Fescue Toxicosis
Karen McDowell
Tall fescue (Lolium arundinaceum [Schreb.] Darbysh.) is one of the most widely grown perennial grasses in the world and covers approximately 14 million ha in the United States alone.
It can be infected with an endophytic fungus, Epicbloe coenophiala (previously classified as Neotypbodium Coenopbialum or Acremonium Coenopbialum), which, in a symbiotic relationship with the plant, produces a variety of potentially toxic alkaloids that may adversely affect grazing livestock.100,101 It is the ergot alkaloids, a class of compounds including ergopeptines, lysergic acid amines, and clavines, that are the principle toxins responsible for fescue toxicosis in livestock.102-104 Perennial ryegrass (Lolium perenne L.) may be infected with a similar endophyte, N. Lolli, and also produce ergot alkaloids, resulting in a toxicosis in livestock that is similar to fescue toxicosis.105 Tall fescue toxicosis is the major grass-induced toxicosis in the United States,106 and ergovaline is the most abundant ergot alkaloid in tall fescue.103Clinical Signs of Fescue Toxicosis
Ergot alkaloids have an ergoline ring structure with a molecular architecture similar to various biogenic amines, including dopamine, serotonin, norepinephrine, and epinephrine, and this structural similarity allows them to bind to the respective biogenic amine receptors.103 Clinical signs of fescue toxicosis in livestock have been well documented.106-112
| ■ BOX 12.11 | |
| Causes of Pregnancy Loss in Ruminants | |
| Common Causes | Endotoxemia (B, O, C: EED, Ab) |
| Campylobacter infection (B: EED; O, C: Ab) | Cache Valley virus (B, O: EED, Ab) |
| Epizootic bovine abortion (B: Ab) | Maternal stress (O, C: Ab) |
| Arcanobacterium (Actinomyces) pyogenes (B: Ab) | Pregnancy toxemia (O, C: Ab) |
| Bacillus species (B: Ab) | Umbilical cord, placental abnormalities (B, O, C: Ab) |
| Bovine protozoal abortion (Neospora species) (B, C: Ab) | Fetal anomalies (B, O, C: Ab) |
| Infectious bovine rhinotracheitis—infectious pustular vulvovaginitis | Deficiency of uridine monophosphate synthase (DUMPS) (B: EED) |
| (IBR-IPV) virus (B: EED, Ab) | Listeria (B, O, C: Ab) |
| Leptospirosis (B, O, C: Ab) Trichomoniasis (B: EED, Ab) | Uncommon Causes |
| Brucellosis (B, O, C: Ab) | Pine needle poisoning (B: Ab) |
| Bovine virus diarrhea (BVD) (B: EED, Ab) | Chlorinated naphthalene toxicity (B: Ab) |
| Toxoplasmosis (O, C: EED, Ab) | Osteopetrosis (B: Ab) |
| Border disease (O, C: EED, Ab) | Lathyrus, poisoning (B, O, C: Ab) |
| Chlamydiosis (O, C: Ab) | Cobalt deficiency (B: EED, Ab) |
| Embryonic defects (B, O, C: EED) | Yersinia pseudotuberculosis (B, O, C: Ab) |
| Bacterial abortion (B, O, C: Ab) | Death camas (Zigadenus species) (O: Ab) Foxglove (B: Ab) |
| Less Common Causes | Phosphate fertilizer toxicity (O: Ab) |
| Twinning (B: Ab) | α-Mannosidosis (B, O, C: Ab) |
| Prenatal asphyxia (B, O, C: Ab) | Ergot toxicity (B, O: EED, Ab) |
| Akabane virus (B, O, C: Ab) | bgcolor=white>Iodine deficiency (O, C: EED, Ab)|
| Q fever (Coxiella burnetii) (O, C: Ab) | Hydrops fetalis (B, O: Ab) |
| Mycotoxicosis (B, O, C: Ab) | Iatrogenic causes (B, O, C: EED, Ab) |
| Anaplasmosis (B, O, C: Ab) | Lead toxicity (B, O: EED, Ab) |
| Ureaplasma infection (B, O: EED, Ab) | Liver fluke disease (B, O, C: Ab) |
| Mycoplasma infection (B, C: Ab) | Locoweed (Astragalus, Oxytropis species) (B, O, C: EED, Ab) |
| Chromosomal abnormalities (B, O, C: EED, Ab) | Ryegrass poisoning (B, O: Ab) |
| Malnutrition, protein-calorie starvation (B, O, C: EED, Ab) | Sarcocystis infection (B, O, C: Ab) |
| Bluetongue (B, O: EED, Ab) | Veratrum poisoning (O, C: EED, Ab) |
| Histophilus (Haemophilus) somni (B: Ab) | Vitamin A deficiency (B, O, C: Ab) |
| Tuberculosis (B: Ab) | Polybrominated biphenyl toxicity (B: EED, Ab) |
| Uterine torsion (B: Ab) | Broomweed (Gutierrezia species) (B, O, C: Ab) |
| Water deprivation-salt toxicity (B, O, C: Ab) | Bacillary hemoglobinuria (B, O: Ab) |
| Selenium deficiency (B, O, C: Ab) | Tetraglymia glabrata (O: Ab) |
| Mycotic, fungal abortion (B, O, C: Ab) | Copper deficiency (O, C: Ab) |
| Salmonellosis (B, O, C: EED, Ab) | Caprine herpesvirus infection (C: Ab) |
| Nitrate-nitrite poisoning (B, O: Ab) Drug-induced causes (B, O, C: EED, Ab) | Habitual abortion in Angora goats (C: Ab) |
Ab, Abortion; B, bovine; C, caprine; EED, early embryonic death; O, ovine.
