Combined genotoxicity of low-dose-rate radiation and tobacco-specific nitrosamine NNK

Combined genotoxicity of low-dose-rate radiation and tobacco-specific nitrosamine NNK

Takehiko Nohmi

Authors: Takehiko Nohmi¹, Megumi Ikeda^{1, 2}, Ken-ichi Masumura¹, Yasuteru Sakamoto¹, Bing Wang³, Mitsuru Nenoi³,　Keiko Sakuma², Isamu Hayata³

¹Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, 158-8501 Japan, ²Graduate School of Nutrition and Health Sciences, Kagawa Nutrition University, Saitama, 350-0288 Japan, ³Radiation Effect Mechanisms Research Group, Research Center of Radiation Protection, National Institute of Radiological Sciences Chiba, 263-8555 Japan

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 chemicals. Here, we report 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. In this mouse model, base substitutions and deletions can be separately analyzed at the molecular level. 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 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, the dose-response curve became bell-shaped where the frequency at the highest radiation dose decreased substantially. Possible mechanisms underlying the combined genotoxicity of radiation and NNK are discussed, and the importance of evaluation of combined genotoxicity of more than one agent is emphasized.

Key words: combined genotoxic effects; radiation; NNK; lung cancer; gpt delta mice; deletion