Chapter 65 Brittany Baughman Mississippi Veterinary Diagnostic Laboratory, Jackson, Mississippi, USA A toxicant is a material that interferes with normal biological processes and causes adverse effects when it enters the body via ingestion, inhalation, dermal contact, or injection.1 Reproductive toxicants are those capable of causing infertility, subfertility, early embryonic death, fetal developmental deformities (teratogens), fetal death, abortion, and stillbirths. Reproductive toxicants can cause deleterious effects by acting alone or by interacting with environmental, nutritional, or infectious stressors.2 The effect of naturally occurring toxicants as well as anthropogenic compounds on reproduction in cattle while often sporadic can have considerable economic impacts.3 Ruminants, particularly cattle, are at increased risk for developing acute nitrate/nitrite poisoning from the ingestion of excessive amounts of nitrate-accumulating forages, weeds, and crops. Plants attain nitrogen from the soil in the form of nitrate and nitrite. Excessive nitrogen accumulation may occur in a variety of grasses and weeds under specific environmental and artificial conditions including increased fertilization, drought, hail, frost, herbicide damage, decreased sunlight, increased soil acidity, and in soils deficient in sulfur, phosphorus, and molybdenum. Commonly incriminated nitrate-concentrating plants include cereal grains, forage crops, and common weeds.2,4,5 Nitrate accumulates greatest in the roots and lower portions of the plant including the stalks and stems due to decreased photosynthesis-dependent nitrate reductase activity at these sites.2 Cattle may also ingest excessive nitrite and nitrate compounds directly from nitrate-based fertilizers (storage of fertilizers in areas accessible to cattle) and from water contaminated with manure or fertilizer runoff.4,6 A few of the more commonly implicated nitrate-accumulating weeds are Johnson grass (Sorghum halepense), pigweed (Amaranthus retroflexus), jimsonweed (Datura stramonium), and lamb’s quarters (Chenopodium spp.).6,7 However, a variety of other plants species have also been implicated in nitrate poisoning4 (Table 65.1). Table 65.1 Nitrate-accumulating plants. Normally dietary nitrate is converted to nitrite within the reticulorumen and is slowly metabolized to ammonia. However, when present in levels that overwhelm the microbial organisms’ ability to reduce them, nitrate and nitrite are rapidly absorbed into the circulation. Once in the circulation nitrite ions readily interact with hemoglobin molecules of blood, promoting the oxidation of hemoglobin iron from the ferrous (Fe2+) to the ferric (Fe3+) state and forming methemoglobin. The methemoglobin molecule is incapable of binding and transporting oxygen molecules. Once sufficient hemoglobin is oxidized to methemoglobin, clinical signs of hypoxia develop including exercise intolerance, dyspnea, muscle tremors, and cyanotic and occasionally brown-colored membranes and blood. Although maternal methemoglobin molecules are incapable of crossing the placenta, nitrite and nitrate readily cross and can induce fetal erythrocyte methemoglobinemia and anoxia. Typically, reproductive repercussions including abortions, stillbirths, and the birth of weak calves have been reported approximately 3–7 days or more following maternal toxic exposure. In addition to the effects of methemoglobinemia, nitrite and nitrates also act as potent vasoactive compounds resulting in vasodilation and hypotension.2,8 In adult cattle nitrate/nitrite poisoning may be suspected based on clinical signs including brownish discoloration of the blood and mucous membranes and a history of exposure to possible nitrate-accumulating forages.2,4 However, the characteristic chocolate-colored mucous membranes and blood are not always present and can become less obvious as autolysis proceeds.9 In cases of suspect nitrate toxicosis-induced abortion, a full necropsy should be performed on the fetus to rule out other potential causes. Ocular fluid from the fetus or cow can be collected for postmortem nitrate/nitrite analysis by ion chromatography with a conductivity detector. This test can be quite reliable when fluid is collected within hours of death and refrigerated. Standard nitrate dipsticks are also available and can be used to make a presumptive diagnosis of nitrate poisoning. Ideally, nitrate levels should approach 30 ppm or greater to be highly suggestive of nitrate/nitrite-associated abortion. However, a compatible history including maternal grazing on potential nitrate-accumulating forages, or some other form of excessive maternal ingestion of nitrates, is also needed.6 Forage nitrate analysis should also be conducted for confirmation. Forages containing greater than 0.6–1.0% nitrates (6000–10 000 ppm on a dry-matter basis) have been associated with reproductive losses (abortion, stillbirths, and weak calves).2 Treatment of individual animals with intravenous methylene blue in a 1% or 2% aqueous solution at a rate of 1–2 mg/kg body weight with up to 10 mg/kg in severe cases can be performed. However, due to withdrawal times, cattle should not be sold for slaughter for up to 180 days.9 Although methylene blue treatment can be effective in individual animals, it is likely cost prohibitive in herd outbreaks. When nitrate/nitrite poisoning is suspected cattle should be removed from pasture. Propionibacterium acidipropionici strain P5 (a bacterial feed additive) may be supplemented if exposure to high nitrate concentrations in feed or water is unavoidable. Water should be tested when nitrate contamination is suspected from manure or fertilizer runoff. Water nitrate concentrations should be below 440 mg/L, although acute toxicity is typically not appreciated until water nitrate levels exceed 1300 mg/L.6 Ponderosa pine or western yellow (Pinus ponderosa) are common large coniferous trees of the pine tree family (Pinacea) found in all states west of the Great Plains and throughout western Canada. Pinus ponderosa is characterized by 18–28 cm long, yellow-green needles with two to three needles per fascicle.4,10 Ponderosa pine contains a number of compounds that have been associated with toxicity including phytotoxins, mycotoxins, resins, and ligands.4 Overt toxicosis and death in cattle have occasionally been reported; however, the primary toxicological effects of ponderosa pine needle ingestion in cattle are abortion, retained fetal membranes, and metritis. Open cows, steers, and bulls appear to be unaffected by pine needle ingestion.11 Isocupressic acid, a labdane resin acid, is the principal abortifacient compound found in pine needles and the bark of P. ponderosa.12 Two related derivatives of isocupressic acid, acetylisocupressic acid and succinylisocupressic acid, have also been found to be abortifacient following hydrolytic conversion to isocupressic acid in the rumen.13 Other potentially abortifacient acids present in lesser amounts in ponderosa pine needles include agathic acid, imbricatolic acid, and dihydroagathic acid.14 Cattle most often ingest early green ponderosa pine needles as well as dry pine needles from the ground in the late fall, winter, and early spring when normal forages are scarce or when they are stressed.4,10,11 Ponderosa pine needle toxicity can result in late-term abortion in cows when ingested primarily during the last trimester. However, abortions have been reported as early as 3 months of gestation. Cattle may undergo premature parturition anywhere from 2 to 21 days following ingestion of pine needles, although occasionally immediate abortions have been reported.4,11 Premature parturition has been induced in cattle fed pine needles 2.2–2.7 kg/day for a period of at least 3 days.4,15 Calves may be born stillborn or premature (small and weak) depending on the stage of the gestation at the time of ingestion.16 Affected pregnant cows develop edematous swelling of the vulva and mucoid vaginal discharge followed by premature parturition or abortion.4 Abortions are typically