■ TABLE 12.1
Tissue Samples to Be Submitted for Diagnosis of Cause of Abortion
| Source | Preservation Method | |
| Chilled or Frozen | Fixed | |
| Aborted fetus | Lung, liver, kidney, spleen, thymus, skeletal | Lung, liver, kidney, spleen, thymus, skeletal |
| muscle, heart, heart blood, abomasum, and | muscle (diaphragm), heart, adrenal gland, | |
| stomach contents | lymph node, thyroid, brain, gonads | |
| Placenta | Allantochorion (ruminants: cotyledons and | Allantochorion (ruminants: cotyledons and |
| intercotyledonary areas), allantoamnion, | intercotyledonary areas), allantoamnion, | |
| amniotic fluid, cord blood | umbilical cord | |
| Dam or herd | Paired serum samples, vaginal or uterine swabs | |
a10% Formalin or Bouin fixative should be used.
Historically, the endocrine hallmark of fescue toxicosis in several species has been a decrease in circulating concentrations of prolactin.112,113 Prolactin is secreted from the lactotrophs of the anterior pituitary gland, and control of its secretion is complex and not completely understood. However, inhibition by dopamine (from the hypothalamus) is a major regulator of its release.114 Dopamine exerts inhibition of prolactin by interacting with the dopamine type-2 receptors (DRD2) of the lactotroph.112 Ergovaline is a dopaminergic agonist, and it is through interaction with this DRD2 receptor that it inhibits release of prolactin.
Dopamine receptors in ovarian tissues, including the CL, have been reported for a number of species, including horses115 and cattle,116 but the role of those receptors in fescue toxicosis, if any, has not been fully elucidated.A second hallmark of fescue toxicosis is vasoconstriction, which has been reported in cattle,117-119 sheep,120,121 goats,122 and horses,123 126 and this vasoconstriction may adversely affect reproductive performance.
Horses
In horses the most frequently reported problems associated with endophyte infected (E+) fescue consumption are in late pregnancy and include altered hormone concentrations, extended gestation, thickened placenta, premature placental separation, placental retention, dystocia, birth of dysmature foals, increased foal and placental weights, and agalactia.109,113,127 Pregnancy may be prolonged as much as 2 to 4 weeks.109,127,128 For pregnant mares grazing E+ versus E- (endophyte negative) fescue, Monroe109 reported significantly reduced circulating prolactin concentrations throughout gestation, as well as reduced progesterone and estrogen concentrations at foaling. Gestation length averaged 360 days for mares on E+ fescue and 333 days for mares on E- fescue, and more mares grazing E+ fescue had retained and thickened placentas than in mares grazing E- fescue. Similarly, Cross113 reported increased gestation length, agalactia, and weak and dysmature foals, as well as reduced concentrations of progesterone in pregnant mares grazing E+ versus E- fescue.
In addition to lactogenesis,129 prolactin also exerts effects on steroidogenesis (estrogens, progesterone and testosterone)130,131; hair growth and shedding132; libido; and synthesis of surfactant by the fetal lungs,133 so perturbations in prolactin secretion may affect a variety of systems. Importantly, prolactin may also exert an effect on the feto-placental unit by altering steroid synthesis and/or metabolism and maturation of the fetal adrenal-pituitary axis necessary for parturition.107 Placental lactogens have not been identified in mares, and as such physiological effects related to inhibition of pituitary prolactin release associated with fescue toxicosis in pregnant mares may be severe.
