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Cholesterol Prevents the Teratogenic Action of AY 9944: Importance of the Timing of Cholesterol Supplementation to Rats¹

Véronique Barbu^*, Charles Roux, Danièle Lambert, Rolande Dupuis, Jean Gardette, Jean-Claude Maziere^*, Cécile Maziere^*, Elisabeth Elefant and Jacques Polonovski^*

^* Laboratoire de Biochimie Laboratoire d'Embryologie, Faculté de Médecine St. Antoine, 75012 Paris, France Laboratoire de Biochimie Médicale, Unité INSERM 181, Faculté St. Antoine, 75012 Paris, France

These studies were conducted to determine whether dietary cholesterol supplementation could prevent fetal malformations induced by the amphipathic drug AY 9944, which is well known as a cholesterol biosynthesis inhibitor, and to investigate whether the plasma maternal sterol level and the nature of the sterols found in treated Wistar rats could explain this prevention. Pituitary agenesis was the most constant element of holoprosencephaly when AY 9944 was administered on d 4 of gestation at two dosages, 50 or 75 mg/kg. The rate of malformed fetuses was dose related. A strong negative correlation was established between maternal plasma sterol levels on d 10 of gestation (day of pituitary gland formation) and the rate of fetal anomalies (r = -0.97, P < 0.01). Supplementation of AY 9944-treated rats with cholesterol had an obvious preventive action on fetal malformations. When cholesterol was added to the diet the same day as AY 9944 treatment and maintained until d 15, the prevention of malformations was almost complete. When the supplementation was initiated later, the prevention of anomalies decreased. The nature of plasma maternal sterols shows that the cholesterol supplementation modifies significantly the ratio of cholesterol to 7-dehydrocholesterol in treated rats. Therefore, maternal plasma sterol perturbations may play a role in the teratogenic action of AY 9944.

KEY WORDS: • sterols • AY 9944 • pituitary agenesis • prevention of abnormalities

¹ This work was supported by CRE-INSERM Grant No. 841022.

Manuscript received 25 August 1987. Revision accepted 18 February 1988.

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