characterized by weak uterine contractions, uterine bleeding, incomplete cervical dilation, dystocia, birth of weak calves, agalactia, and retained placentas. The mechanism of action of isocupressic acid on pregnancy is not completely understood.16 However, decreased blood flow to the uterus and increased caruncular arterial tone resulting in chronic vasoconstriction of the vascular bed with subsequent fetal parturition are reported. Histologic lesions of placental tissues may include necrosis and hemorrhage secondary to vasoconstriction.11,16 There are no methods to completely prevent pine needle-induced abortions, although the potential impacts may be minimized. Ideally, pregnant cows should be denied access to pine needles when they are most susceptible to the abortifacient effects of isocupressic acid (third trimester). Pregnant cows should be maintained in adequate body condition when grazing ranges with ponderosa pines to reduce consumption. Adequate food and shelter should also be provided for cattle to minimize stress and consumption of pine needles. Calving schedules may also be changed to late spring or fall when winter weather conditions are less likely to increase pine needle ingestion.10 There is no effective treatment for pine needle toxicosis. Supportive care including antibiotic treatment and uterine infusion in cases of placental retention are recommended for cows that abort. Supplemental colostrum and milk may be required for live premature calves.11 Abortions similar to those caused by ponderosa pine in cattle have also been associated with accidental ingestion of Monterey cypress (Cupressus macrocarpa) in New Zealand. Monterey cypress is a native of California that has been widely planted throughout Europe and New Zealand. Analysis of Cupressus macrocarpa in New Zealand detected elevated concentrations of isocupressic acid. Isocupressic acid is also the primary diterpene acid in Pinus contorta (lodgepole pine), Juniperus communis (common juniper), Korean pine (Pinus koraiensis), and California juniper (Juniperus californica), all of which have been associated with late-term abortions in cattle. Cattle abortions have also been attributed to the ingestion of bark from the Utah juniper (Juniperus osteosperma) and western juniper (Juniperus occidentalis), both of which contain increased concentrations of agathic acid but minimal isocupressic acid.13 Abortions and neonatal mortality in cattle have been attributed to Ateleia glazioviana, Tetrapterys acutifolia, and Tetrapterys multiglandulosa poisoning in Brazil. Ateleia glazioviana is a deciduous tree found in western Santa Catarina and northwestern Rio Grande do Sul. Cattle may browse the leaves of this tree when other forages are scarce due to overgrazing or drought. Ingestion of leaves can cause abortions at any time during pregnancy but most occur when green leaves are ingested during the fall and winter months. Tetrapterys acutifolia and Tetrapterys multiglandulosa are toxic shrubs that can cause significant outbreaks of abortion and deliveries of weak calves. Ateleia glazioviana, T. acutifolia, and T. multiglandulosa can cause similar clinical signs and lesions. Although abortions can occur at any stage of pregnancy, reports are most often described between 6 and 9 months of gestation. Pregnant cows become lethargic 1–3 days prior to abortion and occasionally exhibit blindness. Fetal lesions are similar to those observed in adult intoxications. Aborted fetuses may demonstrate subcutaneous edema of the limbs, yellow clear thoracic and abdominal effusion, and myocardial pallor with increased thickness of the right ventricular wall and interventricular septum. The toxin or toxins responsible for abortions and clinical disease in these plants has not yet been identified.17 Stryphnodendron spp. and Enterolobium spp. are trees in the family Fabaceae that produce pods that when ingested have been linked to gastrointestinal signs, photosensitization, and abortions in cattle and other ruminant species in Brazil.18 Stryphnodendron obovatum trees grow in the central-western region of Brazil and are considered to be one of the most important causes of cattle abortions in this region. Cattle readily ingest the fallen pods during the dry season. Abortions may occur during all stages of gestation but are often observed during late pregnancy. The abortive effects of S. obovatum were experimentally reproduced by feeding mature pods to seven pregnant cows that were between 3 and 7 months of gestation. Three of seven cows aborted between 20 and 30 days following the start of the study. A fourth expelled a mummified fetus 7 months following the experiment. The underlying toxic properties of S. obovatum pods were not identified.19 The abortive properties of Enterolobium contortisiliquum have been demonstrated experimentally in guinea pigs but not in cattle.18 Enterolobium contortisiliquum and Dimorphandra mollis (also of the Fabaceae family) are commonly blamed for abortions in Brazil although this has not yet been proven experimentally.19 Hairy vetch (Vicia villosa Roth) (Figure 65.1), originally introduced from Europe as a forage legume and cover crop, can be found throughout much of the United States and in many other countries including Argentina, Australia, and South Africa.4,20,21 Hairy vetch poisoning in cattle is most often associated with the development of multiorgan, granulomatous and eosinophilic perivascular inflammation most notably the kidney, heart, adrenal gland, and skin. Clinical findings in affected cattle most often include pruritic dermatitis, conjunctivitis, weight loss, hematuria, and diarrhea. However, reports of sporadic abortion, neurologic dysfunction, subcutaneous swelling of the head, neck, and body, multifocal ulceration of the oral mucous membranes, purulent nasal discharge, rales, cough, and pulmonary congestion have also been reported.21 Figure 65.1 Hairy vetch (Vicia villosa). USDA-NRCS PLANTS Database. Hairy vetch poisoning in cattle is most often a diagnosis of exclusion based on clinical signs, histologic findings, and grazing history.20 Clinical manifestations of hairy vetch toxicity typically develop weeks following ingestion of the plant. The toxic principle of hairy vetch has not been definitively determined, but the pattern and composition of the inflammatory response is highly suggestive of a type IV hypersensitivity reaction. It has been postulated that the inflammatory reaction may be caused by one or more ingested plant constituents (absorbed as haptens or complete antigens) sensitizing antigen-specific lymphocytes that then become distributed throughout the body. Subsequent exposure to these antigens presumably evokes a type IV hypersensitivity response. Another proposed mechanism of toxicity is that vetch lectins bind directly to T-lymphocytes inducing T-lymphocyte activation, lymphokine production, cytotoxicity, and the classic granulomatous inflammatory response.21 Once clinical signs develop recovery is not promising as there is no effective treatment. Cattle do not appear to be uniformly susceptible to hairy vetch poisoning. Cattle under the age of 3 years appear to be less prone to clinical disease. Vetch toxicosis has been reported in multiple breeds of cattle, although Holstein and Angus breeds appear to be more commonly affected.4 Broom snakeweed (Gutierrezia sarothrae) (Figure 65.2) is an invasive, herbaceous, short-lived, woody perennial shrub native to the western rangelands of North America. The plant can be found from Saskatchewan and Alberta, Canada south through western Nebraska and Kansas into Texas and central Mexico and extending to Washington, Oregon, California, and Baja California. Heavy growth of broom snakeweed in rangelands is often indicative of poor range management (such as overgrazing), or may be seen in times of drought or following fires.4,22 There are two major species of broom snakeweed, Gutierrezia sarothrae (turpentine weed, slinkweed, perennial snakeweed) and G. microcephala (threadleaf broomweed). Gutierrezia