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THE URINARY BLADDER EXHIBITS A U-SHAPED GENOMIC DOSE-RESPONSE FOLLOWING SHORT- AND LONG-TERM EXPOSURE OF MICE TO ARSENATE IN DRINKING WATER
Citation:
CLEWELL, H. J., R. S. Thomas, E. M. KENYON, M. F. HUGHES, AND J. W. Yager. THE URINARY BLADDER EXHIBITS A U-SHAPED GENOMIC DOSE-RESPONSE FOLLOWING SHORT- AND LONG-TERM EXPOSURE OF MICE TO ARSENATE IN DRINKING WATER. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
This work was undertaken to investigate the nature of interactions of arsenic with key proteins and genes in the cell regulatory network. Urinary bladders from mice exposed subchronically to arsenic in drinking water at concentrations ranging from 0.5 to 50 mg/L were analyzed using whole genome arrays.
Description:
A number of studies have demonstrated increased urinary bladder tumor incidence in populations exposed to inorganic arsenic in drinking water at concentrations on the order of several hundred micrograms per liter, but experimental animal studies at much higher concentrations have been equivocal. Previous studies have indicated that the interactions of arsenic with key proteins and genes in the cell regulatory network change dramatically between low (sub-micromolar) and high concentrations. In order to investigate the nature of these differences more comprehensively, urinary bladders from mice exposed to inorganic arsenic in drinking water at concentrations ranging from 0.5 to 50 mg/L were analyzed using whole-genome arrays. After 5 days of exposure, the number of genes with statistically significant changes in expression from controls were 15, 0, 302, and 341 at 0.5, 2, 10, and 50 mg/L, respectively. After 12 weeks of exposure, the number of altered genes were 419, 18, 843, and 1822. There was less than 10% overlap in the genes changed at 0.5 mg/L with those changed at 10 or 50 mg/L at either time-point. There was also less than 5% overlap in the genes changed after short- and long-term exposure. At 12 weeks, gene changes at the low concentration were primarily associated with extracellular matrix, cytoskeleton, and morphogenesis, while the high concentration gene changes were associated with such processes as metal binding, regulation of transcription, RNA processing, and dephosphorylation. Benchmark analysis of the dose-response by gene ontology category was also performed. The lowest benchmark doses for single genes were on the order of 0.7 mg/L, while the lowest benchmark doses for gene categories were 10.7 mg/L at 1 week (for anti-apoptosis) and 4.0 ml/L at 12 weeks (for negative regulation of cell proliferation). In vitro studies with mouse and human mouse and human urothelial cells are now in progress to support a parallelogram approach for predicting the in vivo genomic dose-response in the human.