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

Abstract

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.

Epigenetic changes and nontargeted radiation effects—Is there a link?

“…Other studies focused on heritable alterations in cancer incidence and teratogenesis following the parental preconception irradiation [Mohr et al, 1999;Pils et al, 1999;Nomura, 2003;Nomura et al, 2004;Dasenbrock et al, 2005]. In addition to this classic evidence for transmitted effects, it is now apparent that risks to the progeny of irradiated parents also include transgeneration genomic instability [Carls and Schiestl, 1999;Mohr et al, 1999;Barber et al, 2002Shiraishi et al, 2002;Dubrova, 2003a,b;Morgan, 2003b;Niwa, 2003;Nomura, 2003;Nomura et al, 2004;Slovinska et al, 2004;Dasenbrock et al, 2005;Tawn, 2005;Singer et al, 2006].…”

Comments on the Paper by Wickliffeet al.(Radiat. Res.159, 458–464, 2003)

“…Weak evidence indicative of transgenerational effects on p un reversion after irradiation of male p un /p un mice has been reported (83). No significant elevation in fur spot frequency was reported; however, spots tended to be larger in irradiated mice.…”