Gamma irradiation of Type B spermatogonia leads to heritable genomic instability in four generations of mice.

Mice conceived 6 weeks after paternal exposure to ionizing radiation were fathered by sperm that were Type B spermatogonia at the time of irradiation. Previous studies of these offspring showed that this paternal F0 germ cell irradiation led to decreased embryonic cell proliferation rates, altered enzyme activities, protein levels and whole-body weights. In the present study, we examined four generations of CD1 mice following paternal F0 irradiation of the Type B spermatogonia (1.0 Gy, (137)Cs gamma rays) to determine the stability of the heritable effects. Offspring were evaluated for changes in protein kinase C and mitogen-activated protein kinase enzyme activities and Trp53 and p21(waf1) protein levels. Two or more endpoints were significantly altered in all four generations of offspring from the irradiated F0 sire (P <or= 0.05). To test the hypothesis that these heritable biochemical effects are random stochastic responses rather than some predictable uniform response, each endpoint was also evaluated in terms of a variability index (VI). Results of VI analyses show that the observed heritable phenotype is unpredictable in magnitude and direction of change for an endpoint between generations and within generations. These results indicate that irradiated spermatogonia develop a capacity to transmit a type of heritable genomic instability to four generations of offspring.