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Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMA(V), a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the mouse urothelium. DMA(III) was shown to be the likely urinary metabolite of DMA(V) inducing urothelial changes and is also postulated to be one of the active metabolites of iAs. To evaluate potential DMA(III)-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 DMA(III), 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 1-5, with higher rating indicating greater extent of cytotoxicity visualized. DMA(III) 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. DMA(III) 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, DMA(III) induces urothelial toxicity and regenerative hyperplasia in mice and most likely plays a role in inorganic arsenic-induced urothelial changes. However, DMA(V) does not induce hyperplasia in mice, suggesting that urinary concentrations of DMA(V) do not reach cytotoxic levels in DMA(V)-treated mice. (C) 2013 Elsevier Ireland Ltd. All rights reserved.