INHIBITION OF 7-DEHYDROCHOLESTEROL REDUCTASE BY THE TERATOGEN AY9944 - A RAT MODEL FOR SMITH-LEMLI-OPITZ SYNDROME

Our aim is to verify the validity of a rat model proposed for Smith-Le mli-Opitz (SLO) syndrome, a developmental disorder characterized by a defect in 7-dehydrocholesterol-Delta 7 (7DHC)-reductase and by facial dysmorphism close to the holoprosencephaly caused by the teratogen AY9 944. We investigated the sterol profile in rats treated with AY9944 bl ocking 7DHC-reductase. AY9944 was given orally to rats on gestation da y 3 (D3). The sera were sampled for kinetic data on D3, D6, D9, D12, a nd D21. Cholesterol was measured in parallel by the routine enzymatic method and by the gas chromatography/mass spectrometry (GC-MS) procedu re used in SLO diagnosis. In addition to sterols, we dosed steroid hor mones punctually on D4 and on D10, and examined D21 fetuses in other a nimals. The enzymatic method was not specific for cholesterol, and mea sured 70% pure 7DHC added to a normal serum. On D21, 77% live fetuses showed pituitary agenesis. Cholesterol was rapidly reduced by more tha n 50% on D6 involving an accumulation of 7DHC, 8DHC, and trienols, as identified in SLO-affected children. The most abundant 7DHC reached a maximum from D9 to D12, equaling cholesterol on D9 (11 mg/dl). On D10, the magnitudes of hypocholesterolemia and of 7DHC accumulation were f ound to be dose-dependent. Progesterone was reduced as early as 24 hr after treatment and dropped to 40% of the levels in the controls on D1 0, correlating to the decrease in cholesterolemia. This rat model repr oduces the same biochemical perturbations as seen in SLO, strongly sug gesting that aberrant sterols (7DHC, 8DHC, or nortrienol) may contribu te to the developmental defects. (C) 1996 Wiley-Liss, Inc.