Paul Victor

Graduate Student, PhD


Donna Zhang, PhD


Pharmacology and Toxicology


Increasing evidences substantiate the role of contamination of soil and water by metal-containing hazardous substances, particularly at sites near mining has led to chronic exposure toxic metal mixtures which is a major burden worldwide. Epidemiological studies have demonstrated a positive correlation between chronic arsenic (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 expose communities.

Arsenic has been shown to upregulate Nrf2, the master regulator of cellular stress response. 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(canonical), NRF2 is upregulated at the protein level via oxidative modification of KEAP1 or sequestration of Keap1 into autophagosomes during As-induced autophagy dysfunction (non-canonical). While controlled Nrf2 activation through the Keap1-C151 dependent canonical mechanism is protective, whereas prolonged activation due to heavy metal exposure is deleterious to cellular mechanism and eventually leads to cellular and metabolic dysfunction and tissue damage.

Here we investigate the As-containing mine tailing may promote onset and progression of As induced prolonged activation of Nrf2 may leads to diabetes and its associated complications. This study will lead to how As mediated Nrf2 activations and causing diabetes and its associated complications both in-vitro and in-vivo model systems may provide a novel mechanistic approach towards heavy metal exposure triggers complex metabolic diseases.