Cyclopamine, a steroidal
alkaloid, from the plant Veratrum californicum is teratogenic, causing a range of different
birth defects. The critical window for
cyclopamine-induced
synophthalmia formation has been reported to be gestational day (GD) 14. The objectives of this study were to better describe
cyclopamine-induced craniofacial
deformities, to better define the window of susceptibility to
synophthalmia formation, and to characterize
cyclopamine toxicokinetics in sheep. Ewes were dosed i.v. with purified
cyclopamine for toxicokinetic analysis. Another four groups of ewes were dosed orally twice daily with 0.88 g/kg of V. californicum on GD 13, 14 or 15 or consecutively on GD days 13-15. Pregnancy and pre-partum
fetal malformations were determined by ultrasound imaging on GD 60. At parturition lambs were assessed for gross malformations. The elimination half-life of
cyclopamine in ewes was determined to be 1.1 +/- 0.1 h. The rapid clearance of
cyclopamine indicates that ingestion of V. californicum must occur during a very narrow window for
synophthalmia formation to occur. Ewes dosed with V. californicum on GD 13 or 14 had lambs with various craniofacial malformations including
cyclopia, maxillary dysplasia and
mandibular micrognathia. Ewes dosed on GD 15 delivered normal lambs. Ewes dosed consecutively on GD 13-15 were not pregnant at GD 60 and Veratrum-induced embryonic death was assumed to be the cause. Interestingly, lambs with
cyclopia were smaller, under-developed and appeared premature even though their twin appeared fully developed. Initial evaluations suggest this was due to placental dysplasia.