CHOLESTEROL-BIOSYNTHESIS INHIBITED BY BM15.766 INDUCES HOLOPROSENCEPHALY IN THE RAT

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 teratoge n 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 dehydr ocholesterols in all groups and steroid hormones in protocol B. D21 fe tuses showed the holoprosencephaly spectrum of malformations and the t reated dams low cholesterol and accumulation of 7DHC, 8DHC, and trieno ls, as in SLOS-affected children. In the 3 dosage groups the malformat ions were dose-related and enzymatic cholesterol decreased to a platea u. The DHC reached 25-44% of the total sterols in the dams. In protoco l B, one-third of the BM15.766-treated fetuses presented facial malfor mations and almost two-thirds pituitary agenesis. On D10, cholesterol reached a minimum and the DHC a maximum while estradiol 17 beta and pr ogesterone were lowered, the latter decreasing in correlation with cho lesterolemia. A sterol profile similar to that previously observed aft er AY9944 associated with a similarly high incidence of pituitary agen esis confirmed that time-limited inhibition of 7DHC reductase induces holoprosencephaly and that pituitary agenesis is the minor form of hol oprosencephaly. (C) 1997 Wiley-Liss, Inc.