GERM-CELL MUTAGENICITY OF 3 METABOLITES OF 1,3-BUTADIENE IN THE RAT -INDUCTION OF SPERMATID MICRONUCLEI BY BUTADIENE MONO-EPOXIDE, DI-EPOXIDE, AND DIOLEPOXIDE IN-VIVO

Three metabolites of the industrial chemical 1,3-butadiene (ED), namel y butadiene monoepoxide (BMO, 3,4-epoxy-1-butene), diepoxide (DEB, 1,2 ;3,4-diepoxybutane), and diolepoxide (DE, 3,4-epoxybutane-1,2-diol) we re studied for germ cell mutagenicity using the rat spermatid micronuc leus (MN) test. All three epoxides increased slightly, but significant ly, the frequency of spermatid MN. The most sensitive stage to the act ion of BMO and DEB was preleptotene (meiotic S phase) harvested at 18- day time intervals after treatment. The dose-response for BMO followed a second order curve at this time interval, with maximum MN induction at the dose of 186 mu mol/kg and lower induction at higher doses. Lat e stages of the meiotic prophase (late pachytene-diplotene-diakinesis) also showed some sensitivity to the three epoxides. Stem cell spermat ogonia were affected by DEB as observed by a slight induction of sperm atid micronuclei 50 days after treatment. No clear cytotoxic effects w ere observed by measuring testicular weight or cell numbers of seminif erous epithelial stage 1 18 days after the treatments. DEB at the dose 387 mu mol/kg caused a slight inhibition of spermatogonial DNA synthe sis in stage I and a delay of meiotic DNA replication observed in stag e XII 72 hr after treatment. Since BMO is able to induce spermatid MN in the rat, the present results, together with previous data, indicate that rat bone marrow MN results that are negative for both ED and BMO cannot directly predict mutagenicity in male germ cells. The results also emphasize that tissue-, species-, and strain-specific differences in metabolism have to be taken into account when the genetic risks of human butadiene exposure are evaluated. The results support the concl usion that 1,3-butadiene is a germ cell mutagen-possibly also in human s. (C) 1997 Wiley-Liss, Inc.