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Effect of Dietary Treatment with Dimethylarsinous Acid (DMAIII) on the Urinary Bladder Epithelium of Arsenic (+3 Oxidation State) Methyltransferase (As3mt) Knockout and C57BL/6 Wild Type Female Mice
Dodmane, P., L. Arnold, K. Pennington, D. Thomas, AND S. Cohen. Effect of Dietary Treatment with Dimethylarsinous Acid (DMAIII) on the Urinary Bladder Epithelium of Arsenic (+3 Oxidation State) Methyltransferase (As3mt) Knockout and C57BL/6 Wild Type Female Mice. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 305:130-135, (2013).
Abstract Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAv, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the mouse urothelium. DMAIII was shown to be the likely urinary metabolite of DMAvinducing urothelia changes and is also postulated be one of the active metabolites of iAs. To evaluate potential DMAII1-induced urothelial effects, it was administered to As3mt knockout mice which cannot methylate arsenicals. Female C57BL/6 wild type and As3mt knockout mice (10/group) were administered DMAIII, 77.3 ppm in water for four weeks. Urothelial effects were evaluated by light and scanning electron microscopy (EM) and immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation. EM findings were rated 1 to 5, with higher rating indicating greater extent of cytotoxicity visualized. DMAIII significantly increased the BrdU labeling index, a ratio of BrdU labeled cells to non-labeled cells, in the treated knockout group compared to control and wild type treated groups. DMAIII induced simple hyperplasia in more knockout mice (4/10) compared to wild type mice (2/10). All treated knockout mice had more and larger intracytoplasmic granules compared to the treated wild type mice. Changes in EM classification were not significant. In conclusion, DMAIII induces urothelial toxicity and regenerative hyperplasia in mice and most likely plays a role in inorganic arsenic-induced urothelial changes. However, DMAv does not induce hyperplasia in mice, suggesting that urinary concentrations of DMAIII do not reach cytotoxic levels in DMAv-treated mice. Key words: Organic arsenicals; urinary bladder; cytotoxicity; proliferation; electron microscopy
This study provides initial data related to evaluating the role of DMAsm as a mediator of toxic and carcinogenic actions associated with exposure to arsenic. As such, it contributes to an evolving understanding of a mode of action for arsenic. The identification of key events in arsenic's actions as a toxicant and carcinogen can materially affect the risk assessment for this metalloid.
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 LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION