Fescue toxicosis

C

H

A

P

T

E

R

87 Fescue toxicosis Tim J. Evans, Dennis J. Blodgett and George E. Rottinghaus

INTRODUCTION

greater than 95% of tall fescue pastures containing mostly the Kentucky 31 variety are infected by the endophyte, Neotyphodium coenophialum (Yates and Powell, 1988). Endophyte-infected (E) fescue is estimated to cause more than $1 billion in lost livestock production in the United States each year (Oliver, 1997).

“Fescue toxicosis” is one of the most economically costly grass-related intoxications of livestock in the United States, as well as other regions of the world. Historically, there were portions of the United States where particularly unpredictable weather conditions resulted in less than desirable pasture development for grazing livestock. A hardy tall fescue grass, which has undergone a series of changes in nomenclature during the past 40 years (currently Lolium arundinaceum [Shreb.] Darbysh., Schedonorus arundinaceus [Schreb.] Dumort., or Schedonorus phoenix [Scop.] Holub; formerly Festuca arundinacea Schreb. var. arundinacea Schreb. or Festuca elatior L.), was obtained from a Kentucky farm in 1931 and was first marketed commercially in 1943 (Ball, 1984; Burrows and Tyrl, 2001; Strickland et  al., 2011). Today, this variety of tall fescue, Kentucky 31, occupies more than 20 million ha in the United States and represents an important grazing grass, especially within the southeastern and southern midwestern regions of the United States (Evans et  al., 2004b; Stuedemann and Seman, 2005), as well as internationally. It is a cool-season grass that grows well in the fall, producing substantial forage for the winter months. By 1948, a disease syndrome referred to as “fescue foot” had been described in New Zealand, and in 1950, the same syndrome was reported in the United States (Bacon, 1995). In 1973, it was noticed that cattle on a Kentucky 31 pasture were very unthrifty compared to cattle on an adjoining nonfescue pasture (Schmidt and Osborn, 1993). This observation initiated an investigation that revealed a fungus growing within the plant (endo  within; phyte  plant) (Bacon et al., 1977). Today, it is believed that

Veterinary Toxicology, Edited by Ramesh C. Gupta ISBN: 978-0-12-385926-6

BACKGROUND Endophyte name Endophytes are not uncommon in a number of forage grasses and other pasture plants, and unlike other fungal infections, such as those associated with species of Claviceps, they are not visible to the naked eye because they grow “within” the plant (Evans et al., 2004a, 2004b). Bacon et  al. (1977) initially discovered the endophyte and based on earlier morphologic research classified it as Epichloë typhina. This endophyte was later renamed Acremonium coenophialum (Morgan-Jones and Gams, 1982). Further molecular phylogenetic evaluation has generated the latest name for the tall fescue endophyte, N. coenophialum (Morgan-Jones and Gams, 1982; Glenn et al., 1996), and a similar endophyte, Neotyphodium lolii, is found in perennial ryegrass.

Mutualism (symbiosis) and endophyte survival The tall fescue plant and its endophyte enjoy a mutualistic or symbiotic relationship (Thompson et  al., 2001). Each benefits from the survival of the other. The plant

1166

© 2012 Elsevier Inc. All rights reserved. DOI: 10.1016/B978-0-12-385926-6.00115-0

Background

supplies a comforting and safe internal environment for the endophyte along with all the required nutrients. In return, the endophyte lives in intercellular spaces in the plant without disrupting cells of the plant. The endophyte generates multiple toxins that are distributed throughout the plant. The toxins make the plant more resistant to drought, insects, parasitic nematodes, fungi, and herbivores. The endophyte invades seed heads of the plant and is able to continue its relationship with the next generation of fescue through its contamination of the seed. Unlike ergotized (Claviceps purpurea-infected) tall fescue, endophyte infections cannot be transferred naturally to a non-endophyte-infected variety of tall fescue (Evans et al., 2004a). However, E varieties of fescue are more hardy and persistent. They produce more forage and seeds than non-endophyte fescue plants and, thereby, may eventually take over a pasture.

Endophytic toxins Multiple classes of toxins are produced by N. coenophialum, including ergot alkaloids, loline alkaloids, and peramine (Porter, 1995). Loline alkaloids and peramine are primarily insect deterrents. Loline alkaloids belong to an aminopyrrolizidine group of alkaloids but are not known to cause hepatic problems similar to the pyrrolizidine alkaloids in other plant species. The loline alkaloids found in fescue include loline, N-acetyl loline, N-formyl loline, N-acetyl norloline, and N-methyl loline (Porter, 1994). Several of these compounds, particularly N-acetyl norloline, have been associated with equine fescue edema syndrome involving a genetically modified form of N. coenophialum in the Mediterranean variety of tall fescue (Bourke et al., 2009).

Ergot alkaloids General classification and toxicity The ergot alkaloids are a large class of compounds, for which the nomenclature can sometimes be confusing. Ergot alkaloids found in fescue include the lysergic acid amides (e.g., ergonovine), sometimes also referred to as ergoline alkaloids; the clavine alkaloids; and the peptide or peptine alkaloids (Porter, 1995; Evans et al., 2004b; Strickland et al., 2011). Ergovaline is a peptide or ergopeptide (i.e., peptine or ergopeptine) alkaloid with a lysergic acid structure combined with three amino acids. It differs in structure from ergotamine by one amino acid. Among the ergot alkaloids found in tall fescue, ergovaline is by far the most prevalent ergopeptine (Porter, 1995). It accounts for approximately 90% of the ergopeptine alkaloid content of tall fescue (Lyons et al., 1986). The

1167

concentrations of ergovaline in the stems and leaves of tall fescue usually range between 200 and 600 ppb and in the seed heads from 2000 to 4000 ppb (Evans et al., 2004b). Estimates of the minimum threshold toxic concentrations of ergovaline in fescue, which have the potential to cause clinical problems in livestock, range from 50 to 500 ppb (Moubarak et  al., 1993; Tor-Agbidye et  al., 2001; AldrichMarkham et al., 2003; Evans et al., 2004b). These minimal threshold concentrations depend on the species affected, the type of syndrome being considered, and environmental temperatures, and they will most likely vary with geographical location. Species susceptibility from most to least susceptible is as follows: horses (i.e., late-gestational mares)  cattle   sheep  camelids (Aldrich-Markham et al., 2003; Evans et  al., 2004b). In general, total dietary ergo­ valine concentrations greater than 100–200 ppb on a dry weight basis are potentially toxic for cattle and horses, depending on other contributing factors (Rottinghaus et al., 1991; Blodgett, 2001; Evans et al., 2004b). The clinical signs observed following animal exposure to ergopeptine alkaloids are dependent on animal species and physiological state, environmental conditions, relative toxicities of and interactions between different ergopeptine alkaloids, and the level as well as duration of ergopeptine alkaloid exposure (Evans et  al., 2004b). For example, dietary concentrations of ergovaline as low as 50 ppb have been associated with clinical cases of agalactia in mares.

Role of ergovaline in fescue toxicosis The ergopeptine alkaloids are believed by many to be the major toxins responsible for the multiple fescue toxicosis syndromes observed in animal species (Porter and Thompson, 1992; Evans et al., 2004b). Because ergovaline is the most prominent ergopeptine alkaloid, it probably either dictates the likelihood of a toxicosis occurring or, at least, is a reliable biomarker for toxicity. Ergovaline has traditionally been difficult to purify and synthesize, and therefore little research has been done with pure ergovaline to prove that it is the primary toxin in fescue. Although subject to some debate, there are multiple reasons to believe that ergovaline is the primary toxin or, minimally, at least serves as a biomarker for the content of ultimate toxicant in E fescue. An experiment with synthetic ergovaline in sheep reproduced most clinical signs of the summer slump syndrome seen in cattle (Gadberry et al., 2003). Ergovaline injected intraperitoneally into cattle for 3 days produced increased rectal temperatures and respiratory rates observed with summer slump (Spiers et al., 2005a,b). Other ergopeptine alkaloids, including ergotamine and bromocryptine, are also able to reproduce fescue toxicosis syndromes (Evans et  al., 1999, 2004b; Blodgett, 2001). Ergovaline is a very potent vasoconstrictor in in vitro models (Oliver et  al., 1998). In addition, ergovaline is also a strong prolactin

1168

87.  Fescue toxicosis

inhibitor, whereas ergonovine, a lysergic acid amide in E fescue, is unable to produce typical signs of fescue toxicosis or lower prolactin concentrations in cattle (Oliver et  al., 1994). Antibodies against ergot alkaloids, including – to some extent – the ergopeptine alkaloids, are able to ameliorate some clinical features of fescue toxicosis in cattle and mice (Hill et al., 1994; Rice et al., 1998). New, novel endophyte varieties of fescue that lack ergo­ valine, but not other types of fescue endophytic toxins, do not cause fescue toxicosis (Roberts and Andrae, 2004). Syndromes similar to fescue toxicosis are seen when ergotized grains infected by C. purpurea are ingested by livestock (Thompson et  al., 2001; Evans et  al., 2004a). Finally, it has been shown that D2 dopamine antagonists, which stimulate prolactin secretion, are able to alleviate most of the toxic effects of fescue (Lipham et  al., 1989; Cross, 1997; Evans et al., 1999). With improved analytical capabilities, it might be possible in the future to discern more accurately the exact roles of specific ergot alkaloids and their various isomers in the pathogenesis of fescue toxicosis (Strickland et al., 2011).

Seasonal variation The concentration of ergot alkaloids in fescue pastures varies with the season, with ergovaline concentrations reported to be low in the spring (300–500 ppb) and reaching peak concentrations in seed heads (up to 1000– 5000 ppb) during the summer months (Rottinghaus et al., 1991). Concentrations of ergovaline decrease somewhat during the early fall and rebound with fall regrowth. Seed heads consistently contain the highest concentration of ergovaline. Stockpiled fescue pasture has more ergot alkaloids early in the winter than late in the winter (Roberts and Andrae, 2004). Drought and rainy conditions tend to increase ergovaline concentrations (Arechavaleta et al., 1992; Aldrich-Markham et al., 2003). Fertilization of fescue pastures with nitrogen- and phosphorus-based fertilizers or poultry litter also increases ergot alkaloid concentrations (Stuedemann and Seman, 2005). Because ergovaline is a mycotoxin and mycotoxin production and persistence are dependent on multiple seasonal and environmental conditions, it is not surprising that concentrations of ergovaline in tall fescue would be expected to vary from season to season and year to year (Lyons et al., 1986).

Interactions with Claviceps purpurea Although ergotism in livestock is sometimes considered a historical problem, instances of clinical disease associated with the ingestion of ergotized small grains or pasture grasses, including E and non-endophyte-infected tall fescue, continue to occur in the United States (Evans,

et  al., 2004a,b). This is especially true when grain or grass screenings (fines) are used in feedstuffs. Because of the much higher concentrations of ergopeptine alkaloids present in ergot sclerotia, compared to endophytic mycelia, it is important to evaluate the potential for ergotism in instances in which the typical clinical signs of fescue toxicosis appear to be less dependent on environmental temperature or there is no history or evidence of exposure to E  fescue (Evans et al., 2004a).

PHARMACOKINETICS/ TOXICOKINETICS Absorption Although relatively little research has been devoted to in vivo absorption of ergot alkaloids in livestock species, a growing body of literature involving the pharmaco­ kinetics/toxicokinetics of ergot alkaloids provides at least some additional insight into how ergot alkaloids are handled by the body following oral exposure (Strickland et al., 2011). The rumen and small intestine are most likely the principal sites of ergot alkaloid uptake, which, depending on pH, animal species, and physiological state, can involve both passive and active processes. After cannulation of ruminal, gastric, and mesenteric veins of sheep consuming E fescue, ergot alkaloids were detected only in ruminal veins (Hill, 2005). However, in vitro tissue specimens of rumen, reticulum, and omasum are all capable of ergot alkaloid transport. It is currently thought that most of the gastrointestinal absorption of the ergopeptine alkaloids takes place in the small intestine (Strickland et  al., 2011). Ergovaline is difficult to detect in rumen fluid and is metabolized by rumen microbes to lysergic acid. Other researchers have found that although 50–60% of ingested ergovaline is in the abomasal contents, minimal amounts of ergovaline remain in the ileal contents or feces (Oliver, 1997).

Distribution/metabolism Ergovaline is present only in parts per billion or low parts per million concentrations in E tall fescue, so the dilution factor in the body and sensitivity of various methods make evaluation of the concentration in any organ extremely difficult. Therefore, relatively little is known about the distribution of ergovaline and other ergot alkaloids in the body. Intravenous injection of several ergopeptides in calves documented a distribution and tissue equilibrium phase in serum lasting approximately 1 h (Moubarak et al., 1996). This was followed by

Mechanisms of Action

an elimination phase with a half-life of approximately 20–30 min. It is known that multiple systems in the body may show some effects of ergot alkaloid consumption, including the cardiovascular system, central nervous system, and abdominal fat. There is evidence that ergopeptine alkaloids accumulate in adipose tissue, but experimental results have not been entirely consistent (Strickland et  al., 2011). In ruminants, ergovaline undergoes microbial breakdown to lysergic acid and related compounds. Ergovaline is believed to be metabolized in the liver by the cytochrome P450 3A subfamily of enzymes (Moubarak and Rosenkrans, 2000; Moubarak et  al., 2003; Settivari et  al., 2008; Strickland et  al., 2011). Cytochrome P450 3A4 is responsible for adding one or two hydroxyl groups to the peptide ergoline ring to make it more hydrophilic for excretion (Moubarak and Rosenkrans, 2000). Interestingly, this enzyme family is inducible in rats treated with dexamethasone but is not induced in rats with prior ergot alkaloid exposure (Moubarak et  al., 2003). However, CYP450 induction has been shown in in vitro studies (Settivari et al., 2008), and sheep fed E fescue had increased hepatic activity of mixed function oxidases (Zanzalari et  al., 1989). The indole ring of ergopeptine alkaloids may also undergo eventual oxidation (Moubarak and Rosenkrans, 2000). Whether or not other groups of enzymes are involved in metabolizing or conjugating ergovaline is not known.

