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 less than 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.