Abstract
It is well known that several oncogenes or tumor suppressor genes are mutated in carcinogen-induced tumors. However, little is known about the accumulation of mutations after combined exposure to radiation and chemical carcinogens. In the present study, we examined frequency and spectrum of Kras point mutation in thymic lymphomas (TL) of B6C3F1 mice, which were induced by different combined exposure protocols of X rays and ENU, comparing with those of Ikaros.
Both combined exposure of X rays followed by ENU (X to ENU) and simultaneous exposure (X+ENU) increased TL incidence in a synergistic manner, and exposure of ENU followed by X rays (X to ENU) increased it in a sub-additive manner. In TL after (X to ENU) exposure, frequency of both Kras and Ikaros point mutation increased in supra-additive manner. In contrast, in TL after reverse sequence exposure (ENU to X) , neither Kras nor Ikaros mutation increased significantly. When X rays were exposed simultaneously with ENU (X+ENU), Ikaros mutation frequency significantly increased in a supra-additive manner, but, unexpectedly, Kras mutation frequency showed sub-additivity. Mutation spectrum of Ikaros differed between TL after (X to ENU) exposure and those after (X+ENU) one. These results indicate that the effect of combined exposure on lymphoma development and target gene is dependent upon the mode of carcinogen exposure.
