Inhaled cigarette smoke induces the formation of DNA adducts in lungs of rats

Abstract

Cigarette smoking causes a variety of adverse human health effects, including lung cancer. The molecular events associated with smoke-induced carcinogenesis are thought to be related in part to the genotoxic activities of the chemicals associated with smoke. The purpose of this investigation was to determine the molecular dosimetry of compounds in cigarette smoke in lungs of rats exposed by inhalation. These studies investigated the effects of exposure mode, sex, and time (adduct persistence) on the level of DNA adducts. Male and female F344 N rats were exposed 6 hr/day, 5 days/week for 22 days to cigarette smoke by nose-only intermittent (NOI), nose-only continuous (NOC), or whole-body continuous (WBC) exposures. Separate groups of rats were sham-exposed nose-only (NOS) or whole-body (WBS) to filtered air. All smoke exposure modes yielded daily smoke exposure concentration × time products of 600 mg particulate · hr/m 3 for the first week and 1200 mg particulate · hour/m 3 thereafter. Groups of rats were killed at 18 hr and 3 weeks after the 22-day exposure period and DNA adducts in lung tissues were quantified by the 32P-postlabeling method. There were significant ( p < 0.05) increases in levels of clearly resolved lung DNA adducts in male and female rats exposed to smoke compared to sham-exposed rats. There were no significant effects of exposure mode or sex on lung DNA adducts. Mean levels (±SE) of clearly resolved lung DNA adducts for both sexes combined in NOI, NOC, WBC, NOS, and WBS groups were 50 ± 4, 52 ± 6, 52 ± 7, 21 ± 6, and 22 ± 4 adducts per 10 9 bases, respectively. Levels of clearly resolved DNA adducts were significantly less in lungs of rats killed 3 weeks after exposure and had declined to near control levels, suggesting that smoke-induced adducts are repaired by lung DNA repair enzymes. A single unidentified adduct accounted for about 20% of the total clearly resolved lung DNA adducts quantified in smoke-exposed rats and was increased 9- to 14-fold over control levels. Levels of this adduct in NOI, NOC, WBC, NOS, and WBS were 14 ± 0.9, 9± 0.7, 11 ± 0.9, 1.4±0.2, and 1.1±0.2 adducts per 10 9 bases, respectively. The results from these experiments indicate that inhaled cigarette smoke induces lung DNA adducts which may play an important role in cigarette smoke-induced lung carcinogenesis.