Carcinogenicity of dimethylarsinic acid in Ogg1-deficient mice.
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.
Kinoshita
Anna
A
Department of Pathology, Osaka City University Medical School, Osaka 545-8585, Japan.
Wanibuchi
Hideki
H
Morimura
Keiichirou
K
Wei
Min
M
Nakae
Dai
D
Arai
Tsuyoshi
T
Minowa
Osamu
O
Noda
Tetsuo
T
Nishimura
Susumu
S
Fukushima
Shoji
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis; D002101:Cacodylic Acid / Q000378:metabolism; D015197:Carcinogenicity Tests; D049109:Cell Proliferation; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D018384:Oxidative Stress; D015996:Survival Rate
D000080242:8-Hydroxy-2'-Deoxyguanosine; D002101:Cacodylic Acid; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003849:Deoxyguanosine