Exposure of unweaned calves to the toxic compound of giant fennel

Introduction: Vitamin K are essential molecules involved in the post-transcriptional activation of some proteins called protein vitamin K dependent (PVKD). The best know PVKD are the four involved in the coagulation cascade: factor II, VII, IX and X. In mammals, vitamin K has two origins: foods and a recycling system lead by an enzyme called Vitamin K epoxide reductase complex subunit 1 (VKORC1). Some natural molecules are able to inhibit VKOR, which may involve coagulopathy by lack of PVKD. The most famous natural inhibitor is dicoumarol which is responsible for the “sweet clover disease”. Dicoumarol is produced by fermentation from coumarin contained in clover hay. More recently, ferulenol produced by giant fennel (Ferula communis) has been described as a VKORC1 inhibitor [1]. Giant fennel is a common Apiaceae of the Mediterranean Basin. Many cases of intoxication by giant fennel has been reported. Nevertheless, few information are present on the excretion in milk of ferulenol and dicoumarol. Animals and material and methods: Thirty-six suckler-bovines, coming from Corsica in an area with giant fennel, were blood sampled. Precisely, there were 27 adults, 5 unweaned calves (1-3 weeks) and 4 weaned calves (3-6 months). Samples were analysed with LC-MS-MS according to the method developed by Fourrel et al. [2].Results and discussion: Results are presented in figure 1. In adult bovine only one sample is negative to the ferulenol analysis that confirms the exposure of bovine to giant fennel and its anticoagulant compound. The majority of blood samples (25/27) are positive to dicoumarol. This element raises the question on the quality of conservation of hay which is given. The most interesting results concern the unweaned calves. They are almost all positive to ferulenol (4/5) and negative to dicoumarol (5/5). As they do not begin to graze the only source of exposure to ferulenol is the milk. Weaned calves are positive to ferulenol (4/4) and to dicoumarol (3/4). This study seems to show that ferulenol is excreted in milk. The difference between both molecules might be explained by their pharmacokinetic properties or by different transporter[3]. More studies are necessary to characterise ferulenol pharmacokinetics. This new element raises many questions on the consequences of these excretion. Currently, no intoxication has been reported in unweaned calves which is consistent with the weak level of ferulenol in their blood (median: 1.1 ng/mL). Further investigations are necessary to assess the possible importance of this exposure on animals and the impact of the excretion on the milk destined to human use. Conclusion: Cows exposed to ferulenol after eating giant fennel can excrete ferulenol in milk which can conduct to an exposure of unweaned calves.References: 1. Louvet M-S, Gault G, Lefebvre S, Popowycz F, Boulven M, Besse S, et al. Comparative inhibitory effect of prenylated coumarins, ferulenol and ferprenin, contained in the ‘poisonous chemotype’ of Ferula communis on mammal liver microsomal VKORC1 activity. Phytochemistry. oct 2015;118:124‑30. 2. Fourel I, Hugnet C, Goy-Thollot I, Berny P. Validation of a new liquid chromatography- tandem mass spectrometry ion-trap technique for the simultaneous determination of thirteen anticoagulant rodenticides, drugs, or natural products. J Anal Toxicol. mars 2010;34(2):95‑102. 3. Espana B, Couturier S, Prouillac C. Role of ABC transporters in trans-epithelial transport of vitamin K antagonists. Biopharm Drug Dispos. 1 janv 2017;38(1):20‑32.