Dose response evaluation of gene expression profiles in the skin of K6/ODC mice exposed to sodium arsenite.
Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, we characterized gene expression profiles from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin-labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips, and pathway analysis was conducted with DAVID (NIH), Ingenuity Systems and MetaCore's GeneGo. Differential expression of several key genes was verified through qPCR. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) 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, including several genes known to be associated with carcinogenesis or tumor progression including cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers.
Ahlborn
Gene J
GJ
United States Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Environmental Carcinogenesis Division, Research Triangle Park, NC 27711, USA.
Nelson
Gail M
GM
Ward
William O
WO
Knapp
Geremy
G
Allen
James W
JW
Ouyang
Ming
M
Roop
Barbara C
BC
Chen
Yan
Y
O'Brien
Thomas
T
Kitchin
Kirk T
KT
Delker
Don A
DA
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D051379:Mice; D008822:Mice, Transgenic; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D017670:Sodium Compounds / Q000633:toxicity*
D018053:Arsenites; C000715535:Dnmt3a protein, mouse; D017670:Sodium Compounds; C017947:sodium arsenite; D000090205:DNA Methyltransferase 3A