Oxidized derivatives of 7-dehydrocholesterol induce growth retardation in cultured rat embryos: a model for antenatal growth retardation in the Smith-Lemli-Opitz syndrome

Dehydrocholesterol accumulates in fetuses af- fected by the Smith-Lemli-Opitz syndrome as a result of a deficit in the ultimate step of cholesterol synthesis catalyzed by D 7 reductase. Rat embryos explanted at gestation day 10 and cultured for 48 h in the presence of the D 7 reductase inhibitor AY 9944 were used as a model to discriminate be- tween the beneficial effect of supplementation with choles- terol and the deleterious effect of supplementation with 7- dehydrocholesterol. Cholesterol supplementation in the form of mixed cholesterol/lecithin liposomes added to se- rum serving as the culture medium restores the growth of embryos which is markedly decreased in the presence of the inhibitor. 7-Dehydrocholesterol under identical conditions does not restore growth and impairs the beneficial effect of cholesterol added simultaneously. UV-photooxidation of 7- dehydrocholesterol-supplemented culture medium enhances its embryotoxicity, which suggests uptake by the embryo of toxic by-products formed from 7-dehydrocholesterol. By contrast photooxidation of cholesterol-supplemented cul- ture medium does not induce embryotoxicity. a -Tocopherol reduces the toxicity of photooxidized 7-dehydrocholesterol supplementing the culture medium. We conclude that 7- dehydrocholesterol does not fulfill the cholesterol require- ment of the developing embryos and exerts an additional embryotoxic effect probably via oxidized by-products. This could explain the antenatal growth retardation of SLOS by a blockage of the maternal compensatory cholesterol in- flux. —Gaoua, W., F. Chevy, C. Roux, and C. Wolf. Oxidized derivatives of 7-dehydrocholesterol induce growth retarda- tion in cultured rat embryos: a model for antenatal growth retardation in the Smith-Lemli-Opitz syndrome. J. Lipid Res. 1999. 40: 456-463.