Excretion Urine, bile, feces, and, to a much lesser extent, milk are the primary routes of elimination and excretion for ergot alkaloids (Strickland et  al., 2011). Metabolites of ergot alkaloids have been measured indirectly with lysergol antibodies in bile and urine of cattle (Stuedemann et al., 1998). Ninety-six percent of the metabolites in cattle are found in urine. Ergot alkaloids are detected in urine within 12 h of exposure to E fescue and are maximal within 24 h. After removal from a fescue pasture, ergot metabolites are gone within 48 h from the urine of cattle. Similarly, when removed from pastures containing E fescue, post-term mares may show signs of mammary development and impending parturition within 48 h of removal from pasture (Schmidt and Osborn, 1993).

MECHANISMS OF ACTION D1 dopaminergic antagonist Activation of D1 dopamine receptors has been reported to be associated with vasodilation, and antagonism of

1169

these receptors has been reported in conjunction with ergot alkaloids (Cross et al., 1995). The precise role of this mechanism in the gangrene of the extremities described later has not been determined.

D2 dopaminergic agonist Prolactin inhibition Ergovaline is a dopamine D2 receptor agonist (Oliver, 1997). Ergopeptine alkaloids have a 10-fold greater affinity for dopamine D2 receptor binding than do ergoline alkaloids (Larson, 1997). Dopamine agonists mimic the endogenous tonic inhibition of pituitary lactotropes by dopamine and inhibit prolactin secretion by the anterior pituitary. Prolactin inhibition is one of the most consistent problems observed in multiple species exposed experimentally to ergopeptine alkaloids and/or experiencing clinical fescue toxicosis. In essence, this effect of erovaline and other ergot alkaloids is an exquisite, naturally occurring example of “endocrine disruption” and is a sensitive biomarker for exposure to these compounds.

Lactation suppression One of the roles of prolactin is induction of mammary gland growth and milk production (i.e., lactogenesis). Hypoprolactinemia is often associated with agalactia at parturition in many species, especially the horse and pig. Ruminant species have a placental lactogen that can overcome this initial lack of prolactin stimulation of the mammary gland prior to and at birth (Cross, 1997). However, lower prolactin concentrations in dairy and beef cows consuming E fescue, as well as diminished feed intake associated with the ingestion of E fescue, can be reflected by decreased milk production (up to 50%) observed after the perinatal period (Schmidt and Osborn, 1993; Thompson et al., 2001; Evans et al., 2004b).

Effect on other reproductive hormones Prolactin facilitates corpus luteal function and gonadotropin secretion (Porter and Thompson, 1992). Altered luteal function in heifers grazing E fescue can result in reduced progesterone. Consumption of E fescue and ergopeptide exposure have been associated with low progesterone production in both cows and horses, diminished progestagens in late-gestational mares (5α-pregnanes rather than progesterone normally predominate the last two trimesters of equine pregnancy), suppressed relaxin associated with possible impaired placental function, and, somewhat more variable, alterations in estrogen concentrations in pregnant mares (Cross, 1997; Evans et  al., 1999; Thompson et  al., 2001; Evans, 2011). These imbalances of reproductive

1170

87.  Fescue toxicosis

hormones lead to early pregnancy problems in cattle and late pregnancy problems in horses. Ergopeptide potency for prolactin inhibition has been correlated with inhibition of ovum implantation in rats (Fluckiger et al., 1976). Ergovaline is intermediate among the ergopeptides in its ability to inhibit implantation, but it is approximately twofold more potent than ergotamine.

Effect on hypothalamic thermoregulatory center Another role of dopamine and/or prolactin is control of the thermoregulatory center in the hypothalamus (Strickland et  al., 1993). Diminished prolactin and/or dopamine receptor perturbation causes the thermoregulatory center to deregulate and contributes to the development of hyperthermia or hypothermia observed in exposed animals. Deregulation is more likely when environmental temperatures are outside of the thermoneutral range of the animal (Spiers et  al., 2005a,b). Fescue foot problems are more likely at temperatures less than 8°C (Tor-Agbidye et al., 2001), whereas summer slump problems are more apparent when temperatures exceed 31°C (Schmidt and Osborn, 1993; Spiers et al., 2005a,b).

Effect on lipogenesis Prolactin also has a role in lipogenesis through control of metabolism of cholesterol and triglycerides by the liver (Strickland et  al., 1993). Cattle suffering from summer slump traditionally have low serum cholesterol and triglyceride concentrations (Oliver, 1997). Low serum cholesterol is also commonly found in cattle herds with abdominal fat necrosis (Schmidt and Osborn, 1993). Necrotic abdominal fat is lower in ether-extractable material, but it has a much higher cholesterol content of the ether-extractable fraction. Lipolysis in cattle experiencing fescue toxicosis is decreased (Thompson et  al., 2001). Metoclopramide, a dopamine antagonist and prolactin enhancer, increases serum cholesterol levels in steers grazing E fescue pastures (Lipham et  al., 1989). Serum triglycerides and cholesterol are also reduced by α1 adrenergic receptor antagonists and α2 adrenergic agonists, which are both physiologic effects of ergot alkaloids (Oliver, 1997).

Effect on winter hair loss Change in photoperiod with the end of winter and the start of spring normally will increase prolactin production and stimulate shedding of long winter hair in favor of new spring hair coat growth (Thompson et  al., 2001). Associated with a decrease in prolactin, cattle experiencing fescue toxicosis often fail to shed some or all of their long winter hair. This long hair may become bleached out by the summer sun and contributes to an unthrifty appearance. In addition, fescue toxicosis has

been associated with alterations in copper homeostasis (probably associated with decreased feed intake), which most likely also contributes to the discolored appearance of the hair coat in animals on E fescue pasture.

Effect on immunity Prolactin is considered an immunomodulator (Strickland et  al., 1993). Impaired immune function from E fescue seed was noted in mice and rats, whereas cattle were not affected. However, numerous other E fescue studies in cattle cite decreased antibody response, reduced globulins, or increased morbidity and mortality (Thompson et al., 2001). In contrast, Rice et al. (1997) noted increased humoral immunity in cattle fed E fescue.

Miscellaneous neurologic effects Other miscellaneous neurologic effects include a consistently negative effect of dopamine agonists on feed intake, which can have a major impact on consumption of both macro- and micronutrients. Ergopeptine alkaloids may also interfere with gastrointestinal motility, and there evidence that at least motility of the reticulorumen compartment is inhibited by these compounds (Strickland et  al., 2011). Use of a dopamine antagonist, metoclopramide, increased feed intake in lambs fed E fescue without an effect on body temperature (Thompson et  al., 2001). Nervous behavior in cattle fed E fescue might be related to the ability of ergopeptine alkaloids to release dopamine in in vitro synaptosomal preparations (Larson, 1997).

