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

7-Dehydrocholesterol accumulates in fetuses affected by the Smith-Lemli-Opi tz syndrome as a result of a deficit in the ultimate step of cholesterol sy nthesis catalyzed by Delta 7 reductase, Rat embryos explanted at gestation day 10 and cultured for 48 h in the presence of the Delta 7 reductase inhib itor AY 9944 were used as a model to discriminate between the beneficial ef fect of supplementation with cholesterol and the deleterious effect of supp lementation with 7-dehydrocholesterol, Cholesterol supplementation in the f orm of mixed cholesterol/lecithin liposomes added to serum serving as the c ulture medium restores the growth of embryos which is markedly decreased in the presence of the inhibitor, 7-Dehydrocholesterol under identical condit ions does not restore growth and impairs the beneficial effect of cholester ol added simultaneously. UV-photooxidation of 7-dehydrocholesterol-suppleme nted culture medium enhances its embryotoxicity, which suggests uptake by t he embryo of toxic by-products formed from 7-dehydrocholesterol. By contras t photooxidation of cholesterol-supplemented culture medium does not induce embryotoxicity, alpha-Tocopherol reduces the toxicity of photooxidized 7-d ehydrocholesterol supplementing the culture medium.jlr We conclude that 7-d ehydrocholesterol does not fulfill the cholesterol requirement of the devel oping embryos and exerts an additional embryotoxic effect probably via oxid ized by-products. This could explain the antenatal growth retardation of SL OS by a blockage of the maternal compensatory cholesterol influx.