Diethylstilbestrol: placental transfer, metabolism, covalent binding and fetal distribution in the Wistar rat

Abstract

The disposition of [14C]diethylstilbestrol (DES) was investigated in the near-term pregnant Wistar rat. Both constant maternal i.v. infusions and direct fetal i.p. injections of [14C]DES were utilized as exposure routes. Maternal femoral vein infusions (total dose: 0.3-0.4 mg of DES/kg of maternal b.wt.) resulted in a stable maternal plasma level of DES during a 3-hr period. At 3 hr, fetal plasma levels were 2 to 3 times higher than maternal plasma DES. The chorioallantoic placenta and visceral yolk sac concentrated DES to levels 5 to 7 times that in the maternal plasma. DES was highly concentrated in the extraembryonic membranes and did maintain high fetal plasma levels of DES. Fetal reproductive tract had total 14C-activity levels 20 to 25 times higher than those in maternal plasma. The extractable 14C-activity in the reproductive tract was 20% DES, 15% glucuronides and 65% oxidative metabolites (beta-dienestrol, 4-OH-propiophenone, omega-OH-DES + unknowns). Fetal liver contained DES (approximately 2%), glucuronides (75%) and oxidative metabolites (approximately 20%). 14C analysis of the whole fetus indicated that the DES was 75% and glucuronides was 25%. Maternal and fetal liver had similar metabolites. Direct fetal injections of [14C]DES resulted in similar metabolite profiles in fetal tissues. The degree of covalent binding of [14C]DES to cellular constituents was tissue-specific, especially the fetal reproductive tract. Thus, DES and its oxidative metabolites were concentrated in the fetus and selected fetal tissues. It is proposed that both the estrogenic activity of DES and the potential reactivity of its metabolites may be responsible for the toxicity expressed in the fetus. Inasmuch as direct fetal injections of [14C]DES resulted in high tissue localization of both oxidative and conjugative metabolites within the fetus, it is suggested that fetal tissues may metabolize DES.