GENOMIC INSTABILITY IN HEMATOPOIETIC-CELLS OF F1 GENERATION MICE OF IRRADIATED MALE PARENTS

Preconceptional paternal irradiation has been implicated as a causal f actor in childhood cancer and it has been suggested that this exposure to radiation may play a role in the occurrence of childhood leukaemia clusters in the vicinity of nuclear installations, Using a transgenic mouse system employing a lambda shuttle vector allowing mutations (in the lacI gene) to be analysed in vitro, we have investigated the poss ibility that preconceptional paternal irradiation can lead to such tra nsgenerational transmission of genomic instability. We have examined t he mutation frequencies in vector recovered from the bone-marrow cells of the F-1 offspring of male parents exposed to doses of gamma-rays o f 0.1-4 Gy. Our results show that as parental dose increases there is a trend towards higher mutation frequency in vector recovered from the DNA of bone-marrow of F-1 progeny, At 4 Gy the frequency of mutations was increased by a factor of approximately two (control mutation freq uency, 2.39 x 10(-5); mutation frequency in offspring of 4 Gy male gro up, 4.26 x 10(-5); P < 0.001), We were unable to confirm reports of sp ermatogenesis stage sensitivity. The 2-fold increase in mutation frequ ency was evident in offspring derived from stored spermatozoa (irradia ted transgenic males mated with unirradiated non-transgenic females 1- 7 days after irradiation). Our data indicates that there exists a rout e for transgenerational transmission of factor(s) leading to genomic i nstability in F-1 progeny, resulting from preconceptional paternal irr adiation.