Heritable effects of paternal irradiation in mice on signaling protein kinase activities in F-3 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 modul ate cell proliferation rate and that may be markers for genomic instability . The F-3 generation was selected for evaluation as a stringent test for he ritability of effects from paternal F-0 germline irradiation. Male CD1 mice were bred 6 weeks after irradiation so that the fertilizing sperm were typ e 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 w ere heterozygous for the neo transgene. These F-2 XY-XY chimeras, consistin g of cells derived from both an embryo with a paternal F-0 radiation histor y and a control embryo, were transferred to foster mothers, raised to adult hood and bred to produce F-3 offspring. F-3 offspring were evaluated for he patic activities of receptor tyrosine kinase, protein kinase C and MAP kina se and for protein levels of nuclear p53 and p21(waf1). All three protein k inase activities were altered and nuclear levels of p53 and p21(waf1) prote in 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 co ntrol group. To our knowledge, this is the first observation in the descend ants of paternal germline irradiation of effects on signal protein kinase a ctivities and downstream nuclear target proteins that can influence cell pr oliferation rates.