sarothrae grows up to 70 cm tall and has a woody base and branching stems with alternate linear leaves and clusters of small yellow flowers. Gutierrezia microcephala is similar in appearance to G. sarothrae but has smaller flowers.4 Figure 65.2 Broom snakeweed (Gutierrezia sarothrae). Photograph courtesy of Clarence A. Rechenthin, USDA-NRCS PLANTS Database. Broom snakeweeds are toxic and abortifacient to cattle and other livestock species (sheep and goats).11 Potentially toxic and abortifacient compounds in broom snakeweed include saponins, furanoditerpene acids, terpenoids, steroids, and flavones.22 Furanoditerpene acids and flavones found in the leaves of broom snakeweed are similar to isocupressic acid, the abortifacient compound in ponderosa pine. In a study by Molyneux in 1980, saponin extracts from threadleaf snakeweed induced abortion in cattle at low concentrations and death in cattle at high concentrations.11 Abortions caused by broom snakeweed occur mainly when cattle graze during the last trimester of pregnancy.23 Reported clinical signs include anorexia, weight loss, poor hair coat, listlessness, mucopurulent nasal discharge, abortion, diarrhea, constipation, jaundice, rumen stasis, and death. Abortions can occur throughout gestation and are often accompanied by retained fetal membranes that may lead to uterine infection. Signs of abortion include weak uterine contractions, occasional incomplete cervical dilation, and excessive discharge of vaginal mucus. Low nutrition exacerbates fertility problems caused by broom snakeweed. Supplemental nutrition may enhance degradation and elimination of terpenes. Treatment of clinically affected animals is symptomatic and may include antibiotic use in cows with retained placentas to prevent infection.4,11 Snakeweed is typically not very palatable to cattle and is usually only grazed when there is significant grazing pressure due to depleted vegetation. The overall palatability of snakeweed is dependent on the concentrations of plant resins (including terpenes) which accumulate over the growing season. Higher resin concentrations decrease palatability.22 Proper range management, including providing adequate nutrition for cattle by maintaining the range in good condition, decreases the likelihood of snakeweed toxicosis in cattle. In range regions where snakeweed dominates management strategies to control the shrub may include the use of herbicides such as Tordon® 22 K (active ingredient: picloram) and Escort® XP (active ingredient: metsulfuron methyl) or prescribed burning. Low nutrition exacerbates fertility problems caused by broom snakeweed, whereas supplemental protein and energy may enhance degradation and elimination of terpenes.11 Marshelder, also known as narrowleaf sumpweed, is a native warm-season annual found throughout the south central United States and is a member of the sunflower family (Asteraceae). Reportedly cattle consuming large amounts of the plant may display premature mammary development, premature milk let-down, and abortion. Sumpweed is seldom eaten by cattle; however, ingestion of young plants during the two- to eight-leaf stage of development has been associated with cattle abortions during 4 to 8 months of gestation and premature calves. The toxic agent/compound is not known.24 White sweet clover (Melilotus alba) and yellow sweet clover (Melilotus officinalis) are biennial legumes (family Fabaceae) commonly grown as forages in the northwestern United States and western Canada. Both species have compound leaflets with serrated edges and pea-like flowers produced on axillary racemes.4 Ingestion of hay or silage containing spoiled sweet clover (yellow or white) can induce toxicity. Sweet clover naturally contains coumarin which may be converted to the toxin dicoumarol, a potent vitamin K antagonist, by dimerization and oxidation through the actions of fungi such as Aspergillus, Penicillium, and Mucor.25,26 Dicoumarol interferes with synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X. These factors are necessary for prothrombin conversion to thrombin, which polymerizes fibrinogen to fibrin. Impaired fibrin production causes poor stabilization of platelet plugs, predisposing affected animals to hemorrhage.26 Clinical signs of moldy sweet clover toxicity are often nonspecific and vary from excessive hemorrhage following trauma to spontaneous hemorrhages including epistaxis, melena, hemarthrosis, hematuria, and anemia. Hemorrhages typically occur several days to weeks following ingestion of moldy sweet clover. Dicoumarol levels of 20–30 mg/kg in hay are usually required before clinical disease develops.27 Dicoumarol can cross the placenta causing fetal hemorrhage and has been associated with sporadic abortions in cattle.4,25,28 Clinical signs of dicoumarol toxicity secondary to moldy sweet clover ingestion are indistinguishable from anticoagulant rodenticide toxicosis. A diagnosis of moldy sweet clover poisoning should be suspected when cattle have a history of prolonged consumption of sweet clover combined with compatible clinical signs, and prolonged blood clotting times. Dicoumarol analysis of blood from affected animals (live or dead) and analysis of silage or hay can confirm the diagnosis. In cases of clinical disease affected silage or hay should be removed. Animals demonstrating clinical signs should receive an intramuscular or subcutaneous injection of vitamin K1 (phytonadione) at a dose of 1.1–3.3 mg/kg body weight every 12 hours for 5 days or until prothrombin time and activated partial thromboplastin time return to normal.26 In severe cases cattle may be treated with whole blood transfusions (2–4 L of blood per 450 kg) from a donor animal not being fed moldy clover.28 Blood transfusions are typically indicated when packed cell volumes fall below 12%.26 Other plants containing coumarin include sweet vernal grass (Anthoxanthum odoratum), Lespedeza stipulacea, many species of Umbelliferae, and other species of Melilotus (melilot).4,26 Herd outbreaks of dicoumarol toxicity have also been reported in cattle ingesting moldy A. odoratum hay or silage.26 Teratogens are compounds that are capable of inducing developmental malformations or birth defects via insult to a developing fetus. The vast majority of scientific research and investigation in the field of veterinary and human teratology has involved laboratory animals due to their short gestation periods compared with livestock and due to the significant differences in cost involved with project design and the care and maintenance of large animal subjects.29 Many factors are involved in the development of teratogen-induced congenital defects. Teratogen susceptibility can vary greatly among genotypes within the same species which may result in variations in incidence and severity of malformations within the same herd. In order for a teratogenic compound to exert its effect on a fetus, it and/or its metabolites must first reach the conceptus by crossing the placenta. Teratogens, like many other toxins, are dose dependent. Sufficient amounts of the toxic compounds must be ingested by the dam, absorbed into the maternal circulation, and eventually pass through the placenta to the embryo or fetus. Teratogenic compounds in sufficient quantity may result in early fetal loss (abortion or resorption) rather than congenital malformation. In order for a teratogen to cause a specific defect, it must first exert its effect at the appropriate period of time during gestation. For example, for cyclopia to develop in a fetus exposed to Veratrum californicum, the toxic plant must be ingested on day 14 of gestation by sheep during the stage of primitive neural plate development.29 Locoweeds, or milk vetches (Figure 65.3), include several species of plants in the genera Astragalus and Oxytropis.23 Astragalus and Oxytropis are members of the Fabaceae (Leguminosae) or pea family. These plants are characterized by their butterfly-like flowers displaying a single large banner petal, two side petals, and two lower fused petals forming a