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DNA Replication and Unscheduled DNA Synthesis in Lungs of Mice Exposed to Cigarette Smoke¹

Department of Community and Environmental Medicine, University of California, Irvine, Irvine, California 92717 [R. E. R., C. H. B.], and Departments of Experimental Oncology and Biochemical Oncology, Microbiological Associates, 5221 River Road, Bethesda, Maryland 20016 [D. R. D., R. E. K., C. J. H.]

Mice of the hybrid strain BC3F1/Cum (C57BL/Cum x C3H/AnfCum) were chronically exposed to measured amounts of machine-generated whole Kentucky reference 2A1 cigarette smoke. DNA replication and unscheduled DNA synthesis (UDS) were measured in lung tissue in vitro using a short-term organ culture method. Within one week of beginning smoke exposure, DNA replicative activity, as indicated by incorporation of [³H]thymidine into total lung DNA, was increased more than two-fold over sham-exposed controls and remained elevated as long as smoke exposure was continued. Treatment of lung tissues in vitro with either the lung carcinogen 4-nitroquinoline-1-oxide or methylmethane sulfonate stimulated UDS, measured as incorporation of [³H]thymidine into lung DNA in the presence of hydroxyurea, presumably as the result of DNA repair activity. Until the 10th to 12th week of smoke exposure, at which time the accumulated deposition of total particulate material in the lung was approximately 40 mg, the level of UDS stimulated by the alkylating chemicals declined to approximately 50% of that seen in lung tissue from sham-exposed control mice. If the mice were removed from smoke exposure, DNA replicative activity returned to normal levels within one week, but the UDS response to DNA damage remained depressed up to five months after ending smoke exposure. The results show that both transient and apparently permanent changes are produced in mouse lung as the result of exposure to cigarette smoke. The role of these changes in lung neoplasia is under investigation.

¹ Supported by the Council for Tobacco Research—U. S. A., Inc. Presented in part at the Annual Meeting of the American Association for Cancer Research, New Orleans, La., May 1979 (23).

² To whom requests for reprints should be addressed.

Received 10/31/80. Accepted 3/23/81.