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GENE EXPRESSION DOSE-RESPONSE IN THE BLADDERS OF MICE EXPOSED TO ARSENIC IN DRINKING WATER FOR 13 WEEKS
Citation:
CLEWELL, H. J., R. S. THOMAS, P. R. GENTRY, E. M. KENYON, AND J. W. YAGER. GENE EXPRESSION DOSE-RESPONSE IN THE BLADDERS OF MICE EXPOSED TO ARSENIC IN DRINKING WATER FOR 13 WEEKS. Presented at 11th International Congress of Toxicology, Montreal, QC, CANADA, July 15 - 17, 2007.
Description:
The association between drinking water exposures to inorganic arsenic and life-threatening tumors in the human is strongest for bladder cancer. To investigate the mode of action for inorganic arsenic carcinogenicity in the bladder, a study was conducted to characterize the dose-response for genomic expression in bladder epithelial cells resulting from exposure of C53Bl/6J mice to arsenate in drinking water for up to 12 weeks at concentrations ranging from 0.05 to 50 mg As/L. Bladder and urine concentrations of all major arsenic species, including arsenite and the methylated metabolites, were also determined. Animals exposed at 0.05 mg/L arsenate showed no significant differences from controls in urinary arsenic species, tissue concentrations, or bladder gene expression. However, tissue concentrations were significantly increased at the higher exposures, with MMA as the dominant species in kidney tissue and DMA in bladder and urine. In addition, dose-dependent up-regulation of a variety of genes related to DNA repair, cell cycle control, proteotoxicity, and apoptosis was observed. The gene expression dose-response for inorganic arsenic is consistent with data on other proteotoxic chemicals, in that there appears to be a transition from an adaptive state at low concentrations to an impaired state at higher concentrations. In vitro studies with human bladder cells are planned to determine whether there is evidence of species differences in the gene expression dose-response. (This abstract does not necessarily reflect EPA policy).