Submitted to: International Journal of Poisonous Plant Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 31, 2012
Publication Date: October 1, 2012
Citation: Welch, K.D., Panter, K.E., Stegelmeier, B.L., Lee, S.T., Gardner, D.R., Cook, D. 2012. Veratrum-induced placental dysplasia in sheep. International Journal of Poisonous Plant Research. 2:54-62. Interpretive Summary: Cyclopia and a number of other birth defects occur in lambs from ewes that graze Veratrum californicum early in gestation. Incidences as high as 25 percent have been reported in flocks of 5-10 thousand range ewes. The alkaloids responsible for causing malformations have been identified as well as the critical period of susceptibility. The mechanism of cyclopamine-induced birth defects has been shown to result from the inhibition of the Sonic Hedgehog signal transduction pathway. The Hedgehog signaling pathway plays an integral role in cell growth and differentiation, including embryonic development of the eyes and maxilla. Previous studies by our group have demonstrated that lambs with cyclopia were smaller, under developed, and appeared premature compared to normal lambs of similar gestation age. Preliminary observations suggested this was due to deficiencies in placental development. The objective of this study was to determine if there are deficiencies in placental development in ewes with lambs with cyclopia and other less severe head and face malformations. The results from this study confirmed that cyclopic lambs are smaller than normal lambs as well as less severely malformed lambs. Additionally, we demonstrated that placental development in ewes with cyclopic lambs is compromised. Due to the lack of brain and pituitary gland development in many of the cyclopic lambs, it is quite likely that the lack of normal placental development in ewes with cyclopic lambs is a result of insufficient contribution of the embryo during critical periods of placental development.
Technical Abstract: Cyclopamine, a steroidal alkaloid, from Veratrum californicum is teratogenic causing a range of birth defects including cyclopia (synophthalmia) as well as other craniofacial and structural malformations. Previous studies have indicated that lambs with cyclopia are smaller, under developed, and appear premature compared to gestational matched normal lambs. Preliminary observations suggest this was due to placental dysplasia. The objective of this study was to determine if there are placental dysplasias in ewes with lambs with synophthalmia and other less severe craniofacial malformations. Ewes were dosed orally twice on gestation day (GD) 14 with 0.88 g/kg of V. californicum. Pregnancy, pre-partum fetal malformations, and placentome diameter were determined by ultrasound imaging on GD 45, 60, 75, 105, and 135. At GD 135 the ewes were euthanized and the lambs were assessed for gross malformations and several fetal measurements were made as well as several measurements in the ewe. There was no difference between the controls and the treated animals in the placentome diameter measurements made in utero by ultrasound imaging. The 23 treated ewes were carrying to 26 lambs. Eleven of the lambs were cyclopic, 9 had other craniofacial malformations including maxillary dysplasia, mandibular micrognathia and superior deviation of the rostral mandible, while 6 lambs appeared normal. Cyclopic lambs were smaller than lambs with less severe craniofacial malformations, which were similar in size to normal lambs. The number of placentomes, placentome area, and placentome weight were all significantly smaller for ewes with cyclopic lambs. There was no difference in the size or weight of the fetal pituitary glands between the different groups of lambs. However, weights of the fetal adrenal glands were significantly less in the cyclopic lambs. In summary, there appears to be a correlation between the severity of the malformed lambs and placental dysplasia.