Genomic instability in haematopoietic cells of F1 generation mice of irradiated male parents

Abstract

Preconceptional paternal irradiation has been implicated as a causal factor 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 λ shuttle vector allowing mutations (in the lacI gene) to be analysed in vitro, we have investigated the possibility that preconceptional paternal irradiation can lead to such transgenerational transmission of genomic instability. We have examined the mutation frequencies in vector recovered from the bone-marrow cells of the F1 offspring of male parents exposed to doses of γ-rays of 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 F1 progeny. At 4 Gy the frequency of mutations was increased by a factor of approximately two (control mutation frequency, 2.39 x 10-5 ; mutation frequency in offspring of 4 Gy male group, 4.26 x 10-5; P < 0.001). We were unable to confirm reports of spermatogenesis stage sensitivity. The 2-fold increase in mutation frequency was evident in offspring derived from stored spermatozoa (irradiated transgenic males mated with unirradiated non-transgenic females 1-7 days after irradiation). Our data indicates that there exists a route for transgenerational transmission of factor(s) leading to genomic instability in F1 progeny, resulting from preconceptional paternal irradiation.