Effect of ionizing radiation on transgenerational appearance of p(un) reversions in mice

Multiple genetic changes are required for the development of a malignant tumor cell and many environmentally induced cancers show a delayed onset of > 20 years following exposure. In fact, the frequency of genetic changes in cancer cells is higher than can be explained by random mutation. A high level of genetic instability in a subpopulation of cells may be caused by a mutator phenotype transmitted through many cell divisions. We have determined the effects of irradiation of parental male mice on the frequency and characteristics of mitotically occurring DNA deletion events at the p(un) locus in the offspring. Reversion of the p(un) marker in mouse embryos is due to deletion of 70 kb of DNA resulting in fur spots in the offspring. We found that irradiation of male mice caused a significantly higher frequency of large spots in the offspring, indicative of the induction of DNA deletions early in embryo development. These deletion events occurred, however, many cell divisions after irradiation. The present data indicate that exposure of the germline to ionizing radiation results in induction of delayed DNA deletions in offspring mice.