Carcinogenesis, Vol. 20, No. 2, 325-332,
February 1999
© 1999 Oxford University Press
Possible carcinogenic effects of X-rays in a transgenerational study with CBA mice
Institut für Experimentelle Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany,
1 Fraunhofer-Institut für Toxikologie und Aerosolforschung, Nikolai-Fuchs-Straße 1, D-30625 Hannover, Germany,
2 Departamento de Anatomia Patologica, Hospital Cliníc, Villaroel 170, E-8036 Barcelona, Spain and
3 Istituto per l'Infanzia, Via dell'Istria 65/1, I-34137 Trieste, Italy
A lifetime experiment using 4279 CBA/J mice was carried out to investigate whether the pre-conceptual exposure of sperm cells to X-ray radiation or urethane would result in an increased cancer risk in the untreated progeny, and/or increased susceptibility to cancer following exposure to a promoting agent. The study consisted of four main groups, namely a control group (saline), a urethane group (1 mg/g body wt) and two X-ray radiation groups (1 Gy, 2 Gy). At 1, 3 and 9 weeks after treatment, the males of these four parental groups were mated with untreated virgin females. The offspring of each parental group was divided into two subgroups: one received s.c. urethane (0.1 mg/g body wt once) as a promoter, the other saline, at the age of 6 weeks. All animals were evaluated for the occurrence of tumours. K-ras oncogene and p53 tumour suppressor gene mutations were investigated in frozen lung tumour samples. The female offspring of male parents exposed to X-rays 1 week before their mating showed a trend towards a higher tumour incidence of the haematopoietic system than the F1 controls. In addition, a higher percentage of bronchiolo-alveolar adenocarcinomas in male offspring born to irradiated paternals mated 1 week after X-ray treatment points to a plausible increased sensitivity of post-meiotic germ cell stages towards transgenerational carcinogenic effects. On the other hand, no increased tumour incidence and malignancy were observed in the offspring born to irradiated paternals mated 3 and 9 weeks after X-ray treatment. Paternal urethane treatment 1, 3 and 9 weeks prior to conception did not result in significantly altered incidence or malignancy of tumours of the lung, liver and haematopoietic tissue in the offspring. K-ras mutations increased during tumour progression from bronchiolo-alveolar hyperplasia to adenoma. Codon 61 K-ras mutations were more frequent in lung tumours of urethane-promoted progeny from irradiated parents than from control parents. P53 mutations were absent from these lung alterations.
Abbreviations: DEN, diethylnitrosamine; H & E, haematoxylin and eosin; PCR–RFLP, polymerase chain reaction–restriction fragment length polymorphism; SSCP, single-strand conformation polymorphism.
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