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Concentration-and time-dependent genomic changes in the mouse urinary bladder following exposure to arsenate in drinking water for up to twelve weeks
Citation:
Clewell, H. J., R. S. Thomas, E. M. KENYON, M. F. HUGHES, B. ADAIR, P. R. Gentry, AND J. W. Yager. Concentration-and time-dependent genomic changes in the mouse urinary bladder following exposure to arsenate in drinking water for up to twelve weeks. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 123(2):421-32, (2011).
Impact/Purpose:
The purpose of this study was to attempt to provide in vivo confirmation of in vitro genomic changes by examining the genomic dose-response in the urinary bladder of mice exposed to arsenate in drinking water over a period of up to 12 weeks. This work is final publication for this project and supports mode of action based dose-response assessment for inorganic arsenic
Description:
Inorganic arsenic (AsD is a known human bladder carcinogen. The objective of this study was to examine the concentration dependence of the genomic response to ASi in the urinary bladders of mice. C57BL/6J mice were exposed for 1 or 12 weeks to arsenate in drinking water at concentrations of 0.5, 2, 10, and 50 mg As/L. Urinary bladders were analyzed using gene expression microarrays. A consistent reversal was observed in the direction of gene expression change: from predominantly decreased expression at 1 week to predominantly increased expression at 12 weeks. These results are consistent with evidence from in vitro studies of an acute adaptive response that is suppressed on longer exposure due to down-regulation of Fos. Pathways with the highest enrichment in gene expression changes were associated with epithelial-to-mesenchymal transition, inflammation, and proliferation. Benchmark dose (BMD) analysis determined that the lowest median BMD values for pathways were above 5 mg As/L, despite the fact that significant pathway enrichment was observed at the 0.5 mg As/L exposure concentration. This disparity may in result from a non-monotonic dose-response for gene expression changes, with a much fewer gene expression changes at 2 mg As/L than at lower or higher concentrations. Pathway categories with concentration-related gene expression changes included cellular morphogenesis, inflammation, apoptosis/survival, cell cycle control, and DNA damage response. The results of this study provide evidence of a concentration-dependent transition in the mode of action for the subchronic effects of ASi in mouse bladder cells in the vicinity of 2 mg As/L.
