INDUCTION OF SPECIFIC-LOCUS AND DOMINANT LETHAL MUTATIONS IN MALE-MICE BY 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA (BCNU) AND 1-(2-CHLOROETHYL)-3-CYCLOHEXYL-1-NITROSOUREA (CCNU)

1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cy clohexyl-1-nitrosourea (CCNU) induced dominant lethal and specific-loc us mutations in male mice. For both compounds the germ cell stage sens itive to the induction of dominant lethal mutations was dose dependent . A dose of 5 mg BCNU per kg b.wt. induced dominant lethal mutations p rimarily in spermatocytes, whereas higher doses of BCNU induced domina nt lethals in spermatids and spermatocytes. Following doses of 5 and 1 0 mg CCNU per kg b.wt. dominant lethals were induced in spermatids and spermatocytes similar to the results for higher doses of BCNU. Higher dose exposure to BCNU and CCNU was associated with dominant lethals e xpressed as pre-implantation loss (reduction in total number of implan ts). In addition, higher doses of CCNU showed a cytotoxic effect in di fferentiating spermatogonia. Both compounds induced specific-locus mut ations in post-spermatogonial germ cell stages of mice. However, CCNU increased also the specific-locus mutation frequency in spermatogonia in two out of three experiments. We conclude in analogy with criteria developed by IARC, that BCNU and CCNU are potential human mutagens. (C ) 1997 Elsevier Science B.V.