Carcinogenicity of dimethylarsinic acid in Ogg1-deficient mice

Abstract

Oxidative stress to DNA is recognized as a mechanism underlying carcinogenic effects of some environmental agents. Here, we hypothesized that dimethylarsinic acid (DMAV), 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 DMAV in their drinking water at a dose of 200 p.p.m. for up to 72 weeks. All DMAV-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 DMAV-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 DMAV-exposed Ogg1-/- mice. Therefore, we strongly suggest that DMAV exerts carcinogenicity in the lungs of Ogg1-/- mutant mice, with a possible role for persistent accumulation of DNA oxidative adducts. © 2007 Japanese Cancer Association.