Abstract
Health effects of low-dose-rate or low-dose radiation should be evaluated in combination with chemicals as humans are exposed to a variety of chemical agents. Here, we examined combined genotoxic effects of low-dose-rate radiation and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the most carcinogenic tobacco-specific nitrosamine, in the lung of gpt delta transgenic mice. Female gpt delta transgenic mice were either treated with gamma-irradiation alone at a dose rate of 0.5, 1.0 or 1.5 mGy/h for 22 h/day for 31 days or combined with NNK treatments at a dose of 2 mg/mouse/day, i.p. for four consecutive days in the middle course of irradiation. The NNK treatments enhanced the frequency of base substitutions significantly, but no obvious combined effects of gamma irradiation were observed. In contrast, the NNK treatments appeared to suppress radiation-induced large deletions. The frequency of large deletions more than 1 kb in size increased in a dose-dependent manner of gamma irradiation. When NNK treatments were combined, however, the dose-response curve became bell-shaped where the frequency at the highest radiation dose decreased substantially. These results suggest that NNK treatments may elicit an adaptive response that eliminates cells bearing radiation-induced double-strand breaks in DNA. Possible mechanisms underlying the combined genotoxicity of radiation and NNK are discussed.
