Normal and inhibited cholesterol synthesis in the cultured rat embryo.

The Smith-Lemli-Opitz syndrome-affected fetus presents a deficiency in A'-dehydrocholesterol reductase, the last enzymatic step in the cholesterol biosynthesis pathway. Development of the abnormal human fetus takes place in a normal environment as the heterozygous mother's cholester- olemia remains normal. An animal model for this disease has been obtained from the offspring of pregnant rats treated with "distal" inhibitors of A7dehydrocholesterol reductase, AY-9944 or BM15766. In the animal model, embryonic devel- opment occurs in a disturbed environment characterized by hypocholesterolemia and accumulation of A7dehydrocholest- erol and A*dehydrocholesteroI in the maternal serum. The purpose of the present study was to assess, in cultured rat em- bryos at early developmental stages, the relative contributions of exogenous and de novo synthesized cholesterol in the total embryonic cholesterol, according to the conditions of normal and altered de novo biosynthesis. Cultured rat embryos are able to synthesize cholesterol as shown by '"Gincorporation into cholesterol from "Glabeled precursors added to the cul- ture medium.I De novo cholesterol biosynthesis is altered by addition to the culture medium of AY-9944 which inhibits the A'-dehydrocholestero1 reductase and the AX-8'-sterol iso- merase as suggested by the emergence of characteristic aber- rant sterols in the embryonic tissues. Cholesterol-rich serum