Oncogene expression profiles in K6/ODC mouse skin and papillomas following a chronic exposure to monomethylarsonous acid

• Published in: Journal of biochemical and molecular toxicology 2009-11, Vol.23 (6), p.406-418
• Main Authors: Delker, Don A., Geter, David R., Roop, Barbara C., Ward, William O., Ahlborn, Gene J., Allen, James W., Nelson, Gail M., Ouyang, Ming, Welsh, William, Chen, Yan, O'Brien, Thomas, Kitchin, Kirk T.
• Format: Article
• Language: English
• Subjects: Animals; Arsenic; Basic-Leucine Zipper Transcription Factors - genetics; Bayes Theorem; Cell Cycle Proteins - genetics; DNA-Binding Proteins - genetics; Dose-Response Relationship, Drug; Female; Gene Expression; Gene Expression Profiling; HSP90 Heat-Shock Proteins - genetics; K6/ODC Mouse; Keratin-6 - physiology; Linear Models; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monomethylarsonous Acid; Oncogenes; Organometallic Compounds - toxicity; Ornithine Decarboxylase - physiology; p38 Mitogen-Activated Protein Kinases - physiology; Papilloma - chemically induced; Papilloma - genetics; Principal Component Analysis; Skin; Skin - metabolism; Skin Neoplasms - chemically induced; Skin Neoplasms - genetics; Squamous Papillomas
• ISSN: 1095-6670; 1099-0461; 1099-0461
• DOI: 10.1002/jbt.20304

We have previously observed that a chronic drinking water exposure to monomethylarsonous acid [MMA(III)], a cellular metabolite of inorganic arsenic, increases tumor frequency in the skin of keratin VI/ornithine decarboxylase (K6/ODC) transgenic mice. To characterize gene expression profiles predictive of MMA(III) exposure and mode of action of carcinogenesis, skin and papilloma RNA was isolated from K6/ODC mice administered 0, 10, 50, and 100 ppm MMA(III) in their drinking water for 26 weeks. Following RNA processing, the resulting cRNA samples were hybridized to Affymetrix Mouse Genome 430A 2.0 GeneChips®. Micoarray data were normalized using MAS 5.0 software, and statistically significant genes were determined using a regularized t‐test. Significant changes in bZIP transcription factors, MAP kinase signaling, chromatin remodeling, and lipid metabolism gene transcripts were observed following MMA(III) exposure as determined using the Database for Annotation, Visualization and Integrated Discovery 2.1 (DAVID) (Dennis et al., Genome Biol 2003;4(5):P3). MMA(III) also caused dose‐dependent changes in multiple Rho guanine nucleotide triphosphatase (GTPase) and cell cycle related genes as determined by linear regression analyses. Observed increases in transcript abundance of Fosl1, Myc, and Rac1 oncogenes in mouse skin support previous reports on the inducibility of these oncogenes in response to arsenic and support the relevance of these genomic changes in skin tumor induction in the K6/ODC mouse model. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:406–418, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20304