Normally progestins in the maternal circulation of pregnant mares increase and estrogens tend to decrease in the last 60 days of gestation. Approximately 24 to 48 hours before parturition progestins decrease dramatically, thus causing an increase in the estrogen-to-progestin ratio.134 However, studies have shown that late-gestation mares consuming E+ fescue do not have the decreased estrogens or increased progestins at the expected 107109
time of parturition.1, In addition, the placental hormone relaxin tends to be lowered when pregnant mares graze E+ fescue.135 Alterations in these hormone concentrations, along with the possibility that the ergot alkaloids from E+ fescue may interfere with the maturation of the fetal hypothalamic- pituitary-adrenal axis and the ability of the fetus to produce cortisol and thyroid hormone,113,136,137 may contribute to the extended gestation exhibited by mares consuming E+ fescue.
Youngblood and coworkers138 fed pregnant mares, between 65 and 100 days gestation, either E+ or E- fescue seed, added to their diet, for 10 days. Serum concentrations of prolactin were not different between the treatment groups. Mean concentrations of progesterone were greater in the mares fed E+ fescue seed, but there was no change in progesterone concentrations over time compared with pretreatment values, and there were no incidences of pregnancy loss. There was, however, a significant decrease in plasma concentrations of endogenous catecholamine activity (3,4-dihydroxyphenyl acetic acid) that occurred in the E+ treated mares, suggesting an endocrine disruptive effect of hypothalamic origin.
Recently, McDowell and coworkers (unpublished) allowed pregnant mares to graze and foal on pastures planted in a novel endophyte (NE) fescue versus those planted in a mixture of orchard grass and Kentucky bluegrass (OGBG). There were no differences in prolactin, progesterone, or estradiol concentrations; foaling rates; or placental weights among the mares on the different pasture types.
In addition, foals from the mares grew at comparable rates regardless of pasture. The NE fescue pastures contained negligible ergovaline. Novel endophyte fescues have been developed to retain alkaloids that confer benefit to the 139 140 plants but not those that are deleterious to grazing animals.1,Reports of the effect of E+ fescue on estrous cycles and/or early pregnancy rates in mares differ. Arns141 reported no differences in pregnancy rates, cycles per pregnancy, or estrous cycle lengths in mares consuming E+ versus E- fescue seed, whereas Brendamuehl142 reported prolonged luteal function, decreased pregnancy rates, and higher early embryonic death rates in mares grazing E+ versus E- fescue pastures. The Arns study reported decreased prolactin in the mares receiving E+ fescue seed, whereas when Hestad and McDowell124 compared cycling, nonbred mares fed either E+ or E- fescue seed, the E+ seed resulted in reduced serum prolactin concentrations only associated with the periovulatory prolactin surge, but not during diestrus. Hestad also reported decreased blood flow to the corpus luteum (CL) in the mares receiving the E+ seed compared with mares receiving E- seed.
For pregnant mares, it is generally recommended that animals be removed from E+ fescue pastures 30 to 90 days before expected parturition. Both horses and cattle respond well to treatment with a DRD2 receptor antagonist, such as 113143144
domperidone.113,143,144 Further discussions and dosing recommendations have been given by Cross,113,145 Evans,107 and Jones.146
That E+ fescue causes vasoconstriction in horses has been demonstrated both in vivo124,126,147 and in vitro.123,148 This vasoconstriction likely contributed to the decreased blood flow in the CL in cycling mares reported by Hestad.124 Decreased blood flow in the CL, while not affecting interovulatory intervals in the Hestad study, might have contributed to increased lengths of diestrus in the 1994 Brendemuehl study, by contributing to CL resistance to PGF2α 149
Responses of individual horses grazing the same pastures are variable, and there are currently no convenient and inexpensive laboratory assays to determine fescue alkaloid concentrations in the circulation of horses grazing E+ pastures.
