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

Authors

Puttappa R. Dodmane, University of Nebraska Medical CenterFollow
Lora L. Arnold, University of Nebraska Medical CenterFollow
Karen L. Pennington, University of Nebraska Medical CenterFollow
David J. Thomas, Research Triangle ParkFollow
Samuel M. Cohen, University of Nebraska Medical CenterFollow

Document Type

Article

Date of this Version

2013

Citation

Toxicology 305 (2013) 130– 135

Comments

© 2013 Elsevier Ireland Ltd. All rights reserved.

Abstract

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. 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. 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.