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Dimethylarsinic acid in drinking water changed the morphology but not the expression of DNA repair genes of bladder transitional epithelium in F344 rats
Wang, A., D. C. WOLF, B. SEN, G. W. KNAPP, S. D. Holladay, W. R. Huckle, T. Caceci, AND J. L. Robertson. Dimethylarsinic acid in drinking water changed the morphology but not the expression of DNA repair genes of bladder transitional epithelium in F344 rats. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, 37(4):425-437, (2009).
Arsenic is a human carcinogen, and arsenic in drinking water is a global health concern. In F344 rats, DMA(V) acts as both a complete carcinogen and a co-carcinogen in the urinary bladder. While arsenic-induced DNA repair has been observed in other tissues and cell lines, arsenic effects on the DNA repair in the bladder had not been studied. If arsenic inhibits DNA repair in the urinary bladder, this could, at least partially, explain the arsenic carcinogenesis and co-carcinogenesis in the bladder.
Inorganic arsenic increases urinary bladder transitional cell carcinoma in humans. In laboratory animals, it is dimethylarsinic acid [DMA(V)], a major arsenic metabolite in the urine of inorganic arsenic-exposed people, that increases transitional cell carcinoma, namely in F344 rats. A potentially important critical effect necessary for arsenic carcinogenesis is inhibition of DNA damage repair, which can increase the chance of DNA errors and contribute to carcinogenesis or cocarcinogenesis. Arsenic-induced inhibition of DNA repair has been observed in various cultured cell lines, in mice, and in the lymphocytes of arsenic-exposed people, but has not previously been studied in the urinary bladder. We investigated morphological changes of the urinary bladder transitional epithelium in F344 rats exposed to DMA(V) through drinking water, and the expression of DNA repair genes in the transitional cells. Mitochondria were found to be very sensitive to DMA(V), and swollen mitochondria appeared to be the main source of vacuoles observed in the transitional epithelium. Real time RT PCR results showed the mRNA levels of tested DNA repair genes [Ataxia Telangectasia mutant (ATM), X-ray repair cross-¬complementing group 1 (XRCC1 ), excision repair cross-complementing group 3/xeroderma pigmentosum B (ERCC3/XPB), and DNA polymerase β (Polβ)] were not altered in the transitional cells by DMA(V). These data suggested that either DMA(V) does not affect DNA repair in the bladder or DMA(V) affects DNA repair without affecting baseline mRNA levels of repair genes. The possibility remains that DMA(V) may lower damage-induced increases in repair gene expression or cause post-translational modification of repair enzymes.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL CARCINOGENESIS DIVISION
CANCER BIOLOGY BRANCH