Journal Article

High accumulation of oxidative DNA damage, 8-hydroxyguanine, in <i>Mmh/Ogg1</i> deficient mice by chronic oxidative stress

Tsuyoshi Arai, Vincent P. Kelly, Osamu Minowa, Tetsuo Noda and Susumu Nishimura

in Carcinogenesis

Volume 23, issue 12, pages 2005-2010
Published in print December 2002 | ISSN: 0143-3334
Published online December 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.12.2005
High accumulation of oxidative DNA damage, 8-hydroxyguanine, in Mmh/Ogg1 deficient mice by chronic oxidative stress

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8-Hydroxyguanine (8-OH-G) is a major pre-mutagenic lesion generated from reactive oxygen species. The Mmh/Ogg1 gene product plays a major role in maintaining genetic integrity by removing 8-OH-G by way of the base excision repair pathway. To investigate how oxidative stress influences the formation of 8-OH-G in Ogg1 mutant mice, a known oxidative agent, potassium bromate (KBrO3), was administered at a dose of 2 g/l in the drinking water to Ogg1+/+, Ogg1+/− and Ogg1−/− mice for 12 weeks. Apurinic (AP) site lyase activity, measured by the excision of 8-OH-G from synthetic oligonucleotides, remained unchanged in kidney cell extracts isolated from Ogg1 mutant mice when the mice were pre-treated by KBrO3. The levels of 8-OH-G in kidney DNA tremendously increased in a time-dependent manner following exposure of Ogg1−/− mice to KBrO3. Of particular note, the amount of 8-OH-G in kidney DNA from Ogg1−/− mice treated with KBrO3 was ~70 times that of KBrO3-treated Ogg1+/+ mice. The accumulated 8-OH-G did not decrease 4 weeks after discontinuing treatment with KBrO3. KBrO3 treatment for 12 weeks gave rise to increased mutation frequencies at the transgenic gpt gene in Ogg1+/+ mice kidney. Absence of the Ogg1 gene further enhanced the mutation frequency. Sequence data obtained from gpt mutants showed that the accumulated 8-OH-G caused mainly GC→TA transversion and deletion. Other mutations including GC→AT transition also showed a tendency to increase. These results indicate that 8-OH-G, produced by chronic exposure to exogenous oxidative stress agents, is not repaired to any significant extent within the overall genome of Ogg1−/− mice kidney.

Keywords: AP lyase, apurinic, apyrimidic lyase; Cm, chloramphenicol; 8-OH-G, 8-hydroxyguanine or 7,8-dihydro-8-oxoguanine; ECD, electrochemical detector; 6-TG, 6-thioguanine

Journal Article.  4828 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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