Even if there were, the minimal amounts of alkaloids necessary for an animal to develop premonitory signs of fescue toxicosis have not been established. It has frequently been reported that pastures with ergovaline concentrations below approximately 300 ppb do not cause detrimental effects in horses.150 However, minimal “safe” levels of ergot alkaloids that do not result in fescue toxicosis in horses are not known, and animals grazing in the same pastures likely consume different amounts of fescue grasses. Thus a sensitive measure of biological responses to fescue toxicosis is necessary. To that end, McDowell and coworkers124,126,147 proposed that monitoring vasoconstriction of the palmar artery in horses can provide a convenient, noninvasive, and satisfactory biomarker to determine premonitory signs of fescue toxicosis.Ruminants
The most consistent deleterious health effects associated with fescue toxicosis in ruminants are due to vasoconstrictive properties of the ergot alkaloids. The vasoconstrictive effects of ergot alkaloids are well documented in cattle151-153 and sheep.154 Fescue toxicosis in ruminants is best characterized by the two maladies of “summer slump” in warm climates and “fescue foot” in cold climates.110-112 Summer slump is associated with decreased weight gain, elevated body temperature and respiration rates, shade-seeking behavior, rough hair coat, excessive salivation, and reduced milk production. Fescue foot is characterized by tenderness and/or swelling around the fetlock, lameness, tissue necrosis, and potential sloughing of the hoof, tips of ears, or tail switch. Clearly the previously described conditions may directly and indirectly affect reproductive performance, particularly elevated body temperatures and decreased weight gain associated with summer slump.
Fescue toxicosis associated with decreased reproductive performance in ruminants has been reported.111,155 Cattle grazing E+ fescue pastures, compared with nontoxic forages, typically have reduced dry matter intake, reduced body condition scores, and reduced calving rates.155-158 However, reports of reduced reproductive performance have not been consistent. Pregnancy rates for cows consuming E+ fescue were reduced 7% to 39% compared with control cows,159,160 but other reports showed no reduction in pregnancy rates.161,162 Serum progesterone concentrations may be reduced in heifers143 and ewes,163 and age of the animal may influence the effect of E+ fescue consumption on reproductive performance in cattle.162 Jones143 reported that heifers consuming E+ diets had shorter estrous cycle lengths and lower midcycle progesterone concentrations than heifers on E- and commented that vasoconstriction in the ovary may result in decreased peripheral progesterone concentrations.
Consumption of E+ fescue causes decreased concentrations of prolactin in cattle and sheep. This decrease in prolactin causes a decrease in milk production,164 but rarely complete agalactia, as ruminants have placental lactogens that are thought not to be affected by fescue toxicosis. In addition to decreased prolactin production, cattle grazing E+ fescue also have altered expression of over 500 different genes in the pituitary gland, including genes controlling growth hormone, GnRH and ACTH,165 decreased glutamatergic neurotransmission capacity,166 and altered expression of several liver genes, including those involved in immune responses, oxidative phosphorylation, and ATP synthesis.167
Male Reproductive Function
E+ fescue may negatively impact reproductive performance in bulls and rams. Looper156 reported that bulls grazing toxic E+ fescue pastures had reduced sperm motility and morphology compared with bulls grazing NE (nontoxic) pastures and that semen quality in bulls grazing E+ pastures was decreased as ambient temperature increased. In other studies, ergot alkoids inhibited sperm motility168 and reduced IVF embryo cleavage rates.169 Jones170 reported that bulls fed a diet containing E+ fescue seed had increased scrotal temperature, reduced scrotal circumference, and increased sperm concentration compared with bulls fed a control diet. In addition, studies using Doppler ultrasonography demonstrated constriction of blood flow to the testes of bulls fed E+ fescue seed or allowed to graze E+ fescue pastures.171 However, it is difficult to differentiate between direct effects of fescue toxicosis on male fertility versus effects of increased core and/or testicular temperatures due to vasoconstriction.
There is little information on the effects of E+ fescue on stallion fertility. One study showed no adverse effects of E+ fescue seed consumption on sperm motility, number, morphology, or testicular size, but it did result in reduced gel-free semen volume compared with control stallions.172 Clearly, much more information on potential effects of fescue toxicosis on male fertility is necessary.
