Superfund Research Program

Arsenic and Innate Immunity in Human Lung

Project Leader: Bruce A. Stanton
Grant Number: P42ES007373
Funding Period: 2005-2021

Project-Specific Links

Final Progress Reports

Year:   2020  2013  2007 

The long-term objective of this research is to elucidate how arsenic affects xenobiotic bioavailability, and increases the incidence of atherosclerotic disease and diabetes mellitus, as well as several types of drug resistant cancers. In the third year of funding, studies focused on elucidating the effects of low, environmentally relevant levels of arsenic on the expression and function of the cystic fibrosis transmembrane conductance regulator (CFTR) in killifish, a model organism. CFTR is a cAMP-activated Cl channel that plays an important role in fluid and salt balance. Mutations in the CFTR gene are responsible for the human disease, cystic fibrosis, as well as male infertility, pancreatitis and chronic sinusitis. Killifish are a model organism that is utilized extensively to study the homeostatic mechanisms regulating salt balance and the effects of environmental toxicants on cellular function. Killifish can acclimate to dramatic changes in the salinity of the water by increasing the expression of CFTR Cl channels in the gills, a process that is mediated by cortisol activation of the glucorticoid receptor (GR), which stimulates CFTR gene expression. Arsenic, the number one environmental toxicant of concern both worldwide and in the U.S. (according to the World Health Organization), is a potent endocrine disrupter, altering hormone-activated gene transcription mediated by GR; however, little is known about the effects of arsenic in intact organisms. Accordingly, studies were conducted to determine if environmentally relevant levels of arsenic block the ability of killifish to adapt to increased salinity by disrupting cortisol activation of the glucorticoid receptor (GR), which stimulates CFTR gene expression.

In the third year of funding, several novel observations were reported in peer-reviewed publications. Notably: (1) chronic exposure to arsenic in the water (48 hrs) blocked the ability of killifish to adapt to seawater by a post translational mechanism involving the ubiquitin/lysosomal mediated degradation of CFTR; (2) arsenic did not disrupt cortisol activation of the glucorticoid receptor (GR) and stimulation of CFTR gene expression; (3) arsenic  promotes ubiquitin/lysosomal mediated degradation of CFTR by inhibiting the gene expression of SGK1, a serum and glucocorticoid induced protein kinase; and (4) arsenic induces the up regulation of MRP2 expression and function in the kidney by a post-translational mechanism. Taken together, these data suggest that environmentally relevant levels of arsenic reduce the ability of killifish to adapt to increased salinity in part by acutely inhibiting CFTR mediated Cl section by down regulating CFTR protein expression by a post-translational mechanism involving SGK1 and the ubiquitin/lysosomal pathway.  These studies are novel because they examine the effects of environmentally relevant levels of arsenic on the ability of fish to adapt to a physiological stress (i.e., increased salinity of seawater), and elucidates the effects of arsenic in a living organism under physiological conditions.