keel. Astragalus and Oxytropis species have a worldwide distribution. Collectively, locoweeds are considered to be the most detrimental poisonous plant of cattle in the western United States and are responsible for significant economic losses.4,30 Figure 65.3 Milk vetch (Astragalus sp.). USDA-NRCS PLANTS Database. Clinical signs of locoweed poisoning are caused by the toxic effects of the indolizidine alkaloid swainsonine found in multiple species of Astragalus and Oxytropis. Swainsonine is produced by the fungal endophyte Undifilum oxytropis (formerly Embellisia oxytropis) which can be found in the parenchymal layers of the infected plant seeds.11 Locoweed poisoning is the chronic condition that develops in ruminants after weeks of ingesting swainsonine-containing plants. Common clinical signs of locoism include depression, incoordination, tremors, weight loss, emaciation, ataxia (staggering), altered mentation, belligerence, aggression, proprioceptive deficits, and eventually death. Reproductive failure, embryo loss, abortion, and occasional birth defects can be associated with locoweed poisoning and are often seen prior to more severe clinical signs in the cow.31 Swainsonine inhibits the lysosomal enzyme α-mannosidase, which is required for normal hydrolysis of mannose-rich oligosaccharides. In the absence of hydrolysis incompletely processed oligosaccharides accumulate within the cells of multiple organs and tissues resulting in a loss of cellular function and cell death.30,31 α-Mannosidosis is the most important acquired lysosomal storage disease in grazing livestock.32 Microscopic lesions of locoism can be found in many organs and tissues throughout the body; however, cellular vacuolation due to accumulated oligosaccharides is reportedly most pronounced within the brain, liver, kidney, pancreas, and thyroid gland.31 Sporadic outbreaks of abortion and congenital limb deformity have been reported in a number of pregnant domestic animal species including cattle, sheep, goats, and horses grazing on species of Astragalus and Oxytropis. Fetal malformations may include brachygnathia, contracture or overextension of joints, limb rotations, osteoporosis, and bone fragility. The toxic agent responsible for the fetal malformations has not been determined but is likely unrelated to those responsible for the development of lysosomal storage disease.33 Because of the transient nature of locoism, adult animals may recover if they are promptly removed from the swainsonine-containing plants early in the course of their intoxication. Swainsonine is readily cleared from the body making recovery rapid unless significant tissue damage is present. Although many locoweeds are not highly palatable to cattle, once forced to graze it (usually due to extreme grazing conditions) cattle may develop a preference for the plant that can lead to intoxication.11 A number of other swainsonine-containing plant species cause livestock poisonings similar to locoweed poisoning. Some of these include Ipomea spp. in Brazil and Africa, Swainsona spp. in Australia (swainsonine was first identified in Swainsona canescens), and toxic species of Ipomea, Sida, Solanum, Physalis, and Convolvulus.11,31 Swainsonine-containing plants in Brazil include Sida carpinifolia, Ipomea carnea subsp. fistulosa, and Turbinata cordata. Fetal malformations and abortions with these plants are similar to those seen with swainsonine-containing locoweed.17,32 Over 260 North American species of Astragalus have been identified as nitrogen accumulators. Nitrogen-containing Astragalus spp. can cause both an acute form and a chronic form of nitrate poisoning in cattle. In the acute form cattle develop methemoglobinemia and respiratory distress. Chronic intoxication manifests as generalized weakness, incoordination, and other central nervous system signs (knuckling of the fetlocks, goose-stepping, heel-clicking paralysis) and death. Methylene blue treatment can reverse methemoglobinemia in affected cattle but does not prevent mortality, indicating that the cause of death is likely attributed to other factors. Over 20 Astragalus species have also been identified as selenium accumulators and may induce selenium toxicosis (“alkali disease”) with prolonged grazing.11 Lupines (Lupinus spp.), commonly known as blue bonnet, belong to the Fabaceae (legume) family (Figure 65.4). These perennial herbaceous plants are indigenous to North America and range throughout much of the United States. Over 100 species of lupines have been identified. Plants grow up to 1 m high. Leaves are alternate and palmately divided with 5–17 leaflets, which can be smooth or hairy depending on the species. Flowers of Lupinus spp. are bonnet-shaped and are present on racemes that are located on a single central stalk. Poisonous varieties of lupine responsible for cattle toxicosis in the United States are predominantly found in the Rocky Mountain region and in states located to the west of the Rockies. Lupines are typically not very palatable to cattle and are most often grazed only when other forages are not readily available.4,11 Figure 65.4 Silver lupine (Lupinus albifrons Benth). Photograph by Pete Veilleux, East Bay Wilds. Three specific syndromes in livestock have been attributed to lupine toxicosis in North America: (i) “crooked calf disease,” a teratogenic condition caused by pregnant cows grazing lupines; (ii) acute fatal neurologic disease in adult cattle; and (iii) lupinosis. Lupinosis is not an alkaloid-induced toxicity but is instead caused by cattle grazing lupines infected with the fungus Phomopsis leptostromiformis that produces the mycotoxin phomopsin. Clinical signs of phomopsin poisoning may include severe hepatic, renal, and muscle disease in cattle and sheep.4 Clinical signs of the neurologic syndrome in adult cattle include muscle weakness, agitation, frequent urination and defecation, depression, frothing at the mouth, relaxation of the third eyelid, muscle fasciculations, ataxia, lethargy, collapse, and sternal recumbency followed by lateral recumbency, respiratory failure, and death.11 Maternal ingestion of toxic lupines during days 40–70 of gestation results in significant fetal malformations depending on the concentration of teratogenic compounds present in the plant.29 Alkaloids responsible for fetal teratogenic effects (crooked calf syndrome) include anagyrine, ammodendrine, and N-methyl-ammodendrine.11 The most commonly observed lupine-induced fetal malformation is arthrogryposis of the forelimbs (Figure 65.5), which may be accompanied by scoliosis, torticollis, lordosis, kyphosis, or palatoschisis (cleft palate).11,34 Muscles from affected limbs are often hypoplastic or atrophied. Muscle atrophy is attributed to disuse of the affected limb(s) in utero.34 The mechanism of action for teratogenic fetal effects is an alkaloid-induced decrease in fetal movement secondary to desensitization of skeletal muscle-type nicotinic acetylcholine receptors. Decreased or inhibited fetal movement results in skeletal malformations including skeletal muscle contractions and cleft palate formation.11 Figure 65.5 Arthrogryposis of hindlimbs (crooked calf). Prevention and management of lupine poisoning can be achieved by coordinating grazing periods of susceptible pregnant cows with growth stages of the plant, ensuring that susceptible pregnant cows do not graze during the flower and pod stages of growth when anagyrine concentrations are at their highest. Other effective measures may include changing the calving periods from spring to fall and by instituting intermittent grazing between lupine-free pasture and lupine-infested pasture to break the cycle of lupine ingestion. Broadleaf herbicides such as 2,4-D can also be utilized to reduce lupine numbers in heavily infested pastures, although lupine populations commonly reestablish due to the presence of resident seeds within the soil. Treatment of clinically ill cattle involves supportive and symptomatic care. Animals displaying signs of intoxication should not be stressed and should be allowed to