Role of radiation-induced mutations in multigeneration carcinogenesis.

Parental exposure to radiation increases the incidence of tumours in resultant F1 offspring. Induced lung tumours are inherited, as they are dominant mutations, indicating that germ line mutation causes cancer in progeny. This finding is now confirmed in three different strains of mice (ICR, LT, and N5). Most of the tumours induced in offspring were transplantable (malignant); furthermore, preliminary experiments reveal involvement of some known and novel oncogenes in these tumours. A germ line mutation causing a tumour ('tumour mutation') is weakly carcinogenic by itself, but it is strongly expressed in the progeny after postnatal treatment with a small dose of the carcinogenesis promoting agent urethane. Tumour yields induced by chemical carcinogens were 20-250 times higher than those induced by tumour mutation alone. Embryonic mutagenesis also causes cancer in offspring. Although radiation in utero at early embryonic stages induces significant yields of somatic mutations, radiation is not or very weakly carcinogenic. However, it induced persistent hypersensitivity to postnatally administered carcinogenic (urethane) and promoting (12-O-tetradecanoylphorbol 13-acetate) agents. The mechanism must be similar to that of germ line mutation in causing tumours. No leukaemia was found in these experiments as in atomic bomb survivors exposed in utero, but all induced tumours were of adult types. The results predicted the recent epidemiological finding that the incidence of adult cancers is now increasing dramatically among atomic bomb survivors exposed in utero.