α1 Adrenergic antagonist Ergopeptine alkaloids are α1 adrenergic receptor antagonists as well as α2 receptor agonists (Oliver, 1997). Many of the most characteristic clinical effects of ergopeptine alkaloids are easily described in terms of α2 receptor agonism (discussed later). The assessment of the net effects of interactions between ergot alkaloids and adrenergic receptors in the animal requires that the antagonistic effects of these compounds on α1 receptors be interpreted in light of the endophytic toxins’ agonistic effects on α2 receptors.

α2 Adrenergic agonist Vasoconstriction Gangrene of extremities Ergovaline acts as a potent α2 adrenergic agonist on blood vessels, especially arterioles (Oliver, 1997). The persistent vasoconstriction of peripheral arterioles in

1171

Toxicity

the back legs of cattle consuming fescue is believed to be responsible for thickening of the smooth muscle wall of the arterioles seen with fescue foot problems (Thompson et  al., 2001; Strickland et  al., 2011). Chronic exposure of cattle to E fescue makes their α2 adrenergic receptors more reactive to ergot alkaloids (Oliver, 1997).

Decreased heat loss Constriction of blood vessels in the skin of cattle also contributes to hyperthermia during the summer months. In addition to the thermoregulatory effects of dopamine/ prolactin on the hypothalamus, the decreased dissipation of heat through the skin of cattle is believed to contribute to the higher body temperature observed when summer temperatures are at or above 30°C (Thompson et  al., 2001).

sodium/potassium–ATPase activity seen with ergot alkaloid exposure (Oliver, 1997).

Serotonergic agonist Ergot alkaloids also act on serotonergic2 receptors (Oliver, 2005). Ergovaline is an agonist at serotonergic2 receptors of uterine and umbilical arteries (Dyer, 1993). This serotonergic activity in blood vessels causes persistent vasoconstriction in vitro. Serotonergic activity of ergot alkaloids may also be important in the enhanced mitogenesis of vascular smooth muscle, hypothalamic thermoregulatory center effects, pulmonary vasoconstriction and brochoconstriction, and, importantly, the appetite suppression seen with fescue toxicosis (Oliver, 1997, 2005).

Serum enzyme decrease Multiple serum enzyme decreases in cattle have been associated with inhibition of adenyl cyclase levels due to α2 adrenergic activity of ergovaline (Oliver, 1997). Ergovaline inhibits cyclic AMP production via the α2a adrenergic receptor (Larson, 1997). In addition to the aforementioned decrease in serum cholesterol and triglycerides, there are also decreases in alkaline phosphatase, γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, creatinine kinase, lipase, and lactic dehydrogenase (Oliver, 1997). Potentially, the inhibition of ATPase in brain and kidney may be mediated by the same mechanism (Moubarak et al., 1993).

Oxidative stress A few studies have noted oxidative stress effects in cattle grazing E fescue pastures (Oliver, 1997). α2 Adrenergic receptor agonists have the capability of depleting glutathione, a peptide integral in defending against oxidative stressors. Lakritz et  al. (2002) noted reduced glutathione concentrations in whole blood samples from cattle exposed to heat stress and E fescue. Settivari et  al. (2008) observed decreases in antioxidant proteins following exposure to endophytic toxins.

Renal-related effects α2 Adrenergic receptor agonists decrease antidiuretic hormone release by the pituitary (Oliver, 1997). This causes an inability of cattle to concentrate their urine. Ergot alkaloids also block aldosterone production in the adrenals (Oliver, 1997). Decreased aldosterone and antidiuretic hormone promote diuresis, and cattle coming to feedlots from E fescue pastures have a reputation for producing a muddy wallow in their pens. Aldosterone action could also be compromised by lowered kidney

TOXICITY Seasonal variation and effects of decreased feed intake Cattle Summer slump Summer slump or summer syndrome is the most common and costly syndrome seen in cattle with fescue toxicosis. Although it is most dramatic during the summer when environmental temperatures reach above 31°C, the problem has been reported to occur during other times of the year as well, but the possibility of concurrent exposure to ergot was not ruled out in these instances (Schmidt and Osborn, 1993; Stuedemann and Seman, 2005). Slump refers to the fact that cattle just “ain’t doing right.” Cattle have an unthrifty appearance with rough hair coats that often have not shed from the winter. The sun may bleach out the hair coats. Because of their high body temperatures, cattle spend more time in the shade or watering holes during the day and less time consuming forage. Beef cows consuming E fescue produce approximately 50% less milk for their calves, which results in lower weaning weights (Schmidt and Osborn, 1993). At weaning time, calves raised on E fescue pasture may be 30–40 kg lighter than similar calves on endophyte-free forage (Schmidt and Osborn, 1993). Other potential clinical signs include nervousness, increased salivation, increased rate of respiration, delayed puberty, and reduced conception rates, possibly arising from adverse effects on the male as well as the female (Schmidt and Osborn, 1993; Looper et  al., 2009; Strickland et al., 2011). The reduced conception rates are

1172

87.  Fescue toxicosis

thought to occur in cattle during the early embryonic period and are generally not associated with late-term abortions or stillborn calves (Thompson et  al., 2001). Although sudden deaths during hot summer months have been reported, negligible mortality is associated with summer slump arising from ingestion of endophytic toxins alone, without concurrent exposure to ergopeptine alkaloids produced by C. purpurea.

Fescue foot Fescue foot refers to a syndrome seen in cattle during the late fall or winter months, which is reported to occur when dietary ergovaline concentrations exceed 400 ppb (Tor-Agbidye et  al., 2001). However, the minimum threshold concentrations of ergovaline necessary for the development of fescue foot are very likely temperature dependent and will vary with geographical region. Peripheral vasoconstriction arising from cold environmental temperatures is additive to the vasoconstrictive properties of ergot alkaloids. However, fescue foot is not as common as summer slump, and determinants other than environmental temperature probably exist that help predict whether fescue foot or summer slump is observed clinically. Differences in concentrations of ergovaline or other vasoconstrictive ergot alkaloids, as well as a host of other factors, probably play a role. Vasoconstriction tends to be more severe in rear legs than in the front legs. The switch of the tail and sometimes the tips of the ears are also affected. Vasoconstriction of the back legs is between the coronary band of the hooves and the fetlock area. Areas proximal to the vasoconstriction may be congested, and areas distal to the vasoconstriction undergo gangrenous necrosis, with hooves potentially being sloughed. Affected cattle have visibly swollen rear legs, with shifting rear leg lameness, muscle tremors, rough hair coats, knuckling of the pastern, arching of the back, and eventually, if severe enough, the inability to stand and ambulate (Spiers et al., 2005a,b).

Lipomatosis Lipomatosis is a syndrome of fat necrosis affecting abdominal fat stores in mature cattle (Burrows and Tyrl, 2001; Schmidt and Osborn, 1993). If mesenteric fat surrounding intestines is involved, scanty feces, bloat, or intestinal obstruction may result. Perirenal fat may also be affected with or without causing significant clinical problems. Fat in the pelvic canal may become necrotic and hardened and cause dystocia. Although the hardened fat may sometimes be detected by rectal palpation, the discovery is often made at necropsy as an additional finding unrelated to the animal’s death. The incidence of fat necrosis in cowherds is highest in those herds with the lowest concentrations of serum cholesterol (Stuedemann and Seman, 2005).

