5.2 Veratrum californicum

Of the five species of Veratrum in North America, Veratrum californicum has been shown to cause birth defects in various livestock and rodent species. Poisoning was first recognized in the mid-20th century, when in some areas nearly 25% of pregnant ewes that grazed on pastures containing Veratrum californicum gave birth to lambs with a variety of craniofacial malformations. These malformations ranged from mild brachygnathism to severe cyclopia with anencephaly (Figure 40.24). The lesions were often so spectacular that the Basque shepherds called affected lambs “chatto” which translates as “monkey-faced” lamb, and the syndrome became known as monkey-faced disease. FIGURE 40.24. Series of lambs with “monkey faced lamb disease” due to maternal engestion of Veratrum califormicum. Notice the spectrum of craniofacial defects that range from mild superior brachygnathism to anencephaly.

Veratrum californicum grows primarily in the high mountain ranges of the western US. Most Veratrum species are found in moist, open, high alpine meadows or in open woodlands, marshes, along waterways, in swamps or bogs, and along lake edges in high mountain ranges. They are coarse, erect plants about 1–2.5 m tall with short perennial rootstalks. The leaves are smooth, alternate, parallel-veined, broadly oval to lanceolate, up to 30 cm long and 15 cm wide, in three ranks and sheathed at the base. The inflorescence has panicle flowers; the lower ones are often staminate and the upper ones are perfect.

Over 50 complex steroidal Veratrum alkaloids have been identified and divided into five classes: veratrines, cevanines, jervanines, solanidines, and cholestanes. The veratrines and cevanines are of considerable toxicologic interest as they are neurotoxins and hypotensive agents that bind to sodium channels, delaying closure and causing cardiotoxic and respiratory effects. The jervanines are most significant for their teratogenic effects; the most notable alkaloids were named cyclopamine and jervine, both potent inducers of the congenital cyclopia or monkey-faced lamb disease. This cyclopic defect is induced in the sheep embryo during the blastocyst stage of development when the pregnant mother ingests the plant during the 14th day of gestation. The lesion is extremely dependent on the time of fetal exposure, as early studies suggest that durations as short as an hour may produce the defect. Later exposure may produce other terata. For example, early embryonic death may occur if the fetus is exposed during other periods before the 19th day of gestation, and pocomelia and tracheal stenosis may occur when maternal ingestion occurs on gestation days 28–33. The mechanism of teratogenesis has been identified as jervanine alkaloid inhibition of the sonic hedgehog signaling pathway. A key player in craniofacial development during embryogenesis, the sonic hedgehog gene pathway and the related genes that it regulates have also been implicated in the development of numerous cancers, birth defects, and other anomalies. As a result, cyclopamine has become a significant tool in the study of this complex pathway and its involvement in such diverse physiologic processes and diseases.

Clinical signs of direct poisoning are most likely caused by the neurotoxic cevanine alkaloids present in most species of Veratrum. Typical signs begin with excess salivation with froth around the mouth, slobbering, and vomiting, progressing to ataxia, collapse, and death. The elimination half-life of cyclopamine in sheep is approximately 1.1 hours, and it is assumed that the elimination rates of the other similar Veratrum alkaloids are similar. This suggests a withdrawal period of 8 hours for > 99% of the Veratrum toxins. Control of Veratrum is relatively easy with broad-leaf herbicides that have been shown to be effective for decades. The teratogenic effects of Veratrum can be avoided by keeping sheep and other livestock species off pastures containing the plants during the first trimester of pregnancy.