Veratrum-Induced Placental Dysplasia in Sheep

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 fetuses with cyclopia are smaller, under developed, and appear premature compared to gestational matched normal fetuses. Preliminary observations suggest this could be due to placental dysplasia. The objective of this study was to determine if there are placental dysplasias in ewes with fetuses with synophthalmia and other less severe craniofacial malformations. Ewes were dosed orally twice on gestation day (GD) 14 with 0.88 g/kg of dried 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 fetuses 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 26 fetuses. Eleven of the fetuses were cyclopic, nine had other craniofacial malformations including maxillary dysplasia, mandibular micrognathia, and superior deviation of the rostral mandible, while six fetuses appeared normal. Cyclopic fetuses were smaller than fetuses with less severe craniofacial malformations, which were similar in size to normal fetuses. The number of placentomes, placentome area, and placentome weight were all significantly smaller for ewes with cyclopic fetuses. There was no difference in the size or weight of the fetal pituitary glands between the different groups of fetuses. However, weights of the fetal adrenal glands were significantly less in the cyclopic fetuses. In summary, there appears to be a correlation between the severity of the malformed fetuses and placental dysplasia. Abbreviation GD, Gestational Day