ARS | Publication request: Investigation of the Susceptibility of Various Strains of Mice to Methyllycaconitine Toxicosis

Submitted to: Journal of Animal Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 9, 2008
Publication Date: March 17, 2009
Repository URL: http://www.pprl.ars.usda.gov
Citation: Welch, K.D., Green, B.T., Panter, K.E., Gardner, D.R., Pfister, J.A., Cook, D., Stegelmeier, B.L. 2009. Investigation of the Susceptibility of Various Strains of Mice to Methyllycaconitine Toxicosis. Journal of Animal Science, 87:1558-1564. doi:102527/jas.2008-1577

Interpretive Summary: The objective of this study was to determine if there is variation in susceptibility of different strains of mice to MLA and to identify factors responsible for the variation that could be used as a model for cattle. The results of this study confirm previous reports that there is a fairly large animal to animal variability to larkspur toxicity, and that this variation is found across numerous strains of mice. In addition to differences in the protein expression of nAChR subunits, other potential differences between these two strains will be evaluated in the future using genomic technologies. Both the protein expression differences and the potential identification of genetic markers discovered in mice will provide the basis for future experiments to identify genetic factors that correlate with susceptibility to larkspur toxicity in cattle. This research will provide livestock producers with specific information that will be useful in breeding, culling, and grazing management programs to reduce or prevent larkspur poisoning on rangelands.

Technical Abstract: Although the mechanism of action for larkspur alkaloids has been described, there is little information on the variation of the physiological response of individual animals to larkspur alkaloids. Anecdotal observations and pilot studies in cattle indicate that there is animal-to-animal variation in response to a debilitating dose of larkspur alkaloids. The objective of this study was to determine if there is variation in susceptibility of different strains of mice to larkspur toxicity and to identify factors responsible for the variation that could then be used as a model for studies in cattle. The acute toxicity of methyllycaconitine (MLA) in ten different inbred strains of mice was compared. The rank order of susceptibility was A/J > B10 > FVB > BALB/c > C57Bl/6 > NZW > C3H > DBA > 129. The calculated LD50s ranged from 3.3 ± 0.2 mg/kg BW to 5.8 ± 0.8 mg/kg BW. The toxicokinetic profiles of MLA in the susceptible A/J and resistant 129 strains were compared in order to determine if their differences in susceptibility are simply due to differences in their ability to eliminate MLA. The differences in toxicokinetic parameters observed did not explain the differences in susceptibility. The protein expression of various nAChR subunits was also compared between the resistant 129 and susceptible A/J strains. The 129 strain of mice had twice the amount of alpha 7 nAChR subunit expression as the A/J strain, which was in direct proportion to the approximate two fold difference in LD50. There was also a significant difference (P<0.05) in the expression of the alpha 3 and alpha 5 nAChR subunits between the 129 and A/J strains, with the 129 strain having a higher expression in each case. These data suggest that the increased susceptibility of the A/J mice could be due to a lower expression of nAChR subunits. Similar analyses need to be made in cattle to determine if there is a difference in susceptibility to larkspur poisoning between breeds and to identify the factors that regulate their susceptibility to larkspur poisoning. This information would be useful for livestock producers in their breeding, culling, and grazing management programs to reduce or prevent larkspur poisoning on rangelands.