Submitted to: Poisoning by Plants, Mycotoxins, and Related Toxins
Publication Type: Book / Chapter
Publication Acceptance Date: January 29, 2010
Publication Date: May 1, 2011
Citation: Welch, K.D., Lee, S.T., Gardner, D.R., Panter, K.E., Stegelmeier, B.L., Cook, D. 2011. Dose-Response evaluation of Veratrum californicum in sheep. In: Riet-Correa, F., Pfister, J., Schild, A.L., Wierenga, T., editors. Poisoning by Plants, Mycotoxins, and Related Toxins. Cambridge, MA. CAB International. 37:243-50. Interpretive Summary: Veratrum belongs to the Liliaceae (Lily) family and is comprised of at least five species in North America. Over 50 years ago scientists at the Poisonous Plant Research Laboratory demonstrated that holoprosencephaly and the related craniofacial deformities, called "monkey face lamb disease” was produced in lamb fetuses when pregnant ewes grazed Veratrum californicum early in gestation. The objective of this study was to determine to maximum tolerated dose of ground Veratrum californicum root and the corresponding dose of cyclopamine that would not severely incapacitate the ewes but still cause craniofacial malformations in the lambs. The results from this study indicate that a dosing regimen of 0.88 mg/kg of ground Veratrum californicum root material administered twice in one day is sufficient to cause minor clinical signs of poisoning but not enough to severely incapacitate the animal. This dose corresponded to a dose of 0.88 mg/kg of cyclopamine for the plant material used in this study. This dose of cyclopamine caused craniofacial malformations in the majority of the lambs from ewes dosed on either GD day 13 or 14. This supports previous findings that the critical window for synophthalmia formation is short. Additionally, toxicokinetic analysis demonstrated that the elimination of cyclopamine from sheep is very quick indicating that the plant must be consumed in sufficient quantities during the very narrow critical window for teratogenesis to occur.
Technical Abstract: Veratrum californicum was discovered to be teratogenic in sheep over 50 years ago. The alkaloids in V. californicum responsible for terata induction are jervine, 11-deoxojervine (cyclopamine), and cycloposine (the glycoside of cyclopamine). Current research objectives are to better describe cyclopamine-induced craniofacial deformities and to better define the window of susceptibility to cyclopia formation in sheep. Before conducting teratogenic experiments, a dose finding experiment was performed in order to determine the maximum dose of V. californicum that would not severely incapacitate the animals and cause birth defects. Initially, four sheep were dosed twice (7 am and 3 pm) at doses of 0.75, 1.0, 1.25, and 1.5 g V. californicum / kg BW. Clinical signs of poisoning were monitored for 48 hours after dosing. From this dose-response experiment, it was determined that a dose of 0.88 g/kg would be used for treating pregnant ewes. In studies wherein pregnant ewes were dosed twice (7 am and 3 pm) with 0.88 g V. californicum / kg BW, minor clinical signs were observed. Importantly, the lambs from these ewes had many craniofacial malformations. Pregnant ewes were also dosed with 0.88 g V. californicum / kg BW twice a day over a three day period. The clinical signs observed in these ewes were more pronounced. However, these ewes all lost their lambs after treatment and Veratrum-induced embryonic death was assumed to be the cause. The results from these studies suggest that two doses of V. californicum at 0.88 g/kg BW are ideal for inducing craniofacial birth defects in sheep.