NRF2 Mediated Arsenic Protection

Project Leader(s): 

Chronic exposure to metal-containing dusts in sites near mine tailings and smelters is both an occupational and public health problem that has been associated with increased risk of lung disease development. Based on data from the Agency for Toxic Substances Disease Registry (ATSDR), the number one contaminant at these sites is the toxic metalloid arsenic (As). However, the precise molecular mechanisms by which As affects lung function have not yet been fully elucidated, despite many years of research and the known severity of the health effects associated with its exposure. One of the main cellular defense responses against As exposure is orchestrated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Nrf2 is normally bound and degraded in the cytosol by Kelch-like ECH-associated protein 1 (Keap1) and is upregulated at the protein level by chemopreventive compounds (canonical, Keap1-C151 dependent) or during autophagy dysfunction (non-canonical). While controlled, intermittent Nrf2 activation through the canonical mechanism is protective, prolonged non-canonical activation causes cellular dysfunction and tissue damage, indicative of a “dark side” of Nrf2 that could contribute to As toxicity.

Specific Aims: 

Aim 1: Determine the molecular mechanisms of airway epithelial dysfunction and Nrf2 induction (canonical vs non-canonical) in response to dust/As dust in vitro. Determine if dust/As dust induce Nrf2 through the canonical mechanism (Keap1-C151-dependent, resulting in intermittent Nrf2 induction) or the noncanonical mechanism (Keap1-C151-independent but autophagy- and p62-dependent, resulting in prolonged Nrf2 induction).  These cells will be tested for Nrf2 induction and airway epithelial dysfunction (barrier function and EMT) by dust/As dust.

Aim 2: Examine the efficacy of prophylactic canonical Nrf2 activation by dietary SF supplementation in maintaining airway epithelial barrier integrity and ameliorating lung damage in mice exposed to inhaled dust/As dust. Nrf2+/+ and Nrf2-/- mice will be fed a peanut butter pellet (control) or a peanut butter pellet supplemented with SF daily, and repetitively exposed to dust/As dust. Structure and biomarkers of barrier function in lung airway epithelia will be compared.