Arsenic (III) and chromium (VI) are considered human lung carcinogens, and arsenic is also associated with increased risk of skin, bladder and kidney cancer. The overall goal of the proposed research is to determine the mechanism by which these toxic metals act as human carcinogens. The specific goal of the project is to determine the mechanistic basis for the preferential effects of these carcinogenic metals on inducible gene expression. Our previous studies have demonstrated that arsenic and chromium have strong preferential effects on the expression of several model inducible that arsenic and chromium have strong preferential effects on the expression of whereas most other genes are refractory to these treatments. These gene-specific effects appear to be mediated, at least in part, by the ability of these metals to modulate specific transcription factors and cell signaling pathways that regulate the expression of these targeted genes. In particular, we observed profound effects of arsenic and chromium on the function of the glucocorticoid receptor, leading to alterations in glucocorticoid receptor-dependent gene expression. These results suggest that arsenic and chromium, and perhaps other toxic metals, may represent a new class of """"""""endocrine disrupters"""""""" that are capable of altering cell phenotype through direct interactions with steroid receptors. The specific objectives of this research are to determine the molecular basis for these effects, genetic and biochemical approaches to investigate these effects in model cell systems.
Our specific aims will be to: 1) determine the mechanism by which arsenic (III) and chromium (VI) specifically alter glucocorticoid receptor function and receptor- mediated gene expression as well as other steroid receptors; 2) determine whether other trans acting transcription factors and/or their cis acting DNA regulatory elements contribute to mediating the specific effects of arsenic (III) and chromium (VI) on inducible gene expression; and 3) determine the sub set of eukaryotic genes whose expression is specifically altered by low dose arsenic (III) or chromium (VI) exposures. We hypothesize that these selective gene effects may contribute to the carcinogenic process by altering cell phenotype in a tissue-specific manner. Some of these interactions, such as alterations in steroid receptor function, may also lead to more global organ and systemic effects of these metals. This may also result in synergy with other metal effects, such as the ability of chromium (VI) to directly cause DNA damage and mutations.
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