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

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