To confirm that blocking
7-dehydrocholesterol delta 7 reductase (7DHC
reductase), as observed in
Smith-Lemli-Opitz syndrome (SLOS), induces craniofacial defects, we tested
BM15.766, which blocks 7DHC
reductase but is chemically unrelated to the
holoprosencephaly-inducing
teratogen AY9944. Rats were given
BM15.766 either in
methylcellulose from days (D) 1 through D11 (3 treated groups: protocol A) or in
olive oil from D4 through D7 (300 mg/kg/d: protocol B). The sera were sampled on D0, D3, and D5 or D6, D10, D14, and D21 to measure
cholesterol and
dehydrocholesterols in all groups and
steroid hormones in protocol B. D21 fetuses showed the
holoprosencephaly spectrum of malformations and the treated dams low
cholesterol and accumulation of 7DHC, 8DHC, and trienols, as in SLOS-affected children. In the 3 dosage groups the malformations were dose-related and enzymatic
cholesterol decreased to a plateau. The DHC reached 25-44% of the total
sterols in the dams. In protocol B, one-third of the BM15.766-treated fetuses presented facial malformations and almost two-thirds pituitary agenesis. On D10,
cholesterol reached a minimum and the DHC a maximum while
estradiol 17 beta and
progesterone were lowered, the latter decreasing in correlation with cholesterolemia. A
sterol profile similar to that previously observed after
AY9944 associated with a similarly high incidence of pituitary agenesis confirmed that time-limited inhibition of 7DHC
reductase induces
holoprosencephaly and that pituitary agenesis is the minor form of
holoprosencephaly.