Mitigating Fescue Toxicosis in Grazing Livestock
Approaches to ameliorating adverse effects of fescue toxicosis have been reviewed113,145,173-175 and include, among other things, renovation to remove or reduce the amount of E+ fescue in pastures; chemical suppression of seedheads in fescue; removal of animals from E+ infected pastures during times of growth or reproductive performance that may be affected by E+ fescue, using NE or E- tall fescues; and treating the animals with domperidone. Interestingly, clover isoflavones have been demonstrated to relieve alkaloid-induced vasoconstriction in goats,122 and a single polymorphism in the DRD2 receptor gene has been associated with resistance to fescue toxicosis in cattle.176,177
Ergotism in Human Populations—in Medicine and Disease
For interesting discussions on ergotism in human populations, see Strickland,112 van Dongen and Groot,178 and Schiff.179
Approach to Diagnosis of Fescue Toxicosis
James P. Brendemuehl
Definitive diagnosis of fescue toxicosis involves identification of the causative endophytic fungus in forage or seed samples by microscopic examination (Boxes 12.12 and 12.13). Ergo- peptine concentrations may additionally be determined by high-pressure liquid chromatography analysis or specific enzyme-linked immunosorbent assay (ELISA). A presumptive diagnosis of fescue toxicosis can be made in cattle on the basis of expression of the characteristic clinical signs of hyperthermia; excessive salivation; long, rough hair coat; necrosis of the tail
■ BOX 12.12
Manifestations of Fescue Toxicity in Mares
Agalactia, hypogalactia Hypoprolactinemia
Decreased relaxin prepartum Prolonged gestation Early embryonic death Cyclic irregularity
Dystocia
Premature allantochorion separation Allantochorion edema
Increased placental weight Retained placenta Corpus luteum persistence Decreased pregnancy rates
Decreased total progestagens prepartum Poor neonatal viability
Reduced colostral immunoglobulin G (IgG) absorption Neonatal hypoadrenalism
Neonatal hypopituitarism
Neonatal hypothyroidism Fetal oversize
Hirsutism Hyperhidrosis
■ BOX 12.13
Manifestations of Fescue Toxicity in Ruminants
Agalactia, hypogalactia Reduced calf birth weight Hypoprolactinemia Reduced serum cholesterol Reduced conception rates Reduced pregnancy rates Early embryonic death Cyclic irregularity Delayed return to cyclicity postpartum Dystocia Hyperthermia Hyperpnea Hirsutism Reduced weight gain Photosensitization Necrosis of the digits Necrosis of the ears and tail Fat necrosis and ear tips; and fat necrosis in association with consuming fescue forage. Hypoprolactinemia is supportive of the diagnosis, but the assay is not commercially available.
A presumptive diagnosis of fescue toxicity in the pregnant mare is based on the observation of failure of normal mammary development for gestational stage. Prolongation of gestation is commonly reported as well. An accurate breeding history should include dates of breeding, dates of confirmed pregnancy diagnosis, and absence of parturition at the anticipated time. A history of recent exposure to fescue pasture or hay is supportive. In tall fescue-endemic areas, pastures that contain tall fescue grass should be considered infected with the endophyte unless specific testing has confirmed otherwise. Determination of total plasma progestogen concentrations is a sensitive indicator of endophyte exposure after 300 days of gestation.180
Management of a mare suspected of endophyte exposure should consist of removing the mare from the suspected pasture or hay source and maintaining the mare in a stall or dry lot under close observation. High-quality hay, preferably legume, should be provided. Because of the increased incidence of dystocia in mares grazing endophyte-infected tall fescue, close monitoring of the mare and attendance at parturition is critical to minimize risk to the mare and loss of the foal. Removal of mares from infected fescue by day 300 of gestation has been demonstrated to alleviate the toxic effects on the mare and foal. Removal after day 300 carries an increased risk of prolonged gestation, agalactia, dystocia, and neonatal death. Induction of parturition is not recommended because of the high incidence of fetal dysmaturity, fetal oversize, and failure of pelvic relaxation associated with endophyte exposure. Elective cesarean section deliveries of postdate gestation mares have resulted in significantly higher foal survival rates than spontaneous deliveries.
Where removal of pregnant mares from infected fescue is not practical or mares are inadvertently grazed on endophyte- infected fescue beyond the recommended stage of gestation for removal, pharmacologic intervention is warranted. Several DA2 dopamine receptor antagonists—perphenazine,181 fluphen- azine,182 and domperidone183—and the dopamine depleter reserpine184 have been investigated prophylactically to prevent or therapeutically to treat clinical fescue toxicosis. Perphen- 181 182
azine181 and Auphenazine182 have demonstrated mixed success in preventing toxicosis in restricted clinical trials. Reserpine184 was ineffective in preventing prepartum agalactia and prolonged gestation but was sufficient to resolve postpartum agalactia. Domperidone185 has demonstrated efficacy in both the prevention and treatment of clinical fescue toxicosis in clinical trials involving large numbers of mares in numerous locations.