Small ruminants Sheep may be affected by fescue and have a syndrome very similar to summer slump in cattle. Ewes grazing fescue have decreased milk production and increased early embryonic mortality (Schmidt and Osborn, 1993; Thompson et  al., 2001). Weight gain and skin temperature in young lambs may be decreased (Gadberry et  al., 2003). Fescue foot problems are possible in sheep with threshold dietary concentrations of 500 ppb ergovaline at environmental temperatures equal to 7.8°C (Tor-Agbidye et  al., 2001). In addition, ergot alkaloids have also been associated with tongue necrosis, along with infertility problems, in sheep (Thompson et  al., 2001). There are also reports of goats and deer experiencing lipomatosis (Evans et al., 2004b; Smith et al., 2004).

Horses Gestational abnormalities Reproductive problems are the most common E fescue-related abnormalities noted in horses (Cross, 1997; Blodgett, 2001; Evans, 2011). Late-term abortion is possible but not common. Pregnant mares are most susceptible to adverse effects associated with ingestion of E fescue after day 300 of gestation (“average” gestational length of 335–345 days). Lack of prolactin in the late-gestational mare, along with decreased progestagens and higher or lower than normal estrogen concentrations, can cause problems in the mare and/or foal (Cross, 1997; Blodgett, 2001; Evans et  al., 2004b; Evans, 2011). Failure to remove mares from fescue pasture or hay during the last month of gestation (30 days prior to a mare’s expected foaling date; approximately day 300 of pregnancy) might result in foal abnormalities, prolongation of pregnancy by 20–27 days or more, and/or, at least, agalactia (Cross, 1997; Blodgett, 2001; Evans et al., 2004b). “Fescue foals” can be smaller than average or normally sized and are predisposed to dysmaturity (birth of dysmature or “dummy” foals). Especially in instances of endophytic toxin-induced prolonged gestation, foals can continue to grow and are likely to become “overmature.” Overmature foals are similar to dummy foals (i.e., slow to stand and suckle, and predisposed to failure of passive transfer and septicemia), but they are generally larger than “normal”-sized foals, with prematurely erupted teeth and overgrown hooves. In situations involving larger than normal foals, which are often “not ready” for birth and postnatal survival, the mare frequently does not prepare well for parturition, and the incidence of dystocia increases dramatically, resulting in possible uterine, cervical, and/or vaginal trauma. In addition, the chorioallantois (i.e., the portion of the equine fetal membranes diffusely attaching to the uterus) might be thickened and edematous and not rupture at the cervical

1173

Treatment

star, as is normal. The chorioallantois might also detach prematurely and precede the foal through the birth canal, presenting as a “red bag.” If the foal is able to successfully break out of the edematous chorioallantois and/or amnion and not suffocate, it invariably faces an agalactic mare with minimal colostral antibodies for passive transfer (Cross, 1997; Blodgett, 2001). In these unfortunate circumstances, the mare and/or particularly the foal can die, and if the mare survives, she frequently experiences rebreeding problems. Retained fetal membranes are also more common with fescue toxicosis.

Subfertility One study noted increased early equine embryonic mortality with exposure to E fescue (Brendemuehl et  al., 1994), and depressed endogenous catecholamine activity has been observed in mares exposed to E fescue early in gestation (Youngblood et  al., 2004). However, other studies have found no increased equine pregnancy loss up to day 300, despite lower progestagen concentrations between gestational days 90 and 120 (Brendemuehl et  al., 1996). In general, equine pregnancy rates are usually fairly good on E fescue pasture, as long as mares have progressed through the transitional phase in the early spring and are already cycling normally and they are not currently being exposed to ergotized grains or grasses (Evans et  al., 2004b). The adverse effects of E fescue toxins on stallion reproductive function remain to be demonstrated, although any observed hyperthermia has the potential to decrease semen quality.

Laminitis Endophytic toxins can predispose horses to laminitis or painful inflammation of the dermal laminae within the hoof, a condition that can result in potentially lifethreatening lameness (Rohrbach et al., 1995).

Camelids (llamas and alpacas) Little research has been done with respect to fescue toxicosis in camelid species. Llamas and alpacas can have hyperthermia problems during summer months. Because endophytic toxins can directly affect the thermoregulatory center in the hypothalamus and decrease dermal heat loss via vasoconstriction, E fescue should be considered a potential contributor to the heat “stroke” or stress syndrome sometimes seen in llamas and alpacas.

Laboratory rodents Although rodents are most likely not naturally exposed to ergopeptine alkaloids, research performed with these species has facilitated initial research evaluating the genomic effects of these compounds (Settivari et  al., 2006). Like cattle, rats ingesting E rations

experience diminished dry matter intake, making them an appropriate and practical model to evaluate the physiological effects of endophytic toxins associated with summer slump, especially those related to restricted caloric intake (Spiers et al., 2005a,b).

TREATMENT Nonspecific treatment/prevention for bovine fescue toxicosis Cattle experiencing summer slump toxicosis are generally unthrifty and are treated by removal from E fescue or by dilution of the ergovaline content of their overall diet. Dilution can be accomplished by feeding supplemental nonfescue forage or concentrates. Clovers or bermudagrass are often oversown into fescue pastures to aid in dilution for a few years (Thompson et  al., 2001). Ergot alkaloid concentrations decrease fairly rapidly in E fescue following cutting so that waiting at least 1 month after clipping E fescue to feed it to cattle is a practical way to control ergovaline exposure (Roberts et  al., 2009). Abnormal copper homeostasis related to decreased feed intake can be addressed by copper supplementation (Stewart et  al., 2010). Providing shade and water holes can help to cool hyperthermic animals. Some researchers have investigated the use of heat stressresistant breeds or lineages of cattle to lessen the impact of summer slump. Gangrenous problems with fescue foot are treated with broad-spectrum antibiotics to diminish secondary infection, and the provision of windbreaks or shelter, in particularly cold climates, might be beneficial.

Specific treatment for fescue toxicosis in various species A D2 dopamine antagonist that does not cross the blood– brain barrier and cause extrapyramidal side effects, as opposed to perphenazine and metoclopramide, has been developed to treat agalactia and prolonged gestation problems in mares (Cross, 1997). The generic name of the drug is domperidone, and it is marketed as an oral gel called Equidone. It is commonly given orally at 1.1 mg/kg once a day during the week before anticipated parturition if the mare shows no signs of milk production or at a point in time when it is determined that gestation is prolonged. The total dose or dosing regimen can be adjusted if the mare begins dripping colostrum. Agalactia in a mare that has already foaled can be treated once or twice a day with the same dosage mentioned previously until milk flow resumes. Experimentally, cattle

1174

87.  Fescue toxicosis

have been treated successfully with domperidone to relieve some of the adverse effects of E fescue on cattle production, and other forms of pharmacologic intervention have also been investigated (Jones et  al., 2003; Strickland et al., 2011). Domperidone has also been given empirically to agalactic camelids at twice the equine dosage, but there are no peer-reviewed reports of the absorption of domperidone in these species or the efficacy of this treatment approach for agalactia. The Rauwolfian alkaloid reserpine (dose of 2.5–5.0 mg/450 kg horse, once a day), which depletes brain depots of dopamine, serotonin, and/or norepinephrine and causes mild sedation, can be used for the treatment of postparturient agalactia but not for less than anticipated mammary development prior to foaling or prolonged gestation associated with exposures to E fescue or other ergopeptine alkaloids (Evans et al., 1999: Evans, 2011).

