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MEETING AT CAMBRIDGE, MA: GENE EXPRESSION IN NORMAL HUMAN KERATINOCYTES MODULATED BY TRIVALENT ARSENICALS
Citation:
BAILEY, K., R. D. OWEN, AND S. Y. THAI. MEETING AT CAMBRIDGE, MA: GENE EXPRESSION IN NORMAL HUMAN KERATINOCYTES MODULATED BY TRIVALENT ARSENICALS. Presented at Gene Expression Profiling to Validated Biology, Cambridge, MA, October 04 - 07, 2005.
Description:
Arsenic exposure has been correlated with the development of several human cancers including those found in the skin, lung, liver, kidney and urinary bladder. Humans are generally exposed to inorganic forms of arsenic, which may be inhaled or ingested. Arsenic forms mono- and di-methylated metabolites in vivo. Both inorganic and methylated arsenicals are excreted in urine. Two of these methylated trivalent species, monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII) have been shown in cell systems to be more cytotoxic and genotoxic than trivalent/pentavalent inorganic arsenic and pentavalent methylated forms. The roles arsenite, MMAIII and DMAIII may play in arsenic carcinogenesis are unknown. We chose normal human epidermal keratinocytes (NHEKs) as a model system to study the contributions of individual trivalent arsenicals to the mode of action of arsenic carcinogenesis. NHEKs are a good model for such studies as 1) trivalent arsenicals are readily absorbed but not metabolized to more methylated intermediates in these cells and 2) skin cells are a major target cell of arsenic carcinogenesis in vivo. The global gene expression profiles of NHEKs exposed for 24 h to non-cytotoxic concentrations of inorganic arsenic (sodium arsenite), MMAIII and DMAIII were studied using Affymetrix® GeneChip Human U133 Plus 2.0 arrays and Genespring® v.7.2 software. For each arsenical, significantly effected genes were modulated in a dose-dependent manner. Many of these altered genes were classified as stress response genes or involved in cell signaling and growth. In arsenitetreated cells, upregulated phase II response genes involved in detoxification were the dominant feature, which were not upregulated to the same extent by exposure to MMAIII or DMAIII. Each of the three arsenicals had a distinct expression profile, including some genes that may serve as biomarkers of exposure. Future studies include determining which signaling pathways are involved in trivalent arsenical-mediated changes in gene expression.