Ergot alkaloid mycotoxins: physiological effects, metabolism and distribution of the residual toxin in mice

Abstract

The complex ergot alkaloids, ergovaline and ergotamine, cause dysregulation of physiological functions, characterised by vasoconstriction as well as thermoregulatory and cardiovascular effects in grazing livestock. To assess the effect of the mycotoxins, blood pressure and heart rate of male mice were measured, and metabolite profiling undertaken to determine relative abundances of both ergotamine and its metabolic products in body and brain tissue. Ergotamine showed similar cardiovascular effects to ergovaline, causing elevations in blood pressure and reduced heart rate. Bradycardia was preserved at low-levels of ergovaline despite no changes in blood pressure. Ergotamine was identified in kidney, liver and brainstem but not in other regions of the brain, which indicates region-specific effects of the toxin. The structural configuration of two biotransformation products of ergotamine were determined and identified in the liver and kidney, but not the brain. Thus, the dysregulation in respiratory, thermoregulatory, cardiac and vasomotor function, evoked by ergot alkaloids in animals observed in various studies, could be partially explained by dysfunction in the autonomic nervous system, located in the brainstem. Ergot alkaloids are produced by certain members of the Clavicipitaceae, including Epichloë, Claviceps, Balansia and Periglandula, as well as the human pathogen Aspergillus fumigatus 1. An array of ergot alkaloids produced by Epichloë endophytes, such as Epichloë festucae var. lolii and Epichloë coenophialum, are commonly found in pasture-based agriculture as they confer benefits to pasture production. Due to its impact on livestock welfare, the best characterised ergot alkaloid producing fungus is E. coenophialum, an endophyte associated with tall fescue grass (Lolium arundinaceum). Ergovaline (Fig. 1) is the major endophyte-derived ergopeptine alkaloid in infected tall fescue and the causative agent of fescue toxicosis or "fescue foot". Tall fescue grasses can also be infected with the parasitic fungus Claviceps purpurea. The major ergopeptide produced by C. purpurea is ergotamine (Fig. 1) which is the main causative agent for the disease "ergotism". These ergopeptides cause vasoconstriction, affecting the animals ability to control body temperature causing conditions called "fescue foot" in colder temperatures and "summer slump" in hot weather 2,3. "Fescue foot" is the result of a reduction of blood flow to the periphery of the animal, affecting thermoregulation and causing dry gangrene (tissue death) 4-6. Animals with this condition show lameness and swelling of the legs, and eventually loss of the tips of the tail or ears and sloughing of the hooves typically from prolonged exposure to the alkaloids. Summer slump indicates hyperthermia or a rise in the animals internal body temperature. Thus, animals spend more time standing in water or shade in order to cool off. Other clinical signs of fescue toxicosis include poor weight gain from reduced feed intake, decreased fertility, and poor milk production 7...

The Impact of Alkaloid-Producing Epichloë Endophyte on Forage Ryegrass Breeding: A New Zealand Perspective

“…Thus, producing a multitude of effects depending on the secondary structure. The ergopeptines ergotamine and ergovaline have similar activities in mice models [ 47 ] causing vasoconstriction, increase in blood pressure and bradycardiac properties. Epichloe festuca var lolii has been studied with respect to its particular ergovaline pathway [ 48 ], this analysis was for a standard toxic strain that follows the published pathway to produce a ‘standard’ level of ergovaline.…”

Effects of Tall Fescue Endophyte Type and Dopamine Receptor D2 Genotype on Cow-Calf Performance during Late Gestation and Early Lactation

“…Kallenbach [ 2 ] estimates that about 12 million beef cows graze tall fescue in this region with reproductivea and liveweight losses estimated at USD 267 per cow in 2015. Most tall fescue contains an endophyte ( Epichloë coenophialia ) that produces ergot alkaloids, a class of mycotoxins that aid the plant in establishment and drought tolerance but is the causative agent for fescue toxicosis when ingested in livestock [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Fescue toxicosis is a syndrome that includes vasoconstriction, high body temperature, low heart rate, increased blood pressure, low serum prolactin, agalactia, reduced forage intake, and poor weight gains observed in livestock grazing endophyte-infected, ergot alkaloid producing tall fescue [ 3 , 5 , 8 ].…”

“…For animals ingesting ergot alkaloids, a classic response is decreased serum prolactin concentrations [ 10 , 11 , 12 , 13 , 18 , 19 ] and vasoconstriction [ 3 , 5 , 8 ]. Ergot alkaloids are dopamine agonists that interact with DRD2 in a competitive manner [ 27 ] to alter serum prolactin [ 28 ] and vasoconstriction [ 5 , 6 , 7 , 8 ]. Campbell et al [ 29 ] identified a SNP in dopamine receptor D2 (DRD2) and established a relationship with serum prolactin concentrations in grazing steers and cows.…”

Effects of ergotamine on the central nervous system using untargeted metabolomics analysis in a mouse model

“…lolii and E. coenophiala, are commonly utilised in pasture-based agriculture as they enhance disease and insect pest control and thus improve pasture performance 3 – 6 . However, ergovaline has well documented effects on animal welfare, including poor weight gain from reduced feed intake, decreased fertility, and poor milk production 7 .…”

“…Ergopeptides, such as ergotamine and ergovaline, are the most structurally complex ergot alkaloids, comprising D-lysergic acid linked via an amide bond to a three-membered peptide 7 . The alkaloids vary only in the composition of the peptide i.e.…”