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Arsenic Mediates Cell Proliferation and Gene Expression in the Bladder Epithelium: Association with Activating Protein-1 Transactivation

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, NIH, Morgantown, West Virginia 26505 [P. P. S., S. W., W. T., V. K., J. M., D. H., M. D., V. V., M. I. L.]; Tanabe Seiyaku Company, Kawagishi, Toda 335, Japan [W. T.]; Department of Urology, West Virginia University Medical Center, Morgantown, West Virginia 26505 [N. U.]; and Tako Chuo Hospital, Katori-Gun, Chiba, Japan [F. K.]

Although the mechanism of action has not yet been defined, epidemiological studies have demonstrated an association between elevated arsenic levels in drinking water and the incidence of urinary bladder transitional cell carcinomas. In the current studies, we demonstrate that mice exposed to 0.01% sodium arsenite in drinking water develop hyperplasia of the bladder urothelium within 4 weeks of exposure. This was accompanied by the accumulation of inorganic trivalent arsenic, and to a lesser extent dimethylarsinic acid, in bladder tissue, as well as a persistent increase in DNA binding of the activating protein (AP)-1 transcription factor. AP-1 transactivation by arsenic also occurred in bladders of transgenic mice containing an AP-1 luciferase reporter. Consistent with these in vivo observations, arsenite increased cell proliferation and AP-1 DNA binding in a human bladder epithelial cell line. Gene expression studies using RNase protection assays, reverse transcription-PCR, and cDNA microarrays indicated that arsenite alters the expression of a number of genes associated with cell growth, such as c-fos, c-jun, and EGR-1, as well as cell arrest, such as GADD153 and GADD45. The proliferation-enhancing effect of arsenic on uroepithelial cells likely contributes to its ability to cause cancer.

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