Effects of side-stream tobacco smoke and smoke extract on glutathione- and oxidative DNA damage repair-deficient mice and blood cells
| Autor: | Mitsuko L. Yamamoto, Robert H. Schiestl, Aaron M. Chapman |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
DNA repair DNA damage Glutamate-Cysteine Ligase Health Toxicology and Mutagenesis Inflammation Biology medicine.disease_cause Article DNA Glycosylases Mice chemistry.chemical_compound Genetics medicine Animals Molecular Biology Mice Knockout Blood Cells GCLM Base excision repair Glutathione DNA Repair-Deficiency Disorders Molecular biology Mice Inbred C57BL Oxidative Stress Biochemistry chemistry DNA glycosylase Female Tobacco Smoke Pollution medicine.symptom Oxidative stress DNA Damage |
| Zdroj: | Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 749:58-65 |
| ISSN: | 0027-5107 |
| DOI: | 10.1016/j.mrfmmm.2013.05.003 |
| Popis: | Cigarette smoke causes direct oxidative DNA damage as well as indirect damage through inflammation. Epidemiological studies show a strong relationship between secondhand smoke and cancer; however, the mechanisms of secondhand smoke-induced cancer are not well understood. Animal models with either (i) deficient oxidative DNA damage repair, or (ii) a decreased capacity to combat oxidative stress may help determine the pathways important in mitigating damage caused by smoke. In this study, we used mice lacking Ogg1 and Myh, both of which are involved in base excision repair by removing oxidatively damaged DNA bases. Gclm-deficient mice, which have decreased levels of glutathione (GSH), were used to look at the role of smoke-induced oxidative damage. Ex vivo experiments show significantly elevated levels of DNA single-strand breaks and chromosomal aberrations in peripheral blood lymphocytes from Ogg1(-/-)Myh(-/-) double knockout mice compared to wild type (WT) mice after 24h of exposure to cigarette smoke extract (CSE). The average γH2AX foci per cell was significantly elevated 3h after exposure to CSE in cells from Ogg1(-/-)Myh(-/-) double knockout mice compared to wildtype mice. In vivo we found that all mice had increased markers of DNA damage after exposure to side-stream tobacco smoke (SSTS). Ogg1(-/-)Myh(-/-) and Gclm(-/-) mice had altered levels of peripheral blood glutathione after SSTS exposure whereas wild type mice did not. This may be due to differential regulation of glutathione synthesis in the lung. We also found that Ogg1(-/-)Myh(-/-) mice had a decreased lifespan after oral gavage with benzo[a]pyrene compared to wildtype mice and sham-exposed Ogg1(-/-)Myh(-/-) mice. Our results are important in investigating the roles of oxidative stress and oxidative DNA damage repair in cigarette smoke-induced cancers and characterizing the role of genetic polymorphisms in smoke-related disease susceptibility. |
| Databáze: | OpenAIRE |
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