IngentaConnect Carcinogenicity of dimethylarsinic acid in Ogg1-deficient mice

Authors: Kinoshita, Anna¹; Wanibuchi, Hideki; Morimura, Keiichirou¹; Wei, Min¹; Nakae, Dai²; Arai, Tsuyoshi; Minowa, Osamu; Noda, Tetsuo; Nishimura, Susumu³; Fukushima, Shoji¹

Source: Cancer Science, Volume 98, Number 6, June 2007 , pp. 803-814(12)

Publisher: Blackwell Publishing

Abstract:

Oxidative stress to DNA is recognized as a mechanism underlying carcinogenic effects of some environmental agents. Here, we hypothesized that dimethylarsinic acid (DMA^V), an organic metabolite of inorganic arsenic in humans, might exert carcinogenic potential in a mouse line carrying a mutant Mmh allele of the Mmh/OGG1 gene encoding the enzyme 8-hydroxyguanine DNA glycosylase 1 (OGG1). Ogg1 mutant and wild type mice were treated with DMA^V in their drinking water at a dose of 200 p.p.m. for up to 72 weeks. All DMA^V-treated Ogg1^−/-animals developed tumors, with a tendency for lower total incidences in the Ogg1^+/+ cases. Lung tumors in particular were induced as compared to the lack in non-carcinogen controls and were significantly more frequent in the homozygotes. At week 4, the levels of DNA 8-OH-dG and cell proliferation were significantly elevated in the lungs of non-treated Ogg1^−/- as compared to Ogg1^+/+ mice and were strongly enhanced by DMA^V treatment. Marked induction of Pola1, Cyp7b1, Ndfua3, Mmp13 and other genes specific to cell proliferation, cell signaling and xenobiotic metabolism in the lungs of DMA^V-treated Ogg1^−/- mice was found. Electron microscopic examination revealed the growth of microvilli, with increased numbers of mitochondria only in lungs and lung tumors of DMA^V-exposed Ogg1^−/- mice. Therefore, we strongly suggest that DMA^V exerts carcinogenicity in the lungs of Ogg1^−/- mutant mice, with a possible role for persistent accumulation of DNA oxidative adducts. (Cancer Sci 2007; 98: 803-814)

Document Type: Research article

DOI: 10.1111/j.1349-7006.2007.00475.x

Affiliations: 1: Department of Pathology, Osaka City University Medical School, Osaka 545-8585; 2: Tokyo Metropolitan Institute of Public Health, Shinjuku, Tokyo 169-0073; 3: Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories, Tsukuba, Ibaraki 300-2611;

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