PREVENTION Prevention of equine fescue toxicosis Breeding and foaling management Knowledge of breeding dates, confirmation of pregnancy, and monitoring of mammary gland development are critical steps in the prevention of equine fescue toxicosis. Removal of the mare from E fescue pasture and hay beginning on gestational day 300, during at least 30 days prior to the anticipated foaling date, will also generally prevent agalactia, prolonged gestation, and foaling problems associated with endophytic toxin exposure. Careful evaluation of mammary gland development, supervision of the mare during foaling (with assistance provided as necessary), and observation of the foal for normal postnatal behavior benchmarks, such as the ability to stand and suckle, as well as successful passive transfer, are also essential steps in ensuring that both the mare and the foal have not been exposed to or adversely affected by exposure to tall fescue endophytic ergopeptine alkaloids (Evans, 2011).

D2 dopamine receptor antagonists In some specific instances and geographical location, it is almost impossible to completely remove mares from any exposure to E fescue and/or hay. Domperidone can be given once a day to mares kept on fescue during the final 10–14 days before expected parturition (Cross, 1997). The dosage is the same as that for the treatment outlined previously. The D2 dopamine receptor antagonist fluphenazine (25 mg administered intramuscularly in pony mares on day 320 of gestation) has

also been used to prevent decreases in relaxin related to ergopeptine alkaloid-induced placental dysfunction (Evans, 2011).

Novel or non-endophyte-infected fescue Endophyte-infected tall fescue pastures can be replanted with other grasses, such as non-endophyte fescue or new novel varieties of endophyte-infected fescue. Renovation requires a nonselective herbicide (e.g., paraquat and glyphosate) to kill off the pasture grasses and planting with a smother crop for a season before spraying again with a herbicide and replanting with another pasture grass (Roberts and Andrae, 2004). Estimated costs of renovation are approximately $450/ha (Fribourg and Waller, 2005). Non-endophyte-infected fescue has been used to replace E fescue, but it is not very drought, insect, nematode, or herbivore resistant; therefore, stand persistence is not good. Novel endophyte varieties have been developed by infecting endophyte-free varieties of fescue with endophytic strains that produce the peramine of tall fescue but minimal or no ergot alkaloids (Roberts and Andrae, 2004; Fribourg and Waller, 2005). Several varieties have shown promise, including MaxQ and ARK Plus, with the novel varieties having insect and drought resistance without adversely affecting cattle, horses, or sheep. However, caution is warranted until more information is available, given the incidence of equine fescue edema syndrome in Australia. This newly reported syndrome occurred, following drought-like conditions, in horses grazing the Mediterranean variety of tall fescue infected with a novel endophyte (Bourke et al., 2009).

Ammoniation of hay Ammoniation of hay will degrade the ergovaline content of hay and make it safe for livestock consumption (Thompson et al., 2001). Ammoniation requires enclosing the hay in an airtight tent structure and pumping anhydrous ammonia gas into the tent for a period of time. Although extremely effective, this process is considered by some to be too time- and labor-intensive, as well as too costly, for routine use. However, there are regions of the United States, where cattle populations are large enough and E fescue pastures sufficiently extensive, which might warrant the investment of the labor, time, and money necessary for proper ammoniation E fescue hay (Evans et al., 2004b; Roberts and Andrae, 2004).

Feed supplements Supplementing livestock with concentrates will decrease the overall dose of ergovaline from fescue. Several different

1175

References

types of feed additives have also been investigated as ways to ameliorate fescue toxicosis. A glucomannan product (FEB-200) from yeast cell walls that is purported to bind ergovaline in the gastrointestinal tract and prevent its absorption improved cattle performance (Fribourg and Waller, 2005). Another feed supplement from seaweed, Tasco, has been reported to ameliorate some of the oxidative effects and immunosuppression associated with exposure of cattle to E fescue (Fike et  al., 2001; Saker et  al., 2001). Copper supplementation can be beneficial in cattle ingesting E fescue (Evans et al., 2004b).

Pasture considerations Pastures might be made less toxic by dilution with other grasses or legumes such as bermudagrass or clover, cutting seed heads from the pasture during the most toxic time period of the summer, or increasing the grazing pressure during the summer to avoid seed heads (Stuedemann and Seman, 2005). Provision of plenty of shade, potable water to drink, and water holes in which to cool off or moving cattle to a nonfescue pasture during the warmest summer months are also reasonable management practices that take into consideration pasture circumstances.

CONCLUDING REMARKS Tall fescue toxicosis is the major grass-associated forage problem in the United States and is worldwide in its occurrence (Oliver, 1997). Because the toxic principles are actually mycotoxins (i.e., secondary metabolites of a fungus), fescue toxicosis is, in fact, a mycotoxicosis rather than a plant intoxication. The production of the ergopeptine alkaloid ergovaline, potentially the primary toxin responsible for clinical disease, by the endophyte N. coenophialum varies seasonally and from year to year. During some years, the ergovaline concentrations in a particular fescue pasture are very high, or there is an increased prevalence of ergotized grasses, including tall fescue. In these circumstances, livestock species, especially cattle and horses, can experience debilitating disease, which can be exacerbated by extremes in ambient temperature. During other years, lower ergovaline concentrations, combined with the nutrient value and hardiness of the endophyte-infected fescue, as well as milder climactic conditions, make its use as a pasture grass or source of hay very practical and, ultimately, extremely profitable. The major disease syndromes associated with fescue toxicosis arise from the prolactin-inhibiting and vasoconstrictive properties of endophytic ergot alkaloids.

Researchers are currently addressing fescue toxicosis in several different ways. One approach is to replace tall fescue with a novel endophyte-infected fescue that is not toxic for animals but is still drought and insect resistant. This has been accomplished, but the costs of pasture renovation are considerable, with some hilly terrain not suitable for renovation. There is also the potential for other, unanticipated toxicoses to be associated with the novel endophyte, under certain growth conditions (Bourke et al., 2009). The other approach to fescue toxicosis has been to find an antidote or preventative for the fescue problem. Domperidone is a suitable treatment or preventative for pregnant mares, but residue concerns will likely prevent its use in the near future for food-producing animals. Other possible preventatives for food animals are still being investigated and include adsorbents, feed supplements, and even vaccines. In addition, newer analytical procedures are being developed, which might help elucidate the precise role of ergovaline, other ergot alkaloids, and their metabolites in the pathogenesis of fescue toxicosis in various livestock species (Strickland et al., 2011).