rest. Because the toxic alkaloids are rapidly excreted in the urine, affected adult animals will often make a full recovery within 24 hours. No treatment is available for severe fetal malformations. However, calves with mild contracture defects, of the forelimbs primarily, may recover if the elbow joint can be locked into place within 1 week of birth.11 Poison hemlock, also known as European hemlock, spotted hemlock, and California fern, is a biennial perennial member of the parsley/carrot (Apiaceae, formerly Umbelliferae) family found all across North America (Figure 65.6). Conium maculatum is one of the most toxic members of the plant kingdom.35 It was originally introduced to North America from Europe as an ornamental plant and is also native to Asia but can be found throughout North and South America, North Africa, Australia, and New Zealand. Poison hemlock is a tall branched plant with distinctive purple spots along its stems, multiple small white five-petaled flowers, a single taproot, and a distinctive mousy odor.4,31,36 Figure 65.6 Poison hemlock (Conium maculatum). USDA-NRCS PLANTS Database. Poison hemlock contains eight known piperidine alkaloids.36 The two major toxic alkaloids are γ-coniceine found in immature growing plants and coniine found in mature plants and seeds.4,31,36 However, all vegetative organs, flowers, and fruits contain alkaloids.35 Alkaloid levels vary based on environmental factors (such as temperature and moisture), stage of growth, and geographic location. Fresh drying the plant in the sun for 7 days results in significantly decreased levels of the toxic piperidine alkaloids.31 Poison hemlock is highly toxic to cattle and in acute poisoning cases clinical signs may develop rapidly following ingestion (30 min to 1 hour). Reported clinical manifestations include depression, abdominal pain, mydriasis (dilated pupils), frequent urination and defecation, increased salivation (ptyalism), lacrimation, muscle tremors and fasciculations, incoordination and ataxia, respiratory distress, recumbency, collapse, and death. Animals surviving acute poisoning usually recover but abortions may result. The teratogenic effects of C. maculatum are most often appreciated in cases of chronic ingestion by pregnant cattle. However, fetal malformations have also been described in piglets and lambs.36 Ingestion of the plant between days 40 and 70 of gestation can result in a wide array of skeletal malformations in the neonate.4 Reported teratogenic malformations are indistinguishable from those caused by lupines and tobacco species. Fetal malformations may include torticollis (twisted neck), scoliosis (vertebral column curvature), palatoschisis (cleft palate), arthrogryposis (multiple joint contractures), and excessive flexure of the carpal joints (crooked calf disease).35,36 Conium alkaloids, specifically γ-coniceine, coniine, and N-methylconiine, act as nondepolarizing blockers (akin to curare) resulting in paralysis of motor nerves through their action on the medulla. It has been proposed that these alkaloids initially stimulate the skeletal muscles and produce subsequent neuromuscular blockade through their action on nicotinic receptors.4,35,36 Death occurs when the phrenic nerve is affected and respiratory muscles become paralyzed.36 Poison hemlock-related fetal malformations, such as joint contractures, are believed to result from fetal immobility induced by neuromuscular blockade of nerves. Palatoschisis in calves may be secondary to the loss of fetal mandibular and tongue movements, which are both required for palatal shelves to become closer in the developing fetus. In the absence of jaw and tongue movements, the tongue permanently occupies the site where palatal shelves should fuse.36,37 Treatment of poison hemlock toxicosis relies largely on supportive care. In cases of acute toxicity gastric lavage and activated charcoal treatment may be performed on individual animals. Control of the weed can be managed through the use of broadleaf herbicides, although populations will reestablish via seed reserves in the soil.11 Nicotiana glauca (tree tobacco), Nicotiana tabacum (cultivated tobacco), Nicotiana trigonophylla (wild or desert tobacco), and Nicotiana attenuata (wild or coyote tobacco) are members of the nightshade (Solanaceae) family. Wild tobacco varieties are indigenous to the southwestern United States while cultivated tobacco grown in the United States is predominantly raised in the southeastern states. Tobacco is a herbaceous branching annual that grows between 0.3 and 1.2 m in height, with hairy stems and leaves and fragrant tubular flowers with five parts. Tree tobacco (N. glauca) is an evergreen shrub or small tree growing 2–6 m tall with alternate bluish-green hairless leaves. Flowers are 5 cm long, tubular, and produced on the leafless branches.4 Tobacco contains numerous alkaloids (over 40) most of which are neurotoxic pyridine alkaloids including nicotine. Animals may become intoxicated by grazing the plant or ingesting cut stalks.38 In adult cattle clinical signs of acute toxicity may include excitation, followed by depression, respiratory failure, and death in severe cases. Treatment of affected animals is symptomatic. The principal toxins responsible for tobacco toxicosis in cattle are nicotine and anabasine. Nicotiana glauca produces the piperidine alkaloid anabasine, a potent nicotinic acetylcholine receptor agonist. Anabasine is acutely toxic as well as teratogenic.38 Ruminants are relatively more tolerant of the neurotoxic alkaloid effects of nicotine. However, the teratogenic anabasine can induce fetal skeletal malformations including arthrogryposis, palatoschisis, torticollis, lordosis, and kyphosis. Fetal defects resulting from tobacco intoxication occur when cattle ingest the plant between days 30 and 60 of gestation. The fetal malformations caused by tobacco toxicosis are indistinguishable from those induced by poison hemlock, locoweeds, and lupine poisoning. This similarity of teratogenic fetal malformations is attributed to the analogous molecular structures of anabasine and coniine (principal toxin of C. maculatum and lupines) and its analogs.4 At low doses anabasine stimulates depolarization of postsynaptic membranes of ganglia and at high does causes neuromuscular blockade. Like poison hemlock and lupine toxicosis, the mechanism of teratogenicity is believed to be caused by the neuromuscular blockade of nerves and subsequent decrease in intrauterine fetal movement resulting in the development of joint contractures, palatoschisis formation, and other skeletal malformations.39,40 In acute toxicosis, cattle should be removed from contaminated fields or pastures. In severe cases supportive and symptomatic treatment is recommended for affected animals and may include gastric lavage.28 Veratrum californicum grows in dense sharply defined stands in high moist meadows or hills.29 Individual plants grow approximately 2–3 m tall and have short rootstalks and alternate smooth, broad, parallel-veined oval leaves that are present in three ranks. Numerous toxic alkaloids have been identified in V. californicum; however, the jervine alkaloids including cyclopamine, jervine, and cycloposine are associated with the plant’s teratgenic effects.4,39 Among the toxic alkaloids, cyclopamine is present at the highest levels and is the principal teratogenic alkaloid.29 Teratogenic effects are predominantly seen in sheep but fetal malformations have also been reported in goats and cattle.33 The teratogenic alkaloids exert their effects by interfering with the sonic hedgehog (SHH) signal transduction pathway, by inhibition of neuroepithelial cell mitosis and migration, and by decreasing chondrocyte proliferation. In pregnant ewes, ingestion of V. californicum on days 12–14 of gestation (most notably day 14) results in cyclopia and prolonged gestation. Embryo death can result from maternal exposure on days 19–21. Cleft palate results from maternal exposure on gestational days 24–30 and metacarpal and metatarsal defects occur when ewes