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GENE EXPRESSION PROFILING OF RESPONSES TO DIMETHYLARSINIC ACID IN FEMALE F344 RAT UROTHELIUM
Citation:
SEN, B., A. WANG, S. D. HESTER, J. L. ROBERTSON, AND D. C. WOLF. GENE EXPRESSION PROFILING OF RESPONSES TO DIMETHYLARSINIC ACID IN FEMALE F344 RAT UROTHELIUM. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 215(3):214-226, (2005).
Impact/Purpose:
To better understand the altered mechanisms associated with bladder cancer
Description:
Arsenic is a human carcinogen and epidemiologic evidence implicates it in the development of urinary bladder cancer. Even though several mechanisms have been proposed for arsenic carcinogenicity, the mode of action of inorganic arsenic (iAs) is confounded by the limited availability of appropriate animal models. On the other hand, dimethylarsinic acid (DMA), the major excreted metabolite of iAs in humans, is a known rat bladder carcinogen. However, the carcinogenic mode of action for DMA has not been determined. To better understand the altered mechanisms associated with bladder cancer, ten week old female F344 rats were exposed to non-carcinogenic (1 and 4ppm) and carcinogenic (40 and 100ppm) doses of DMA in their drinking water for 4 weeks. The transitional epithelium of the treated and control rats was harvested for gene expression and morphological analysis. Microarray analysis revealed that DMA treatment modulated the expression of transcripts of genes that regulate apoptosis (Bad, Bax, Casp3), cell cycle, proliferation (Cdc25a, Cdkn2a, Gadd45�, Tgf�) and, the oxidative stress response (Txn2, Glrxl, Sodl, Gpxl). Expression of genes mapping to pathways involved in the cancer control process were also altered upon DMA exposure. Morphological data suggested a dose dependent increase in cellular toxicity. A definite trend is not observed when the expression level of the genes is examined across dose groups suggesting a complex interaction between dose, duration of exposure, and toxic response. Carcinogenic doses were differentiated from non-carcinogenic doses based on the expression of a subset of genes involved in cell signaling and the stress response (Txn1, Hspa5). Changes in gene expression patterns detected at the lower, non-carcinogenic doses, could serve as indicators of altered toxicity pathways that increase the cell's susceptibility to future insult, even though no overt toxic response is present at these lower doses. These reported changes in gene expression highlight the similarity between the mechanisms of carcinogenicity following DMA exposure in vivo and those previously described for iAs in vitro. Cytotoxicity in association with changes in signaling pathways involved in cell cycle control appear to be necessary for the development of a carcinogenic response to DMA in the rat bladder.