REFERENCES Aldrich-Markham S, Pirelli G, Craig AM (2003) Endophyte Toxins in Grass Seed Fields and Straw: Effects on Livestock. Oregon State University Extension Service, Corvallis, OR. Publication EM 8598. Arechavaleta M, Bacon CW, Plattner RD, Hoveland CS, Radcliffe DE (1992) Accumulation of ergopeptide alkaloids in symbiotic tall fescue grown under deficits of soil water and nitrogen fertilizer. Appl Environ Microbiol 58: 857–861. Bacon CW (1995) Toxic endophyte-infected tall fescue and range grasses: historic perspectives. J Anim Sci 73: 861–870. Bacon CW, Porter JK, Robbins JD, Luttrell ES (1977) Epichloe typhina from toxic tall fescue grasses. Appl Environ Microbiol 34: 576–581. Ball DM (1984) An overview of fescue toxicity research. Agri-Pract 5 (6): 31–36. Blodgett DJ (2001) Fescue toxicosis. Vet Clin North Am Equine Pract 17: 567–577. Bourke CA, Hunt E, Watson R (2009) Fescue-associated oedema of horses grazing on endophyte-inoculated tall fescue grass (Festuca arundinacea) pastures. Aust Vet J 87: 492–498. Brendemuehl JP, Boosinger TR, Pugh DG, Shelby RA (1994) Influence of endophyte-infected tall fescue on cyclicity, pregnancy rate and early embryonic loss in the mare. Theriogenology 42: 489–500. Brendemuehl JP, Carson RL, Wenzel JGW, Boosinger TR, Shelby RA (1996) Effects of grazing endophyte-infected tall fescue on eCG and progestogen concentrations from gestation days 21 to 300 in the mare. Theriogenology 46: 85–95. Burrows GE, Tyrl RJ (2001) Toxic Plants of North America. Iowa State University Press, Ames, IA. Cross DL (1997) Fescue toxicosis in horses. In Neotyphodium/Grass Interactions, Bacon CW, Hill NS (eds). Plenum, New York, pp. 289–309. Cross DL, Redmond LM, Strickland JR (1995) Equine fescue toxicosis: signs and solutions. J Anim Sci 73: 899–908.

1176

87.  Fescue toxicosis

Dyer DC (1993) Evidence that ergovaline acts on serotonin receptors. Life Sci 53: PL223–PL228. Evans TJ (2011) The endocrine disruptive effects of ergopeptine alkaloids on pregnant mares. Vet Clin North Am Equine Pract 27: 165–173. Evans TJ, Rottinghaus GE, Casteel SW (2004a) Ergot. In Clinical Veterinary Toxicology, Plumlee KH (ed.). Mosby, St. Louis, MO, pp. 239–243. Evans TJ, Rottinghaus GE, Casteel SW (2004b) Fescue. In Clinical Veterinary Toxicology, Plumlee KH (ed.). Mosby, St. Louis, MO, pp. 243–250. Evans TJ, Youngquist RS, Loch WE, Cross DL (1999) A comparison of the relative efficacies of domperidone and reserpine in treating equine “fescue toxicosis.” In Proceedings of the Annual Convention of AAEP, Albuquerque, NM. American Association of Equine Practitioners, Lexington, KY. Abstract, p. 207. Fike JH, Allen VG, Schmidt RE, Zhang X, Fontenot JP, Bagley CP, Ivy RL, Evans RR, Coelho RW, Wester DB (2001) Tasco-Forage: I. Influence of a seaweed extract on antioxidant activity in tall fescue and in ruminants. J Anim Sci 79: 1011–1021. Fluckiger E, Marko M, Doepfner W, Niederer W (1976) Effects of ergot alkaloids on the hypothalamic–pituitary axis. Postgrad Med J 52 (Suppl 1): 57–61. Fribourg HA, Waller JC (2005) Neotyphodium research and applications in the USA. In Neotyphodium in Cool Season Grasses, Roberts CA, West CP, Spiers DE (eds). Blackwell, Ames, IA, pp. 3–22. Gadberry MS, Denard TM, Spiers DE, Piper EL (2003) Effects of feeding ergovaline on lamb performance in a heat stress environment. J Anim Sci 81: 1538–1545. Glenn AE, Bacon CW, Price R, Hanlin RT (1996) Molecular phylogeny of Acremonium and its taxonomic implications. Mycologia 88: 369–383. Hill NS (2005) Absorption of ergot alkaloids in the ruminant. In Neotyphodium in Cool Season Grasses, Roberts CA, West CP, Spiers DE (eds). Blackwell, Ames, IA, pp. 271–290. Hill NS, Thompson FN, Dawe DL, Stuedemann JA (1994) Antibody binding of circulating ergot alkaloids in cattle grazing tall fescue. Am J Vet Res 55: 419–424. Jones KL, King SS, Griswold KE, Cazac D, Cross DL (2003) Domperidone can ameliorate deleterious reproductive effects and reduced weight gain associated with fescue toxicosis in heifers. J Anim Sci 81: 2568–2574. Lakritz J, Leonard MJ, Eichen PA, Rottinghaus GE, Johnson GC, Spiers DE (2002) Whole-blood concentrations of glutathione in cattle exposed to heat stress or a combination of heat stress and endophyte-infected tall fescue toxins in controlled environmental conditions. Am J Vet Res 63: 799–803. Larson B (1997) Neotyphodium toxicoses: an animal cellular/ molecular research technique perspective. In Neotyphodium/ Grass Interactions, Bacon CW, Hill NS (eds). Plenum, New York, pp. 347–360. Lipham LB, Thompson FN, Stuedemann JA, Sartin JL (1989) Effects of metoclopramide on steers grazing endophyte-infected fescue. J Anim Sci 67: 1090–1097. Looper ML, Rorie RW, Person CN, Lester TD, Hallford DM, Aiken GE, Roberts CA, Rottinghaus GE, Rosenkrans CF, Jr (2009) Influence of toxic endophyte-infected fescue on sperm characteristics and endocrine factors of yearling Brahman-influenced bulls. J Anim Sci 87: 1184–1191. Lyons PC, Plattner RD, Bacon CW (1986) Occurrence of peptide and clavine ergot alkaloids in tall fescue grass. Science 232: 487–489. Morgan-Jones G, Gams W (1982) Notes on Hyphomycetes, XLI. An endophyte of Festuca arundinacea and the anamorph of Epichloe typhina, new taxa in one of two new sections of Acremonium. Mycotaxon 15: 311–318.

