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GENE EXPRESSION CHANGES IN MOUSE BLADDER TISSUE IN RESPONSE TO INORGANIC ARSENIC
Citation:
YAGER, J. W., E. M. KENYON, H. J. CLEWELL, R. THOMAS, M. F. HUGHES, AND E. A. CRECELIUS. GENE EXPRESSION CHANGES IN MOUSE BLADDER TISSUE IN RESPONSE TO INORGANIC ARSENIC. Presented at Environmental Mutagen Society Meeting, Vancouver, BC, CANADA, September 16 - 20, 2006.
Description:
Chronic human exposures to high arsenic concentrations are associated with lung, skin, and bladder cancer. Considerable controversy exists concerning arsenic mode of action and low dose extrapolation. This investigation was designed to identify dose-response changes in gene expression to support the development of a biologically-based dose-response model to assist in the evaluation of risk in the low dose region.
In this pilot study female C57Bl/6 mice were exposed to 0.00 mg/L (Control), 0.05 mg/L (Low) and 50 mg/L (High) arsenate in drinking water for 14 days. Urine, bladder and kidney tissues were analyzed for concentrations of iAs, MMA and DMA by ICPMS-hydride generation. Gene expression microarray measurements were performed on bladder tissue from four mice per dose using Affymetrix Mouse Genome 430 2.0 arrays. Bladder and kidney tissue arsenic concentrations in Control and Low groups were <0.01 µg/g to 0.02 µg/g. In the High group, mean bladder values were iAs 0.60, MMA 0.04, and DMA 0.97 µg/g. Mean kidney tissue values were iAs 0.22, MMA 3.12, and DMA 1.07 µg/g. Mean urine values:Control iAs 6.4 µg/L, Low 12.1 µg/L, High 3,410 µg/L; MMA: Control 0, Low 0, High 1,494 µg/L; DMA: Control 86.1, Low 139, High 46,400 µg/L. No significant gene expression changes were observed in the bladder tissue of Low dose mice as compared to the Control group. The High dose group showed significant up-regulation in genes related to DNA repair, cell cycle control, proteotoxicity, and apoptosis. Down-regulated genes were related to cell growth, adhesion, and differentiation. Discussion. Exposure at 0.05 mg/L arsenate showed no significant differences from control in urinary arsenic species, tissue concentrations, or bladder-related gene expression. However, following exposures of 50 mg/L, tissue concentrations were increased with MMA as the dominant species in kidney tissue and DMA in bladder and urine. In addition, a significant up-regulation in a variety of genes related to DNA repair, cell cycle control, proteotoxicity, and apoptosis was also observed. A follow up study is underway with multiple doses over a 12 week period in order to further characterize pharmacodynamic changes in the bladder as a function of dose and time. This abstract does not reflect US EPA policy.