Time-dependent formation of 8-oxo-deoxyguanosine in the lungs of mice exposed to cigarette smoke

Active and passive smoking are major risk factors for lung cancer. Pro-oxidants in tobacco smoke have been implicated in smoking-associated disease development due to their potential role in inducing oxidative stress. Previous studies have failed to associate increased levels of oxidative damage to DNA with the formation of the potentially mutagenic lesion, 8-oxo-2-deoxyguanosine (8-oxodG), probably due to repair of this lesion. However, no systematic studies have been performed to assess the dose- and time-dependent formation and removal of this lesion by cigarette smoke exposure. In the present study, female A/J mice were exposed to side-stream cigarette smoke in a whole body exposure chamber for 6 h a day, 5 days a week for up to 6 weeks. Age-matched controls were maintained in filtered ambient air. Lung tissues were harvested from 2, 4, and 6 weeks smoke-exposed mice after 1, 3, 6, and 20 h, following the cessation of smoking. A significant increase in the levels of 8-oxodG in lung DNA was observed in 10 day smoke-exposed mice at 1 (11.5+/-1.1/10(6) nucleotides), 3 (20.2+/-2.7/10(6) nucleotides; p=0.0008), and 6 h (17.2+/-1.0/10(6) nucleotides; p<0.005) postcessation, as compared with age-matched sham treatment (8.8+/-2.3/10(6) nucleotides) (mean+/-SD). The levels significantly declined 20 h after the cessation of smoke exposure (14.0+/-1.6/10(6) nucleotides), although they were still higher than the control. Our results strongly suggest that there is a significant increase in the 8-oxodG levels immediately after the cessation of smoking, which is repaired over time. This initial increase in 8-oxodG levels may lead to gene mutations, and accumulation of such mutations over time can eventually lead to malignant transformation of the cells.