X-ray-induced germ-line mutation leading to tumors. Its manifestation in mice given urethane post-natally

Treatment of parental ICR mice with X-rays resulted in a significant increase of lung tumors in F1 offspring, which were inherited dominantly with about 40% penetrance. If germ-line mutation leads to heritable tumors, all cells composing the lungs must be mutated and have an equal likelihood of forming tumors. After treatment with carcinogenesis-promoting agents, unusually large clusters of tumor nodules developed in the lungs. When urethane was given to F1 offspring of parents that had been irradiated with 216 rad of X-rays, a large number of offspring (18.0%) developed large clusters of tumor nodules in the lung, whereas only 2.8% did so in the non-irradiated control, an indication of germ-line mutations. The incidence of the affected tumor clusters was more than twice (2.4-fold) that of affected progeny without urethane treatment postnatally, indicating enhancement of penetrance. If increased penetrance after urethane treatment (the multiplying ratio being 2.41) was taken into account in the dose-response data of the previous report, doubling doses were estimated to be about 25 and 50 rad for spermatids and spermatogonia respectively. These values are similar to those for other types of gonial mutation. Curiously, no tumors were produced by radiation in the offspring when exposure of male patterns was in utero (day 15 of gestation). The F1 offspring, which had no lung-tumor-causing mutations, were also highly resistant to post-natal treatment with urethane, developing no clusters of tumor nodules in the offspring. This suggests that, without tumor mutations, carcinogens rarely produce tumors.