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GENE EXPRESSION CAN DIFFERENTIATE CARCINOGENIC FROM NON-CARCINOGENIC DOSES OF DIMETHYLARSINIC ACID (DMAv) IN THE TRANSITIONAL EPITHELIUM OF THE URINARY BLADDER FROM FEMALE F344 RATS
Citation:
Sen, B., A. Wang, S D. Hester, J. L. Robertson, AND D C. Wolf. GENE EXPRESSION CAN DIFFERENTIATE CARCINOGENIC FROM NON-CARCINOGENIC DOSES OF DIMETHYLARSINIC ACID (DMAv) IN THE TRANSITIONAL EPITHELIUM OF THE URINARY BLADDER FROM FEMALE F344 RATS. Presented at Society of Toxicologic Pathology, Salt Lake City, Utah, June 13-17, 2004.
Description:
Arsenic is an environmental concern worldwide, and drinking arsenic contaminated water has been associated with increased incidences of skin, lung and bladder cancer. Dimethylarsinic acid (DMAv) is a major metabolite of inorganic arsenic in rodents and humans and is the predominant form detected in the urine. Cytotoxicity and increased cell proliferation are associated with a dose dependent increase in tumors that arise from the cells that line the urinary bladder following chronic exposure to DMAv in the diet or drinking water in F344 rats. Since these arsenic-induced neoplasms arise from the transitional epithelium of the urinary bladder, gene expression profiling of this target cell population was performed to understand the molecular events associated with arsenic-induced carcinogenicity following exposure to DMAv. Female 344 rats were exposed to 1, 4, 40 or 100 ppm DMAv in their drinking water for 4 weeks, RNA extracted from the transitional epithelium and labeled with Cy3 and Cy5 and hybridized to a rat oligonucleotide microarray (4,300 genes). Hybridizations were performed four times using independent total RNA preparations from four different animals in each dose group to ensure reproducibility. Differentially expressed genes were identified based on a 2 fold cut off up or down and statistical (present in all samples, 1 way ANOVA, p<0.01) significance. A companion set of rats were similarly exposed and the bladders were processed for routine light and transmission electron microscopic analysis. Ultrastructural changes were present after treatment with 40 and 100 ppm and were characterized by cellular hypertrophy, increased numbers of cytoplasmic vacuoles, and decreased numbers of mitochondria. Analysis of the gene expression data resulted in a total of 481 altered genes, among them 336 transcripts were induced and 145 were suppressed. Altered expression of genes that control apoptosis (Bad, Bax Pdcd2), cell proliferation (Btg1, Nc1, Vegf), cell cycle regulation (Tgf?, Igf2, Gadd45a), metabolism (Cyp2c, Cyp2e and oncogenesis (Rap7a, Rabac1, Rab7) were observed after exposure to DMAV at any dose. Changes in oxidative stress response genes (Txn, Txn2, Glrxl, Gpxl, Sodl) were induced, consistent with the reported role of reactive oxygen species in DMAv induced toxicity of the rat bladder. Based on a greater than three fold expression in low dose (1 and 4ppm) and high dose (40 and 100ppm) groups compared to control animals, two sets of genes were identified that allow the differentiation between carcinogenic and non-carcinogenic doses of DMAv. These data suggest that together with changes in expression of genes in the cancer control pathways, cellular toxicity which is present at the higher carcinogenic doses is also necessary to drive the DMAv induced cancer process.
(This is an abstract of a proposed presentation and does not necessarily reflect EPA policy).