DNA adducts in relation to lung tumour outcome are not markers of susceptibility following a single dose treatment of SWR, BALB/c and C57BL/6J mice with N-nitrosodiethylamine

DNA represents a valuable marker for assessing exposure to carcinogens but as yet the role of DNA adducts as a biomarker of carcinogenic susceptibilit y still needs to be clearly ascertained. To address this question an animal study was instigated using mice (SWR (high), BALB/c (intermediate) and C57 BL/6J (low)) varying in their susceptibility to lung carcinogenesis. Groups of animals from each strain were dosed with a single intraperitoneal injec tion of saline or N-nitrosodiethylamine (NDEA) at 15 or 90 mg kg(-1) body w eight. Lung and liver tissues were removed at different time points followi ng dosing. Further groups of mice dosed with the same regime had urine samp les collected 24 h post dosing and were then left up to 18 months to allow for the development of tumours. Immunoslot-blot analysis was used for the d etermination of N-7 ethylguanine (N-7EtG) and O-6 ethylguanine (O(6)EtG) ad duct levels in the DNA from the tissues and gas chromatography-mass spectro metry (GC-MS) was used to determine N-3 ethyladenine (N-3EtA) adduct levels in the urine samples. Levels of alkyltransferase (ATase) were also determi ned in the tissues. The results showed that the DNA adduct levels and persi stence were similar across the three strains of mice following dosing with 15 and 90 mg kg(-1) NDEA. High levels of adducts were observed in the urine of the BALB/c strain, implying an increased metabolic or repair capacity i n this strain. However there were no differences in the levels of ATase in the lung and liver of the three strains of mice following dosing with 15 mg kg(-1) NDEA. The incidence of tumours in C57BL/6J mice was lower compared with the other two strains and showed a dose dependent increase. The result s from this study show that the differences in susceptibility to lung carci nogenesis between the three strains of mice do not appear to be linked to t he formation of the two adducts detected. These results imply that dosing w ith NDEA resulted in toxicity which may have led to cell death and inductio n of tumours by compensatory cell proliferation. Although these results do not allow decisive conclusions to be drawn concerning the relationship betw een total levels of DNA adducts and differences in carcinogenic susceptibil ity for the three strains of mice it is clear that the increased presence o f a DNA adduct in the target tissue increases the likelihood of tumour deve lopment.