Oncogene expression profiles in K6/ODC mouse skin and papillomas following a chronic exposure to monomethylarsonous acid.
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(R). 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.
Delker
Don A
DA
National Health and Environmental Effects Research Laboratory, Office of Research and Development Environmental Carcinogenesis Division, United States Environmental Protection Agency, Research Triangle Park, NC 27711, USA. don.delker@hsc.utah.edu
Geter
David R
DR
Roop
Barbara C
BC
Ward
William O
WO
Ahlborn
Gene J
GJ
Allen
James W
JW
Nelson
Gail M
GM
Ouyang
Ming
M
Welsh
William
W
Chen
Yan
Y
O'Brien
Thomas
T
Kitchin
Kirk T
KT
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D001499:Bayes Theorem; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics; D053553:Keratin-6 / Q000502:physiology*; D016014:Linear Models; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009857:Oncogenes; D009942:Organometallic Compounds / Q000633:toxicity*; D009955:Ornithine Decarboxylase / Q000502:physiology*; D010212:Papilloma / Q000139:chemically induced* / Q000235:genetics; D025341:Principal Component Analysis; D012867:Skin / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D050976:Basic-Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; C107835:Hspca protein, mouse; D053553:Keratin-6; D009942:Organometallic Compounds; C498645:Ris2 protein, mouse; C406082:monomethylarsonous acid; D048051:p38 Mitogen-Activated Protein Kinases; D009955:Ornithine Decarboxylase