Moubarak AS, Piper EL, Johnson ZB, Flieger M (1996) HPLC method for detection of ergotamine, ergosine, and ergine after intravenous injection of a single dose. J Agric Food Chem 44: 146–148. Moubarak AS, Piper EL, West CP, Johnson ZB (1993) Interaction of purified ergovaline from endophyte-infected tall fescue with synaptosomal ATPase enzyme system. J Agric Food Chem 41: 407–409. Moubarak AS, Rosenkrans CF (2000) Hepatic metabolism of ergot alkaloids in beef cattle by cytochrome P450. Biochem Biophys Res Commun 274: 746–749. Moubarak AS, Rosenkrans CF, Johnson ZB (2003) Modulation of cytochrome P450 metabolism by ergonovine and dihydroergotamine. Vet Hum Toxicol 45: 6–9. Oliver JW (1997) Physiological manifestations of endophyte toxicosis in ruminant and laboratory species. In Neotyphodium/ Grass Interactions, Bacon CW, Hill NS (eds). Plenum, New York, pp. 311–346. Oliver JW (2005) Pathophysiologic response to endophyte toxins. In Neotyphodium in Cool Season Grasses, Roberts CA, West CP, Spiers DE (eds). Blackwell, Ames, IA, pp. 291–304. Oliver JW, Linnabary RD, Abney LK, van Manen KR, Knoop R, Adair HS (1994) Evaluation of a dosing method for studying ergonovine effects in cattle. Am J Vet Res 55: 173–176. Oliver JW, Strickland JR, Waller JC, Fribourg HA, Linnabary RD, Abney LK (1998) Endophytic fungal toxin effect on adrenergic receptors in lateral saphenous veins (cranial branch) of cattle grazing tall fescue. J Anim Sci 76: 2853–2856. Porter JK (1994) Chemical constituents of grass endophytes. In Biotechnology of Endophytic Fungi of Grasses, Bacon CW, White JF (eds). CRC Press, Boca Raton, FL, pp. 103–123. Porter JK (1995) Analysis of endophyte toxins: fescue and other grasses toxic to livestock. J Anim Sci 73: 871–880. Porter JK, Thompson FN (1992) Effects of fescue toxicosis on reproduction in livestock. J Anim Sci 70: 1594–1603. Rice RL, Blodgett DJ, Schurig GG, Swecker WS, Fontenot JP, Allen VG, Akers RM (1997) Evaluation of humoral immune responses in cattle grazing endophyte-infected or endophyte-free fescue. Vet Immunol Immunopathol 59: 285–291. Rice RL, Blodgett DJ, Schurig GG, Swecker WS, Thatcher CD, Eversole DE (1998) Oral and parenteral vaccination of mice with protein–ergotamine conjugates and evaluation of protection against fescue toxicosis. Vet Immunol Immunopathol 61: 305–316. Roberts C, Andrae J (2004) Tall fescue toxicosis and management. Crop Manage: Online. doi:10.1094/CM-2004-0427-01-MG. Roberts CA, Kallenbach RL, Hill NS, Rottinghaus GE, Evans TJ (2009) Ergot alkaloid concentrations in tall fescue hay during production and storage. Crop Sci 49: 1–7. Rohrbach BW, Green EM, Oliver JW, Schneider JF (1995) Aggregate risk study of exposure to endophyte-infected (Acremonium coenophialum) tall fescue as a risk factor for laminitis in horses. Am J Vet Res 56: 22–26. Rottinghaus GE, Garner GB, Cornell CN, Ellis JL (1991) HPLC method for quantitating ergovaline in endophyte-infested tall fescue: seasonal variation of ergovaline levels in stems with leaf sheaths, leaf blades, and seed heads. J Agric Food Chem 39: 112–115. Saker KE, Allen VG, Fontenot CP, Bagley RL, Ivy RL, Evans RR, Wester DB (2001) Tasco-forage: II. Monocyte immune cell response and performance of beef steers grazing tall fescue treated with a seaweed extract. J Anim Sci 79: 1022–1031. Schmidt SP, Osborn TG (1993) Effects of endophyte-infected tall fescue on animal performance. Agric Ecosyst Environ 44: 233–262. Settivari RS, Bhusari S, Evans T, Eichen PA, Hearne LB, Antoniou E, Spiers DE (2006) Genomic analysis of the impact of fescue toxicosis on hepatic function. J Anim Sci 84: 1279–1294.

References

Settivari RS, Evans TJ, Rucker E, Rottinghaus GE, Spiers DE (2008) Effect of ergot alkaloids associated with fescue toxicosis on hepatic cytochrome P450 and antioxidant proteins. Toxicol Appl Pharmacol 227: 347–356. Smith GW, Rotstein DS, Brownie CF (2004) Abdominal fat necrosis in a pygmy goat associated with fescue toxicosis. J Vet Diag Invest 16: 356–359. Spiers DE, Eichen PA, Rottinghaus GE (2005a) A model of fescue toxicosis: responses of rats to intake of endophyte-infected tall fescue. J Anim Sci 83: 1423–1434. Spiers DE, Evans TJ, Rottinghaus GE (2005b) Interaction between thermal stress and fescue toxicosis: animal models and new perspectives. In Neotyphodium in Cool Season Grasses, Roberts CA, West CP, Spiers DE (eds). Blackwell, Ames, IA, pp. 243–270. Strickland JR, Looper ML, Matthews JC, Rosenkrans CF, Jr, Flythe MD, Brown KR (2011) Board-invited review: St. Anthony’s fire in livestock: causes, mechanisms, and potential solutions. J Anim Sci 89: 1603–1626. Strickland JR, Oliver JW, Cross DL (1993) Fescue toxicosis and its impact on animal agriculture. Vet Hum Toxicol 35: 454–464. Stewart RL, Jr, Scaglia G, Abaye OA, Swecker WS, Jr, Wong EA, McCann M, Fontenot JP (2010) Tall fescue copper and copper– zinc superoxide dismutase status in beef steers grazing three different fescue types. Prof Anim Sci 26: 489–497. Stuedemann JA, Hill NS, Thompson FN, Fayrer-Hosken RA, Hay WP, Dawe DL, Seman DH, Martin SA (1998) Urinary and

1177

biliary excretion of ergot alkaloids from steers that grazed endophyte-infected tall fescue. J Anim Sci 76: 2146–2154. Stuedemann JA, Seman DH (2005) Integrating genetics, environment, and management to minimize animal toxicoses. In Neotyphodium in Cool Season Grasses, Roberts CA, West CP, Spiers DE (eds). Blackwell, Ames, IA, pp. 305–324. Thompson FN, Stuedemann JA, Hill NS (2001) Anti-quality factors associated with alkaloids in eastern temperate pasture. J Range Manage 54: 474–489. Tor-Agbidye J, Blythe LL, Craig AM (2001) Correlation of endophyte toxins (ergovaline and lolitrem B) with clinical disease: fescue foot and perennial ryegrass staggers. Vet Hum Toxicol 43: 140–146. Yates SG, Powell RG (1988) Analysis of ergopeptine alkaloids in endophyte-infected tall fescue. J Agric Food Chem 36: 337–340. Youngblood RC, Filipov NM, Rude BJ, Christiansen DL, Hopper RM, Gerard PD, Hill NS, Fitzgerald BP, Ryan PL (2004) Effects of short-term early gestational exposure to endophyte-infected tall fescue diets on plasma 3,4-dihydroxyphenyl acetic acid and fetal development in mares. J Anim Sci 82: 2919–2929. Zanzalari KP, Heitmann RN, McLaren JB, Sribourg HA (1989) Effects of endophyte-infected fescue and cimetidine on respiration rates, rectal temperatures and hepatic mixed function oxidase activity as measured by hepatic antipyrine metabolism in sheep. J Anim Sci 67: 3370–3378.