis is supported by our
preliminary data indicating that wild type (WT) mice exposed to As showed impaired glucose tolerance and
enhanced insulin resistance, which was not observed in Nrf2-/-, p62-/-, or Nrf2-/-p62-/- mice. Our recent RNAseq
data generated from the liver of mice exposed to As for 20 weeks also showed significant changes in the
expression of genes involved in glucose, insulin, cholesterol, and lipid metabolism. In this application, we will
test our hypothesis by: 1) characterizing the time and dose-dependent diabetogenic potential of chronic
exposure to As in drinking water or mine tailing As-particles (PM10) in WT mice (Aim 1); 2) determining the
role of prolonged NRF2 activation in driving As-induced metabolic reprogramming in diabetes-relevant cell
lines (Aim 2); and 3) in vivo confirmation of important molecular alterations induced by As and prolonged NRF2
activity in promoting diabetes (Aim 3). A mechanistic understanding of arsenic-mediated...

## Key facts

- **NIH application ID:** 10764231
- **Project number:** 5P42ES004940-35
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Donna D Zhang
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $269,633
- **Award type:** 5
- **Project period:** 1997-04-01 → 2025-07-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764231

## Citation

> US National Institutes of Health, RePORTER application 10764231, Diabetogenic Mine Tailings: Mechanistic Link Between Arsenic, NRF2, Autophagy, and Diabetes (5P42ES004940-35). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10764231. Licensed CC0.

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