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GENE EXPRESSION PROFILING OF MOUSE SKIN AND PAPILLOMAS FOLLOWING CHRONIC EXPOSURE TO MONOMETHYLARSONOUS ACID IN K6/ODC TRANSGENIC MICE
Citation:
DELKER, D. A., M. OUYANG, W. WELSH, B. ROOP, D. GETER, Y. CHEN, T. O'BRIEN, AND K. T. KITCHIN. GENE EXPRESSION PROFILING OF MOUSE SKIN AND PAPILLOMAS FOLLOWING CHRONIC EXPOSURE TO MONOMETHYLARSONOUS ACID IN K6/ODC TRANSGENIC MICE. Presented at Society of Toxicology's 45th Annual Meeting, San Diego, CA, March 05 - 09, 2006.
Description:
Methylarsonous acid [MMA(III)], a common metabolite of inorganic arsenic metabolism, increases tumor frequency in the skin of K6/ODC transgenic mice following a chronic exposure. To characterize gene expression profiles predictive of MMA(III) exposure and mode of action of carcinogenesis, K6/ODC mice were administered 0, 10, 50 or 100 ppm MMA(III) or 75 ppm sodium arsenite in their drinking water for 26 weeks. Skin and tumor gene expression changes were determined using Affymetrix Mouse Genome 430A 2.0 GeneChips® and MAS 5.0 normalization procedures. Differential gene expression was determined using principal component analysis, linear regression, and a regularized t-test (Bayesian procedure). Functional gene categorization was assessed using the Database for Annotation, Visualization and Integrated Discovery 2.0 (DAVID, Dennis and Hosack et al. 2003). Principal component analysis revealed three principal components accounting for greater than 75% of the variation in the data. Tissue (skin compared to papilloma) and treatment-related gene expression (MMA(III) compared to control or sodium arsenite) changes were observed. Linear regression analysis revealed changes in multiple cytoskeleton and cell cycle-related genes including enabled homolog (Enah) and the tumor suppressor gene p27 (Cdkn1b). The dose-dependent decrease in p27 mRNA we observed in mouse skin is consistent with the previously reported reduction in p27 protein observed in arsenical-induced urinary bladder lesions. Using a regularized t-test, significant changes were also observed in multiple oncogenes including changes in c-myc (Myc), fra-1(Fosl1 ), and v-maf (Mafb). Significant increases we observed in c-myc mRNA in mouse skin and papillomas are consistent with increases in c-myc during arsenic-induced mouse liver carcinogenesis. Since c-myc protein can bind the promoter of p27 and regulate its transcription, the molecular changes observed in our study are likely related and also important in MMA(III)-induced mouse skin carcinogenesis. Additional gene expression changes observed in chromosome maintenance and steroid metabolism genes may also contribute to the carcinogenesis process in mouse skin. [This abstract does not necessarily reflect EPA policy.]