Arsenic (As) is an inorganic environmental contaminant of major concern in the desert Southwest due to its ubiquitous presence and its occurrence in drinking waters due to wells penetrating arsenic layers in the earth along with standards under consideration. Chronic exposure to arsenic frequently results in skin, lung, bladder, and kidney cancer. The hypothesis of this proposal is that inorganic arsenicals regulate specific genes and therefore specific proteins, and it target tissues are being studied to demonstrate the uniformity or specificity of the signaling and gene responses to arsenic exposure. These investigations will only utilize low level arsenic exposures to more closely mimic to the concentrations observed from environmental exposures and to better reflect the current proposal of lowering the drinking water standard from its current 50 ppb level. To address our hypothesis , we propose 4 independent and non- overlapping specific aims. 1.) Identify proteins that associate with a serine/threonine kinase involved in arsenic signaling. 2.) Characterize the activity of proteins that are regulated by arsenic and correlate protein activity with cellular toxicity. Once a specific protein involved in arsenic signal transduction is identified, we need to determine how arsenic affects the activity of that protein and whether the activity of that protein correlates with cytotoxicity. 3) Identify specific genes whose expression pattern changes after low level exposure to inorganic arsenic. We have already shown that nanomolar levels of arsenate and arsenite increase the binding of specific transcription factors and induce gene expression in renal tissue. Acute, repeated, and chronic exposures of arsenic will be investigated and differential expression of specific genes is predicted. 4) Examine the expression of key genes induced by inorganic arsenic exposure and correlate gene expression with cellular injury. Specific gene expression by the chemical species of arsenic will be correlated with the subsequent response of the target cells to the toxicant. If there is any production of proteins or other biochemical markers that are the result of the specific genes induced, these genes and proteins may potentially serve as early indicators of biomarkers for low-level exposure of this tissue to arsenic. The study of these two tissues will provide a further understanding of the importance of the arsenic-induced signaling processes and gene expression that are responsible for tissue injury.
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