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DOSE-RESPONSE STUDIES OF SODIUM ARSENITE IN THE SKIN OF K6/ODC TRANSGENIC MOUSE
Citation:
AHLBORN, G., G. M. NELSON, W. O. WARD, G. W. KNAPP, J. W. ALLEN, M. OUYANG, B. ROOP, Y. CHEN, T. O'BRIEN, K. T. KITCHIN, AND D. A. DELKER. DOSE-RESPONSE STUDIES OF SODIUM ARSENITE IN THE SKIN OF K6/ODC TRANSGENIC MOUSE. Presented at American Association for Cancer Research, Los Angeles, CA, April 14 - 18, 2007.
Description:
It has previously been observed that chronic exposure to inorganic arsenic and/or its metabolites increase(s) tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, gene expression profiles were characterized from analysis of mouse skin RNA taken from K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Skin gene expression was measured with Affymetrix Mouse Genome 430A 2.0 GeneChips® and statistical analysis included GC-RMA normalization followed by a Bayesian regularized t-test. Pathway analysis was conducted with DAVID (NIH) and MetaCore GeneGo. Only the highest dose (10 ppm) resulted in significantly altered KEGG pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol, and insulin signaling pathways. Approximately 20 genes exhibited a dose response, some known to be associated with carcinogenesis or tumor progression including Cyclin Dl, CLIC4, Ephrin Al, Hmoxl, and STAT3. Although transcription changes in all these genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other animal models suggests that these genes may play a role in the early stages of arsenic-induced carcinogenesis. Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy.