Reproductive toxicity associated with endometrial cell mediated metabolism of benzo[a]pyrene: a combined in vitro, in vivo approach.

We have demonstrated the effect of a highly mutagenic metabolite of benzo[a]pyrene (BP) on postimplantation development of mouse blastocysts exposed in vitro. The full spectrum of metabolism of BP from microsomes of a nontumorigenic, estradiol responsive, mouse endometrial cell strain was established. The mouse endometrial cell microsomes showed inducible cytochrome P-450 mediated oxidation of BP(-)-trans 7,8-dihydrodiol to BP 7,8-dihydrodiol 9,10-epoxides which affect implantation and subsequent development of preimplantation embryos. Embryos obtained from pregnant mice on day 3 post-coitum were incubated with endometrial cell microsomes and BP(-)-trans-7,8-dihydrodiol at various concentrations from 0 to 1.0 microM. Following the incubation, the embryos were transferred to pseudopregnant surrogate mothers which were sacrificed 7 days later. The number of surrogate mothers remaining pregnant following transfer was reduced significantly at the highest concentration of BP(-)-trans-7,8-dihydrodiol. The 50% effective concentration (EC50) of this compound for blastocyst implantation rate was 0.33 microM and the EC50 for decidual swelling volume was 0.57 microM. Blastocyst implantation and decidual swelling volume was reduced in a concentration dependent manner. These data indicate that metabolites of BP formed in the presence of endometrial cell microsomes were capable of disrupting normal blastocyst development.