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Pregnant mice were treated with a single oral dose of [carboxy-14C]2,4,5-T (100 mg/kg; 1.22 mu Ci/mg) on day 12 of gestation and sacrificed after 0.25, 0.5, 2 and 24 hours. Maternal blood, embryos, placentas and yolk sacs were analyzed by solvent extraction, TLC, and countercurrent distribution. Expressed as percentage of the administered dose/g tissue, the unchanged 2,4,5-T found in maternal blood, placentas, yolk sacs, and embryos was 3, 0.5, 0.5, and 0.2%, respectively, after 0.25 hours, and 4, 2, 2, and 0.5%, respectively, after 24 hours. No major metabolites of 2,4,5-T were detected. Urine and feces were also collected and analyzed. Radioactivity was largely eliminated in the urine, 69-78% of the administered dose in 7 days. Feces contained 5-9% of the dose. In the urine unchanged 2,4,5-T accounted for 35-44% of the dose, and 22-23% as very polar material. Unchanged 2,4,5-T in the feces was 3-5% and 1-2% as polar material. 2,4,5-T administered to pregnant mice is largely distributed and eliminated as 2,4,5-T and very polar material.

Treatment of pregnant mice with delta 9-tetrahydrocannabinol (THC) significantly increased the incidence of in utero deaths. SKF-525A pretreatment increased the incidence of THC-induced in utero deaths. THC also significantly reduced the body weight of surviving fetuses. Phenobarbital treatment antagonized THC-induced reduction of fetal body weight, but did not reduce resorption rate. Administration of THC, 50 or 200 mg/kg, did not induce fetal anomalies. However, both SKF-525A and phenobarbital treatment potentiated THC-induced cleft palates. SKF-525A treatment plus THC produced 36% cleft palates. Phenobarbital treatment plus THC produced 77% cleft palates. Pretreatments altered the level of tetrahydrocannabinol plus metabolites found in plasma, placenta, fetus and amnionic fluid. In general, SKF-525A increased levels and phenobarbital decreased levels. Two chemically reactive metabolites of THC are proposed, 9,10-epoxyhexahydrocannabinol and an 11-oxo derivative. SKF-525A pretreatment increased the concentration of both of these metabolites. Phenobarbital treatment increased the levels of the proposed 9,10-epoxyhexahydrocannabinol. Possible covalent binding of THC was observed. An active metabolite theory may apply to the teratogenic properties of THC.

Mercuric chloride, methylmercuric chloride, and cadmium chloride directly affect the human placental syncytiotrophoblast microvillous membrane. These heavy metals alter the facilitated diffusion of alpha-aminoisobutyric acid (AIB) into vesicles of this membrane in microM concentrations. Mercuric chloride abolishes temporal kinetics of AIB transport, inducing an initial increase in AIB transport (27% at 100 microM) but subsequently lowering equilibrium values when compared to equilibrium time points in control. Methylmercuric chloride and cadmium chloride inhibited the initial rate of AIB transport (40% and 21%, respectively, at 200 microM), but did not affect the equilibrium value of AIB transported when compared to equilibrium levels in control. These effects were concentration dependent. Methylmercuric chloride was more potent in inhibiting AIB transport than cadmium chloride. Methylmercuric chloride and cadmium chloride effects on AIB transport were observed with minimal preincubation with placental vesicles. However, preincubation was necessary for mercuric chloride-induced perturbation of AIB transport. Cysteine protects against mercuric chloride- and methylmercuric chloride-induced effects on AIB transport but did not reverse these perturbations. Mercury- and cadmium-induced placental membrane toxicity result from interactions of these heavy metals with the placental plasma membranes.

Increased levels of alpha-fetoprotein in maternal serum or amniotic fluid may be indicative of a fetal neural tube defect. The present investigation compares, prospectively and retrospectively, the analysis of serum or amniotic fluid alpha-fetoprotein from humans using three radioimmunoassays. A total of 46 sera and 137 prospective and 202 retrospective amniotic fluid samples collected at 12-26 weeks' gestation were assayed using our in-house Farr technique assay, a kit Farr technique assay, and a kit double-antibody assay. Analysis of quality control data in all three assays showed that within- and between-assay variations were less with the double-antibody technique. Additionally, the double-antibody assay offers the advantage of considerably lower nonspecific binding (1.7% vs 16-18% for the Farr technique assays). Of the 375 pregnancies sampled during this study, 340 (91%) resulted in normal singleton births, whereas three (1%) pregnancies were found to have elevated serum or amniotic fluid by all three assay methods and resulted in confirmed neural tube defects. Of the remaining, non-normal outcome without neural tube defect or elevated alpha-fetoprotein was determined in 27 (7%) pregnancies, and false-positive elevated alpha-fetoprotein levels were found for 5 (1%). Analysis of maternal alpha-fetoprotein by radioimmunoassay is a sensitive and accurate adjunct in the prenatal diagnosis of neural tube defects.

Anticonvulsant therapy during pregnancy with the hydantoin phenytoin carries a risk of teratologic sequelae and developmental retardation known as the fetal hydantoin syndrome. The putative teratogen is a highly reactive arene oxide intermediate produced during phenytoin metabolism. By using two structurally similar hydantoins, mephenytoin and its in vivo demethylated metabolite nirvanol, we examined the possibility for a stereoselective dissociation of fetal hydantoin toxicity from maternal anticonvulsant activity. The d-isomers (S-enantiomers) of mephenytoin and nirvanol are p-hydroxylated via an arene oxide and hence were suspect teratogens. The l-isomers (R-enantiomers), being eliminated primarily via alternate pathways, were expected to be less toxic. Equimolar doses of the d- or l-isomers of mephenytoin or nirvanol were administered to pregnant Swiss ICR mice i.p. on gestational day 10. An 8-fold increase in fetal resorptions and a significant 11% decrease in fetal body weight was observed in the group treated with l-nirvanol, whereas no or minimal toxicity was observed in the other treatment groups. The blood clearance for d-nirvanol was double that for l-nirvanol, with correspondingly higher urinary concentrations of arene oxide-mediated metabolites. ANIH shift during metabolism supported the presence of an arene oxide intermediate. Contrary to our expectations, only l-nirvanol, the isomer producing less arene oxide, demonstrated fetal toxicity, thus raising some doubt concerning the arene oxide as the putative hydantoin teratogen. Further animal studies with the d-isomers of mephenytoin and nirvanol may lead to an anticonvulsant of choice during pregnancy.