A study has been carried out to test the Knudson hypothesis, which predicts that in offspring of individuals where one allele at a tumour suppressor locus has been mutated or lost in the germ line, only a single inactivational event at the tumour suppressor locus will be required for inactivation. Thus, an F1 generation inheriting a mutated allele would be expected to show greater sensitivity to radiation induced carcinogenesis. The chemical carcinogen ethylnitrosourea (ENU) was given to male mice to induce germ line mutations that were transmitted to the F1 offspring. When the offspring were exposed to low dose irradiation there was a significant increase in the incidence of osteosarcoma formation compared to offspring of control animals. Tissue samples were collected for study of the inheritance pattern of mutations at tumour suppressor loci.
The possible oncogenic effect through the germline of the father should follow molecular genetic mechanisms according to the Knudson two hit hypothesis.
We intend to establish a model, in the mouse, of the specific locus test (in cooperation with the GSF-Institute for Mammalian Genetics, Prof. U.H. Ehling). In this system ethylnitrosurea will be used as a paternal mutagen. 227Th will be applied to F1 mice as a second hit agent. The germline transmitted somatic genetic events and the later changes in the tumour will be studied with a range of oncogene and/or tumour suppressor gene probes (Prof. H. Hofler, Dr.M. Atkinson). These molecular biological studies should allow an early monitoring of paternal oncogenic risk.