Low-level exposure (1-50 ppb) arsenic causes a multitude of toxic effects. The new drinking water standard for arsenic (10 ppb) is based on the occurrence of bladder cancer. The mechanism(s) by which arsenic produces bladder cancer are unknown. Additionally the toxic effects of low-level arsenic exposure to produce bladder injury have not been adequately examined. Our studies will examine mechanisms of low-level arsenic exposure to bladder tissue. An immortalized human epithelial cell line (UTOtsa) will be the primary model system. In preliminary studies UROtsa cells were shown to be capable of biotransforming inorganic arsenic to more toxic methylated metabolites and low-level (1-50 ppb) arsenic chemical species were cytotoxic to the cells.
Our Aims are to: 1.) Determine the role of biotransformation of arsenic in bladder to produce sub-cytotoxic effects. The biotransformation of inorganic arsenic will be manipulated to determine which arsenic metabolite is the ultimate toxicant. 2.) Determine if the low-level arsenic exposure to the bladder is producing toxicity via proteotoxic mechanisms. This study will examine if arsenic species produce toxic effects via direct interaction with critical sulfhydryl targets. 3.) Determine if the low-level arsenic exposure to the bladder produces toxicity via an oxidative stress mechanism. The production of reactive oxygen species and the ensuing toxic effects will be profiled for various arsenic chemical species, 4.) Determine if the low-level arsenic exposure to the bladder is affecting the ubiquitin pathway and its toxic consequences. Arsenic has been shown to alter the processing of proteins in a cell. Our studies show low-level arsenic to cause and an accumulation of ubiquinated proteins. Our studies will characterize this accumulation, identify if specific proteins are accumulated, and determine the impact of these accumulated proteins on cell viability. 5.) Determine if biomarkers of arsenic toxicity to the bladder result from the preceding studies. Bladder samples from surgical patients will be used for in vitro toxicity studies with arsenic to determine if we see similar effects to those seen with the cells and if the potential biomarkers are present (ubiquinated proteins). Overall, these studies will clarify the toxic effects of low-level arsenic in a human bladder model and provide potential biomarkers for arsenic-induced bladder injury.
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