Assessment of endophyte-derived tremorgenic compounds in Ipomoea asarifolia using mouse models

Authors: Welch, Kevin; Pfister, James; Cook, Daniel; CARRIAO DOS SANTOS, FABRICIO - Instituto Federal Goiano; Lee, Stephen

Submitted to: Toxicon
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2018
Publication Date: 11/12/2018
Citation: Welch, K.D., Pfister, J.A., Cook, D., Carriao Dos Santos, F., Lee, S.T. 2018. Assessment of endophyte-derived tremorgenic compounds in Ipomoea asarifolia using mouse models. Toxicon. 156:52-60. https://doi.org/10.1016/j.toxicon.2018.11.008.
DOI: https://doi.org/10.1016/j.toxicon.2018.11.008

Interpretive Summary: Ipomoea species from the Convolvulaceae family have been associated with a tremorgenic syndrome in livestock. In Brazil, I. asarifolia has been shown to cause a tremorgenic syndrome in cattle, goats, water buffalo, and sheep. In Australia, I. muelleri has been associated with a tremorgenic syndrome in cattle and sheep. The prominent clinical signs observed in these animals included muscle tremors, especially in the head and neck region, an uncoordinated gait, and severe ataxia with rigid legs resulting in their inability to. The objective of this study was to determine if the indole diterpenes are the primary tremorgenic principles in I. asarifolia, or if there are other principles that are plant derived such as the leaf lectin that may contribute to its tremorgenic/toxic potential. A mouse model was used to study the tremorgenic nature of plants grown from endophyte-containing and endophyte-free seeds. Additionally, previous research has demonstrated that the tremorgenic compounds in I. asarifolia can be transferred via milk from an exposed dam to her nursing offspring. Therefore, a second objective of this study was to determine if nursing mouse pups are a good model to study the toxicity of I. asarifolia, as neonatal mice are often more sensitive than adults to the adverse effects of toxins. Overall, the data presented in this study suggests: 1) the indole diterpenes are likely the primary tremorgenic principles in I. asarifolia and that there are no plant derived tremorgenic compounds; 2) mice can be used as a small animal model to study the tremorgenic nature of I. asarifolia; 3) I. asarifolia causes a dose-dependent physiological response that results in visually observable muscle tremors; 4) the tremorgenic compounds in I. asarifolia are transferred via milk to nursing young causing similar muscle tremors in the pups; and 5) the muscle tremors caused by I. asarifolia are transient in nature, as they appear to resolve quickly once exposure stops. Consequently, it is likely that once grazing animals are removed from areas where they are exposed to I. asarifolia and they are provided nutritious forage, they will recover and return to normal body weight, as well as normal muscle tone, movement and behavior. However, the data presented in this study suggest that early life exposure to I. asarifolia may have longer lasting effects than exposure as adults, similar to results from other mycotoxins.

Technical Abstract: Ipomoea asarifolia has been associated with a tremorgenic syndrome in livestock. Recently indole diterpene compounds were identified in I. asarifolia, and these compounds have been shown to cause a tremorgenic syndrome. In this study, the tremorgenic nature of I. asarifolia was assessed using a mouse model. Adult mice were fed rodent chow containing 10, 15, 20 and 25% endophyte infected (E+), or 25% endophyte free (E-), I. asarifolia for 14 days. The mice fed E+ chow developed a tremorgenic syndrome as characterized by visually observed muscle tremors and an inability to traverse a balance beam, whereas the mice fed E- chow did not develop tremors and had similar muscle coordination to control mice. A lactating mouse model was also used to determine if the compounds can be transferred to nursing pups via the milk. Nursing pups were exposed via their mother’s milk for 21 days, from post-natal day 0-21. Only the pups from dams exposed to E+ chow developed a similar tremorgenic syndrome. Data presented in this study demonstrate that the tremorgenic compounds in I. asarifolia are endophyte derived. Additionally, both adult mice and nursing pups are good models for studying the tremorgenic nature of I. asarifolia and related plants.