TUMOR-INDUCTION BY METHYL NITROSO-UREA PRECONCEPTIONAL PATERNAL CONTAMINATION WITH PU-239

We have investigated the possibility that transgenerational effects fr om preconceptional paternal irradiation (PPI) may render offspring mor e Vulnerable to secondary exposure to an unrelated carcinogen. Pu-239 (0, 128 or 256 Bq g(-1)) was administered by intravenous injection to male mice, 12 weeks before mating with normal females. Two strains of mouse were used - CBA/H and BDF1. Haemopoietic spleen colony-forming u nits (CFU-S) and fibroblastoid colony-forming units (CFU-F), a compone nt of their regulatory microenvironment, were assayed independently in individual offspring at 6, 12 and 19 weeks of age. Bone marrow and sp leen from each of these mice were grown in suspension culture for 2 or 7 days for assessment of chromosomal aberrations. Female BDF1 were in jected with methyl-nitroso-urea (MNU) as a secondary carcinogen at 10 weeks of age and monitored for onset of leukaemia/lymphoma. Mean value s of CFU-S and CFU-F were unaffected by preconceptional paternal pluto nium-239 (PP-Pu-239), although for CFU-F in particular there was an ap parent increase in variation between individual animals. There was sig nificant evidence of an increase in chromosomal aberrations with dose in bone marrow but not in spleen. By 250 days, 68% of MNU-treated cont rol animals (no PPI) had developed thymic lymphoma (62%) or leukaemia (38%). The first case arose 89 days after MNU administration. In the g roups with PPI, leukaemia/lymphoma developed from 28 days earlier, ris ing to 90% by 250 days. Leukaemia (65%) now predominated over lymphoma (35%). This second generation excess of leukaemia appears to be the r esult of PPI and may be related to inherited changes that affect the d evelopment of haemopoietic stem cells.