Effect of dietary treatment with dimethylarsinous acid (DMA^III) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice

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, 77.3ppm 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^III do not reach cytotoxic levels in DMA^V-treated mice.