are exposed on days 28–31 of gestation.39 Ingestion of V. californicum in pregnant cows between days 12 and 30 of gestation may cause fetal malformations, including cleft palate, harelip, brachygnathia, hypermobility of the hocks, syndactyly, and decreased numbers of coccygeal vertebrae. When pregnant cows ingest the plant in later stages of pregnancy (days 30–36), teratogenic alkaloids inhibit growth in length of metacarpal and metatarsal bones.33 There is no specific treatment for V. californicum-induced fetal malformations. However, malformations can be prevented by removing pregnant animals from V. californicum-infested pastures and ranges during the first trimester of pregnancy.4 Mimosa tenuiflora and Mimosa ophthalmocentra are perennial trees or small shrubs native to Brazil. Mimosa tenuiflora and possibly M. ophthalmocentra (Fabaceae, Mimosoideae) can induce fetal malformations and embryonic death in goats, sheep, and less frequently cattle. Affected calves, lambs, and kids may be born with an array of malformations, which can include arthrogryposis, micrognathia, cheiloschisis (harelip), palatoschisis, kyphosis, lordosis, torticollis, blindness, microphthalmia, corneal opacity, ocular dermoids, acephaly, bicephaly, hydranencephaly, glossal hypoplasia, meningocele, and syringocele. The toxic principle of M. tenuiflora is unknown, but tryptamine-derived alkaloids have been isolated from the leaves and seeds.17 Mycotoxins are naturally occurring compounds or secondary metabolites produced by fungi that cause deleterious effects (mycotoxicoses) when ingested or exposed to susceptible animal species. Mycotoxisosis in livestock occurs when animals graze on infected grasses or crops or are fed infected grains. Chemical analysis via thin-layer chromatography, gas and high performance liquid chromatography, and mass spectrometry can accurately detect the concentrations of various mycotoxins in properly collected and prepared samples.41,42 Ergot alkaloids include more than 80 indole compounds and are associated with two mycotoxicoses in livestock species: fescue toxicosis and ergotism.2 Both conditions may share similar clinical manifestations and in many cases may be indistinguishable from one another.43 Ergot alkaloids are produced by the mold Claviceps purpurea on wheat, rye, and other cereal grains and by the endophyte Neotyphodium coenophialum growing on tall fescue (Lolium arundinaceum [Shreb]). Ergot alkaloids have similar molecular structures to the biogenic amines norepinephrine, serotonin, and dopamine and act as agonists at various serotonin receptors.44,45 This agonistic effect is thought to be responsible for clinical manifestations of ergot alkaloid toxicosis. In both fescue toxicosis and ergotism the principal ergot alkaloid believed to be most responsible for clinical disease is ergovaline. Ergovaline is a potent α2-adrenergic agonist on arterioles and other blood vessels causing vasoconstriction.42 Fescue toxicosis is one of the most costly grass-related intoxications of livestock in the United States and throughout many other countries. Fescue toxicosis is a descriptive term used for several clinical syndromes (summer slump, fescue foot, and fat necrosis) attributed to ingestion of endophyte-infected tall fescue.42 Tall fescue (L. arundinaceum [Shreb]) is a cool-season perennial grass grown in temperate climates and is one of the most abundant forage crops in the continental United States.46 In cases of fescue toxicosis, livestock ingest the fungal endophyte Neotyphodium coenophialum (formerly Acremonium coenophialum and Epichloe typhina) that grows within the intercellular spaces of the leaf sheaths, stems, and seeds of tall fescue grass.2 Tall fescue and its endophyte N. coenophialum share a mutually beneficial relationship. The endophyte produces toxins (ergot alkaloids, loline alkaloids, and peramine) that are distributed throughout the plant making it more resistant to drought, parasitism, and fungal infection.42 The endophyte of tall fescue produces an array of ergot alkaloids but ergovaline is the primary ergopeptine alkaloid believed to be responsible for inducing toxicosis. Ergot alkaloids are highly concentrated within the seeds of tall fescue and levels are greatest in the summer and early fall when seed heads are present.46 Drought and rainy conditions as well as fertilization with nitrogen- and phosphorus-based fertilizers tend to increase ergovaline concentrations.42 Several syndromes including summer slump, fescue foot (Figure 65.7), and fat necrosis (lipomatosis) are associated with fescue toxicosis in cattle. The most costly of the three is summer slump. As the name implies clinical manifestations of this condition are most often appreciated in summer months when the ambient temperature is above 31 °C.42 Affected cattle typically have a rough hair coat, unthrifty appearance, reduced feed intake, decreased milk production with lower weaning weights of calves, reduced conception rates, agitation/nervousness, ptyalism, and increased respiratory rates.42,47 Figure 65.7 Fescue foot: dry gangrenous dermatitis secondary to “fescue toxicosis.” Photograph courtesy of Dr Jim Cooley. Ergot alkaloids are dopamine D2 receptor agonists and mimic the endogenous tonic inhibition of pituitary lactotropes by dopamine, thereby inhibiting prolactin secretion from the anterior pituitary gland.42 Decreased serum prolactin is a relatively consistent finding in livestock feeding studies involving ergot alkaloid-infected forage. Therefore serum prolactin concentrations may be utilized as a diagnostic indicator of endophyte toxicosis.48 The hormone prolactin plays an important role in mammary gland growth, milk production, corpus luteal function, gonadotropin secretion, lipogenesis, copper homeostasis, and immune modulation. Decreased prolactin production caused by the D2 dopaminergic effects of ergovaline and other ergot alkaloids can cause agalactia at parturition, most notably in horses. Cattle and other ruminants produce a placental lactogen that can overcome the initial lack of prolactin stimulation at the time of parturition. However, lower concentrations of prolactin coupled with decreased feed intake can cause decreased milk production in these species.42 Prolactin also plays an important role in gonadotropin secretion and corpus luteal function and development. Decreased concentrations of luteinizing hormone and prostaglandins have been documented in animals exposed to ergot alkaloids.48 Ingestion of endophyte-positive fescue and ergopeptide exposure have been associated with low progesterone production in cattle and horses. Decreased progesterone, as well as other imbalances in reproductive hormones, can result in difficulty maintaining early pregnancy in cattle and in late pregnancy problems in mares.42 In addition to their dopaminergic effects, ergot alkaloids also act as potent serotonergic agonists and α2-adrenergic agonists on blood vessels, particularly arterioles. Peripheral vasoconstriction of vessels is believed to contribute to the hyperthermia exhibited in some cases of summer slump in the warm summer months along with dysregulation of the hypothalamic thermoregulatory center due to decreased prolactin secretion. In winter months, toxicosis may result in fescue foot, a condition caused by peripheral vasoconstriction of vessels of the distal limbs secondary to the combined effects of ergovaline and cold environmental temperatures. The tail switch and ear tips as well as the distal limbs (most often the hindlimbs between the coronary band and fetlock) may also be affected.42 Cattle experiencing clinical signs of summer slump should be removed from endophyte-contaminated pasture or their diet should be diluted by feeding supplemental grain or nonfescue forages.42 Cattle with gangrenous dermatitis (fescue foot) can be treated with antibiotics to prevent secondary infections. Shelter or wind breaks may also be beneficial in minimizing the effects of cold weather. Domperidone, a D2 dopamine antagonist, is used to treat fescue