Heritable effects of paternal irradiation in mice on signaling protein kinase activities in F3 offspring

We evaluated F-3 mouse offspring from paternal F-0 attenuated Cs-137 gamma -irradiation (1.0 Gy) for heritable effects on gene products that can modulate cell proliferation rate and that may be markers for genomic instability. The F-3 generation was selected for evaluation as a stringent test for heritability of effects from paternal F-0 germline irradiation. Male CD1 mice were bred 6 weeks after irradiation so that the fertilizing sperm were type B spermatogonia at the time of irradiation, The resulting F-1 males were bred to CD1 females to produce F-2 four-cell embryos. The F-2 embryos with a radiation history were paired with 'control' CD1 four-cell embryos that were heterozygous for the neo transgene. These F-2 XY-XY chimeras, consisting of cells derived from both an embryo with a paternal F-0 radiation history and a control embryo, were transferred to foster mothers, raised to adulthood and bred to produce F-3 offspring. F-3 offspring were evaluated for hepatic activities of receptor tyrosine kinase, protein kinase C and MAP kinase and for protein levels of nuclear p53 and p21(waf1). All three protein kinase activities were altered and nuclear levels of p53 and p21(waf1) protein were higher in the group off offspring that included F-3 offspring With a paternal F-0 radiation history than in littermates in the neo-positive control group. To our knowledge, this is the first observation in the descendants of paternal germline irradiation of effects on signal protein kinase activities and downstream nuclear target proteins that can influence cell proliferation rates.