PROJECT SUMMARY/ABSTRACT Environmental arsenic exposure is associated with increased rates of pneumonia, bronchiectasis, and diabetes. The underlying biochemical pathways that link arsenic exposure to lung disease and diabetes are difficult to study, but the symptoms of arsenic toxicity overlap with those of cystic fibrosis, a rare autosomal recessive disease most common in people of Northern European ancestry. Accumulating evidence suggests that arsenic toxicity and cystic fibrosis share a common mechanism: dysfunction of the cystic fibrosis transmembrane regulator (CFTR). CFTR is a chloride channel that regulates intracellular fluid transport in the lungs, pancreas, and other organs. Studies in cell culture show that arsenic causes degradation of CFTR, and our recent epidemiological study demonstrates that humans exposed to arsenic also exhibit CFTR dysfunction. It is critical to understand these specific mechanisms in order to develop effective preventive and therapeutic interventions. In this proposal, we plan to study whether CFTR dysfunction in adults with high arsenic exposure contributes to diminished lung function and diabetes. We propose a comprehensive set of studies that leverage an established study population in rural Bangladesh, a country that is currently experiencing an epidemic of arsenic poisoning through contaminated drinking water. We hypothesize that arsenic influences diminished lung function and risk of diabetes by inducing CFTR dysfunction. We will use established biochemical techniques, including sweat test and Western Blot of peripheral blood mononuclear cells, to assess CFTR function. In this application, we present preliminary data that suggest that sweat chloride, a noninvasive measure that is easy to obtain, is elevated among individuals with high arsenic exposure. We will now test whether sweat chloride concentration can be used to identify individuals at higher risk for low respiratory function and diabetes related to arsenic exposure. Our analyses will employ causal mediation analysis to investigate whether diseases related to arsenic can be attributed to CFTR dysfunction. These studies explore mechanisms by which arsenic may increase risk of lung disease and diabetes in humans, and use a unique population of adults with high arsenic exposure in order to test hypotheses. Our long-range goals are to develop novel screening strategies to identify populations at high risk for lung disease and diabetes due to environmental exposure, and to direct the development of more effective preventive interventions.