INDUCTION OF DNA-DAMAGE BY URETHANE IN MOUSE TESTES - DNA-BINDING ANDUNSCHEDULED DNA-SYNTHESIS

The extent and persistence of DNA damage and repair were investigated in mouse spermatogenic cells exposed in vivo to urethane (ethyl carbam ate, EC). Adult male mice exposed to [H-3]EC at 10-1,000 mg/kg were sa crificed 12 hr later. EC/metabolite binding to liver and testicular DN A and to sperm heads from the vasa deferentia was measured. Other male mice were exposed to EC at 50-750 mg/kg, and unscheduled DNA synthesi s (UDS) induction was investigated in early spermatid stages. Similar experiments were conducted with vinyl carbamate (VC; putative EC metab olite) at 10-75 mg/kg. [H-3]EC bound to liver and testicular DNA and t o whole sperm heads. Testicular DNA binding increased linearly with do se, although binding was at least 2 orders of magnitude lower than wit h liver DNA. Sperm head binding also increased linearly with dose. Dos e response studies with the UDS assay showed that EC and VC induced a small but significant increase of the UDS response in early spermatid stages. However, the induced UDS responses were quite variable and did not consistently increase with the administered dose. To determine th e time kinetics of UDS induction, [H-3]dThd was injected at various ti mes after treatment with 500 mg/kg of EC or 60 mg/kg of VC. A slight b ut significant UDS increase was observed 4 hr after treatment with EC but not with VC. Overall, these results suggest that EC metabolites bi nd to testis DNA and cause low-level DNA damage in mouse spermatogenic cells. This type of DNA damage apparently does not have significant g enetic consequences. (C) 1994 Wiley-Liss, Inc.