Cyclopamine‐induced synophthalmia in sheep: defining a critical window and toxicokinetic evaluation

Abstract

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.

LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

“…It remains to be determined whether the observed changes are the result of direct or indirect effects of LPS and Beta with these developmental pathways. On the basis of these results, intervention studies using inhibitors of the Shh pathway [e.g., cyclopamine (53)] would be helpful. The developing lung is plastic in that it is continually changing over gestation.…”

Congenital Abnormalities in Production Animals

“…2A in the article by Middleton elsewhere in this issue), is part of a wide range of craniofacial abnormalities arising from the teratogenic action of the alkaloidal steroid cyclopamine, 19,20 but with a relatively narrow window of activity, both temporally and dose-related. 21 Cyclopamine inhibits the hedgehog signal transduction pathway. Mouse embryos cultured in the presence of cyclopamine to silence their sonic hedgehog gene show these changes of cyclopia and the associated developmental brain defect holoprosencephaly.…”

A Cyclopia Case with Otocephaly in a Pirlak Lamb

“…Based on anamnesis at the same grazing region, there was no malformation case seen either in the herd that the case was observed or in the other closer herds. It may be mentioned that viral agents has no effect on malformation in this lamb.Many cyclopia cases occurring in high incidence (25%) have been reported in the sheep herds grazing in the field containing Veratrum californicum plant which has a teratogenic effect in sheep (Welch et al 2009). It is reported that especially the alkaloid, cyclopamine, has toxic effects on the fetus at the day 14 of pregnancy.…”

“…It is reported that especially the alkaloid, cyclopamine, has toxic effects on the fetus at the day 14 of pregnancy. Thus, it causes craniofacial defects and embryonic death that can be seen later (Welch et al 2009, Welch et al 2012. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction pathway directing the embriyonic cell development and differentiation at the phase of embryonic period (Incardona et al 1998).…”

“…The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction pathway directing the embriyonic cell development and differentiation at the phase of embryonic period (Incardona et al 1998). In addition, it effects maxillary and eye structure development leading to cyclopia cases (Welch et al 2009, Welch et al 2012. However, according to our knowledge there is no Veratrum californicum plant in the fields in Afyonkarahisar region.…”