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EXPRESSON OF AS3MT ALTERS TRANSCRIPTIONAL PROFILES IN HUMAN UROTHELIAL CELLS EXPOSED TO ARSENITE
Citation:
HESTER, S. D., Z. DROBNA, D. DUCHARME, M. WAALKES, D. J. THOMAS, AND M. STYBLO. EXPRESSON OF AS3MT ALTERS TRANSCRIPTIONAL PROFILES IN HUMAN UROTHELIAL CELLS EXPOSED TO ARSENITE . Presented at Society of Toxicology Annual Meeting, San Diego, CA, March 05 - 09, 2006.
Description:
Inorganic arsenic (iAs) is an environmental toxin and human carcinogen. The enzymatic methylation of iAs that is catalyzed by As (3+ oxidation state)-methyltransferase (AS3MT) generates reactive methyl-As intermediates that may contribute to the toxic or carcinogenic effects of iAs. We have previously shown that clonal human urothelial cells (UROtsa/F35) that express rat AS3MT and methylate iAs are more susceptible to acute toxicity of iAs than parental UROtsa cells that do not express AS3MT and do not methylate iAs. The current work examines genomic changes associated with AS3MT expression and identifies specific categories of genes expressed in UROtsa and UROtsa/F35 cells in response to a 24-h exposure to 1 M or 50 M iAs. Here, the expression of 21073 genes was assessed using Agilent Human 1A(v2) arrays. ArrayTrack and Ingenuity software analyses showed exposure to 1 M iAs altered expression of 572 genes in UROtsa/F35 cells as compared to 686 in UROtsa cells. Exposure to 50 M iAs altered 1578 and 2873 genes in UROtsa/F35 and UROtsa cells, respectively. Pathway mapping at 1 M iAs exposure showed similar responses in both UROtsa and UROtsa/F35 cells; genes involved in cell cycle, maintenance, and growth were altered. However, only UROsa/F35 cells showed altered profiles for genes regulating cell death and DNA repair, which may suggest an enhanced susceptibility to iAs. At 50 M, signaling and metabolic pathways were altered in both cell lines. However, changes in UROtsa cells indicated enhanced cell cycling with increases in proliferation and cell death whereas, changes in UROtsa/F35 were consistent with repression in cell proliferation and cell survival. These data suggest that AS3MT expression modifies the genomic responses to iAs exposure in UROtsa cells. Further analysis of these responses will help to characterize the role of AS3MT-catalyzed methylation in modulation of iAs toxicity. (This abstract does not reflect U.S. EPA policy.)