(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 alterations that lead to diabetes will prove extremely valuable in the generation of diagnostic, preventive, and therapeutic strategies for populations exposed to As-containing mine tailings and populations at risk of arsenic exposure.

Public Health Relevance

(Project 1: Donna Zhang) Millions of people are chronically exposed to arsenic, increasing their risk of developing metabolic diseases such as diabetes. Currently, the molecular mechanisms by which arsenic promotes diabetes are not known. Our goal for this project is to investigate the molecular mechanisms by which arsenic alters cellular responses and to achieve a mechanistic understanding of the arsenic-mediated pathophysiologic alterations that lead to diabetes, enabling the generation of diagnostic, preventive, and therapeutic strategies for populations exposed to As-containing mine tailings and at risk of arsenic exposure.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
United States
Zip Code
Zeng, Chao; Nguyen, Chi; Boitano, Scott et al. (2018) Cerium dioxide (CeO2) nanoparticles decrease arsenite (As(III)) cytotoxicity to 16HBE14o- human bronchial epithelial cells. Environ Res 164:452-458
Zeb, Bahadar; Alam, Khan; Sorooshian, Armin et al. (2018) On the Morphology and Composition of Particulate Matter in an Urban Environment. Aerosol Air Qual Res 18:1431-1447
Khan, Muhammad Amjad; Ding, Xiaodong; Khan, Sardar et al. (2018) The influence of various organic amendments on the bioavailability and plant uptake of cadmium present in mine-degraded soil. Sci Total Environ 636:810-817
Yellowhair, Monica; Romanotto, Michelle R; Stearns, Diane M et al. (2018) Uranyl acetate induced DNA single strand breaks and AP sites in Chinese hamster ovary cells. Toxicol Appl Pharmacol 349:29-38
Fu, Xiaori; Dionysiou, Dionysios D; Brusseau, Mark L et al. (2018) Enhanced effect of EDDS and hydroxylamine on Fe(II)-catalyzed SPC system for trichloroethylene degradation. Environ Sci Pollut Res Int 25:15733-15742
Duncan, Candice M; Brusseau, Mark L (2018) An assessment of correlations between chlorinated VOC concentrations in tree tissue and groundwater for phytoscreening applications. Sci Total Environ 616-617:875-880
Virgone, K M; Ramirez-Andreotta, M; Mainhagu, J et al. (2018) Effective integrated frameworks for assessing mining sustainability. Environ Geochem Health 40:2635-2655
Namdari, Soodabeh; Karimi, Neamat; Sorooshian, Armin et al. (2018) Impacts of climate and synoptic fluctuations on dust storm activity over the Middle East. Atmos Environ (1994) 173:265-276
Hossein Mardi, Ali; Khaghani, Ali; MacDonald, Alexander B et al. (2018) The Lake Urmia environmental disaster in Iran: A look at aerosol pollution. Sci Total Environ 633:42-49
Dehghani, Mansooreh; Fazlzadeh, Mehdi; Sorooshian, Armin et al. (2018) Characteristics and health effects of BTEX in a hot spot for urban pollution. Ecotoxicol Environ Saf 155:133-143

Showing the most recent 10 out of 497 publications