Cholesterol deficit but not accumulation of aberrant sterols is the major cause of the teratogenic activity in the Smith-Lemli-Opitz syndrome animal model

Low cholesterol and high 7-dehydrocholesterol (7DHC) levels are associated with a blockade of Delta 7-reductase in the Smith-Lemli-Opitz syndrome (SLO S) and in the animals treated with the inhibitor AY9944, The impact of the cholesterol deficit and of the accumulation of 7DHC on the embryo were inve stigated in AY9944-treated pregnant rats receiving an enriched cholesterol or 7DHC diet. Sterol profiling was performed under the various nutritional conditions, AY9944 caused a severe decrease in the maternal and embryo chol esterol, The deficit in the embryo was sustained by the embryonic uptake of the inhibitor, A cholesterol-rich diet was efficient in restoring the mate rnal and embryonic cholesterol and phenotype but a 7DHC-rich diet did not m odify the sterol status compared with darns treated with only AY9944, The o ffspring phenotype remained deleterious whether or not the dams received 7D HC-rich diet, Over 80% of the 7DHC was absorbed, as was cholesterol, which was not quantitatively influenced by AY9944, When cholesterol and 7DHC were simultaneously administered, a competition for intestinal absorption enhan ced the lowering cholesterol effect of AY9944. Whether or not the dams rece ived a 7DHC dietary supplement, the offspring's phenotype became normal whe n the diet was supplemented with cholesterol. Under conditions in which the ratio of cholesterol/7DHC is substantially varied, the normal development of embryos can be achieved as long as the cholesterol is sufficient. The ph enotype is reversed in vivo by cholesterol which contrasts with the irrever sible effects manifested in vitro by oxidized 7DHC by-products.