toxicosis in mares with agalactia and prolonged gestation. Experimentally, domperidone has been shown to ameliorate some clinical signs of fescue toxicosis in heifers, including reversal of decreased weight gain and increased circulating concentrations of progesterone. These results suggest that treatment of cattle with fescue toxicosis may have clinical and economic merit.49 Ergot is a general term referring to a group of parasitic fungi belonging to the genus Claviceps, most notably Claviceps purpurea, that infect rye, barley, wheat, oats, and other cereal grains.44 Infection of grains with C. purpurea results in colonization of the grain ovary wall or base with fungal mycelia. The mycelia produce a sticky exudate called honeydew containing conidia (asexually produced spores). Following germination within the hardened honeydew (sclerotia), conidia can be transferred to and infect other seeds by insect vectors or direct contact.44,45 Signs of ergotism – the various toxic effect(s) of ergot alkaloids produced by Claviceps spp. – develop secondary to the ingestion of toxic levels of ergot-infected grains.44 Clinical signs of ergotism are primarily caused by the ergopeptine class of ergot alkaloids, which include ergotamine, ergocristine, ergosine, ergocornine, ergocryptine, and ergovaline. Ergot alkaloids act as serotonin receptor agonists due to the similarities of their molecular structures with the biogenic amines dopamine, serotonin, and histamine.44,45 Vasoconstriction results from the agonistic activity of ergot alkaloids. Other potential effects include uterine stimulation and dopaminergic activity at D2 receptors resulting in decreased prolactin secretion.45 Documented cases of ergotism in the United States are uncommon because milling and cleaning processes are successful in removing ergot-infected grains.41 Ergot alkaloid toxicity is known to cause four distinct disease forms in livestock: (i) cutaneous and gangrenous lesions on the tail and extremities, (ii) hyperthermia and production loss, (iii) reproductive failure, and (iv) the less common and frequently debated neurologic form.2,45 The gangrenous form of ergot poisoning represents the chronic form of intoxication by ergot-producing fungi. Clinical signs of gangrenous ergotism include acute lameness with swelling and hyperemia. Lesions present most often in the rear limbs, although all four limbs may be affected in some cases; however, necrosis is usually restricted to below the fetlock but occasionally extend to the metatarsals.20 Vasoconstriction of small arteries and arterioles due to the potent α2-adrenergic agonistic effects of ergovaline causes ischemia and necrosis of the distal limbs, ear tips, and the distal third of the tail. This gangrenous form is most often associated with winter months due to exacerbation of the vasoconstrictive effects by cold weather.45 The hyperthermic form of the disease is the most commonly reported form of ergotism and is seen most often in summer months when weather is warm.44 The neurologic form of ergotism appears to be rare and may be associated with acute intoxication with large doses of ergot alkaloids.45 When ergotism is suspected, infected grains should be removed. No effective treatment is available for ergotism in cattle, although animals with the hyperthermic form should recover given time.45 Aflatoxins (B1, B2, G1, and G2, named for their respective blue or green fluorescence under ultraviolet light) are a group of structurally related difuranocoumarin compounds produced primarily by Aspergillus flavus and Apergillus parasiticus. Aflatoxins can be found throughout the world and can commonly contaminate animal feed and crops in warm subtropical and tropical climates under appropriate conditions.40,41,43 Grains stored under high moisture (>14%), at warm temperatures (>20 °C), or those improperly dried are at risk of becoming contaminated.50 Aspergillus flavus strains invade damaged plant tissue and predominantly produce aflatoxin B1 which is considered to be the most toxic and carcinogenic aflatoxin.43 All animals are susceptible to the toxic effects of aflatoxins, although differences in species sensitivities do exist. Susceptibility can vary with breed, age, dose, nutritional status, and length of exposure.50 Cattle and other ruminants are considered to be relatively resistant in comparison with monogastric species. However, young calves are at greater risk of developing clinical toxicosis compared with adult animals.43 Aflatoxins are primarily hepatotoxic but can also have immunosuppressive, carcinogenic, mutagenic, and teratogenic effects.43 Some aflatoxins have been shown to cross the placenta in laboratory animals and humans. Decreased male fertility via decreased spermatozoa production, embryo loss, fetal death, and possible teratogenic effects have been reported with aflatoxicosis, most notably with aflatoxin B1 and G1 in animals.51 Abortions in cattle are uncommonly reported with aflatoxicosis, but sporadic herd outbreaks have been attributed to ingestion of feeds contaminated with aflatoxin B1, B2, G1, and G2.43 However, the negative reproductive impacts do not appear to be due to any direct activity of aflatoxins in the oocyte or embryo but instead are attributed to altered maternal homeostasis.41 There is no specific treatment for aflatoxicosis. Instead treatment of affected cattle involves supportive and symptomatic care. Contaminated feed should be removed and replaced with aflatoxin-free feeds.51 Zearalenone is a potent estrogenic mycotoxin produced by the fungus Fusarium graminearum and multiple other species of Fusarium. Zearalenone contaminates cereal grains including corn and to a lesser extent wheat, barley, sorghum, millet, rice, and oats under specific environmental and storage conditions.39 Zearalenone can have profound effects on reproductive function due to its estrogenic actions. Clinical signs attributed to zearalenone toxicity are most often reported in swine, although signs may also be observed in ruminant species as well. Clinical signs of zearalenone toxicity mimic those of estrogenic stimulation and can include decreased fertility, abnormal estrous cycles, vulvar swelling, vaginitis, reduced milk production, and mammary gland enlargement. Heifers appear to be more susceptible to the effects of zearalenone than adult cows.41,52 However, in pregnant cows the potential for abnormal embryonic or fetal development with possible fetal death, abortion, and dystocia exists.2 Zearalenone and its derivatives (α- and β-zearalenol) are believed to exert their toxic effects by competitively binding to specific estrogen receptors and by modification of steroid metabolites. Zearalenone and α- and β-zearalenol have chemical structures closely resembling naturally occurring estrogen.53 Zearalenone and its metabolites can directly bind with cytoplasmic estradiol-17β receptors and translocate receptor sites to the nucleus where stimulation of RNA leads to protein synthesis and clinical signs of estrogenism.52 β-Zearalenol appears to be the predominant zearalenone metabolite in cattle as opposed to α-zearalenol which predominates in most other species including swine.2 Treatment of zearalenone intoxication relies on removal of contaminated feedstuff and replacement with high-quality clean feeds. Clinical signs will typically resolve within 3–7 weeks. Prevention of Fusarium spp. growth and subsequent zearalenone production can be achieved by maintaining low moisture concentrations (15–16%).52 Phytoestrogens are biologically active nonsteroidal plant compounds that are similar in structure or function to mammalian estrogen and can compete for estrogen receptors on cells.4,54 Plant estrogens can have broad effects on both human and animal populations. Phytoestrogens are found in a number of legumes including alfalfa (Medicago sativa), soybeans (Glycine max L.), red clover (Trifolium pratense), subterranean clover (Trifolium subterraneum), white clover (Trifolium repens), aslike clover (Trifolium hybridium), and burr medic (Medicago spp.) among others.4,39,55 Concentrations of phytoestrogens in plant material can vary significantly. Estrogenic compounds are often produced in response to environmental or physiologic plant stressors such as fungal infection, insect infestation, and animal predation. Phytoestrogen concentrations have also been shown to increase in cool wet conditions.54 Over 100 phytoestrogen molecules have been identified. Phytoestrogens are subdivided into broad categories based on their chemical structure. Categories of phytoestrogens include isoflavones, flavones, coumestans, stilbenes, and lignans.54,56 Isoflavone compounds can be found in high concentrations in soybean, red clover, and white clover. Coumestrol (potent estrogenic phytoestrogen) can be found in alfalfa as well as white clover and soybean sprouts.54 Stilbenes are found in cocoa- and grape-containing products and lignans are prevalent in flax seed.56,57 Once ingested, phytoestrogens are absorbed in the rumen by resident microbial activity. Because of structural similarity with endogenous hormones, phytoestrogens can bind to nuclear receptors.56 Although phytoestrogens may mimic estradiol-17β (E2), their effects may not always be similar.58 The affinity phytoestrogens have with ERα receptors and ERβ receptors is relatively weak in comparison with endogenous E2.56 However, phytoestrogens can be present in much higher concentrations in the body (as much as 100-fold higher) than endogenous estrogens, allowing for potentially profound effects. Phytoestrogens may exert agonistic, partial agonistic, or antagonistic effects depending on the concentration of E2.56,57 The toxic effects of phytoestrogens are dependent on dose, route of exposure, duration of exposure, and timing of exposure.57 Organ systems in young animals appear to be more sensitive to phytoestrogens than adults. Cattle infertility has been reported in herds fed red clover silage containing isoflavones and alfalfa-containing coumestans.58 However, cattle appear to be less sensitive than sheep to the phytoestrogenic effects of clover forages.54 The effects of high concentrations of phytoestrogens may include clinical signs of hyperestrogenemia (nymphomania, cystic ovaries, swollen genitalia, infertility, impaired pregnancy maintenance) or antiestrogenic effects such as gonadal hypoplasia and signs of anestrus depending on the action of the phytoestrogen on estrogenic receptors. Uterine endometrial release of prostaglandin (PG)F2α is regulated by oxytocin, progesterone, and estradiol (E2) in ruminants and induces luteolysis and corpus luteum regression. In a study conducted by Mlynarczuk et al. the phytoestrogens coumestrol, daidzein, and genistein stimulated genes responsible for synthesis of oxytocin precursors (neurophysin-I/oxytocin), and post-translational synthesis of oxytocin, PGA (peptidyl-glycine-α-amidating monooxygenase) in granulosa cells and luteal cells in cattle. These phytoestrogens stimulated oxytocin secretion from the ovarian follicle and corpus luteum. It is speculated that phytotoxin-induced oxytocin release during early pregnancy or implantation may result in early luteolysis, formation of persistent corpus luteum, and subsequent impaired pregnancy maintenance and early embryonic death.54,55 In order to prevent or minimize potential reproductive problems, forages can be analyzed for isoflavones and coumestrol concentrations and feeds containing low or no levels can be substituted for high phytoestrogen-containing forages. Once phytoestrogen-affected forages have been eliminated from cattle rations, animals will typically resume normal reproductive cycling within a period of 4–6 weeks.54 Heavy metals and trace minerals are common environmental contaminants and when present in sufficient levels can cause significant health and reproductive impacts in domestic livestock. Heavy metals include elements which under appropriate conditions play a necessary role for normal body function, such as iron, copper, zinc, and chromium, as well as toxic elements that have no biological functions. Many minerals are crucial for animal health, survival, and production due to the essential roles they play in the physiological, structural, and regulatory functions of the body. However, ingestion of excessive amounts of minerals may lead to acute poisoning or chronic poisoning, when animals ingest lower concentrations over prolonged periods of time.59 Potentially toxic heavy metals include lead, mercury, cadmium, chromium, arsenic, and nickel. Environmental pollution with trace elements, toxic metals, and metalloids is often attributed to mining, industrial wastes, urbanization, and intensification of farming practices (pesticide and herbicide activity). Transfer of heavy metals from contaminated soils into plants and successive levels of the food chain can be a significant health risk in both animals and humans. Clinical manifestations of trace mineral and heavy metal intoxication can vary depending on the element involved, health of the animal, and degree of exposure. Several heavy metals have been identified as potentially teratogenic and abortifacient in animals.60 However, in cattle the most commonly reported heavy metal toxicities involve lead and arsenic. Arsenic (As) is a ubiquitous metalloid element present in multiple forms, the most common oxidative states being the As3+ and As5+ valence forms.61 Arsenic can be found in both organic and inorganic forms although inorganic arsenite is the most toxic form of the element. Arsenic is predominantly used in the manufacture of pesticides, wood preservatives, glass, alloys, semiconductors, and pharmaceuticals. Environmental contamination of arsenic has been attributed to smelting of lead, copper, and nickel, combustion of fossil fuels, manufacturing of arsenic-containing compounds, and overuse or improper storage of arsenic-containing herbicides and insecticides.62 Peracute exposure to large doses of inorganic arsenic is often fatal and may result in death within minutes to hours depending on dose. Clinical signs of acute toxicosis may be profound and include colic, bloody diarrhea, neurologic signs such as ataxia and incoordination, weakness, and collapse followed by death. Gross postmortem lesions in cattle may include abomasal hyperemia, increased intraluminal intestinal fluid, edema of the rumen, omasum, reticulum, and abomasum, rumenal mucosal necrosis, and gastrointestinal hemorrhage.61 Absorption of arsenic compounds depends on the particle size and its aqueous solubility. Soluble forms of arsenic are readily absorbed via both passive and active means.61,62 In pregnant animals inorganic arsenic crosses the placenta and accumulates in the neuroepithelium of the developing fetus. Organic arsenic accumulates in the placenta but does not appear to cross the membrane. Laboratory animal studies have demonstrated the embryotoxic effects of high doses of inorganic arsenic, with development of teratogenic defects such as cleft palate, encephalocele, microphthalmia in hamsters and failure of limb bud development, prosencephalon hypoplasia, and somite abnormalities in rats and mice exposed during early gestation. Arsenic at lower concentrations can also have significant placental and fetal toxic effects.40,62 However, reports of abortion in cattle with subclinical or chronic arsenic toxicosis are sporadic. A presumptive diagnosis of arsenic toxicosis is often based on an appropriate clinical history of exposure and suspicious clinical signs. Necropsy lesions can also be suggestive. However, definitive diagnosis requires demonstration of elevated liver and kidney arsenic concentrations. Arsenic levels of approximately 8–10 ppm in fresh liver and kidney and 2–4 ppm in liver and kidney from autolyzed carcasses (several days old) are diagnostic. Early recognition and medical intervention is imperative for successful treatment of arsenic intoxication cases. In cattle not showing clinical signs, gastric lavage with a saline purgative and 20–30 g sodium thiosulfate administered orally or intravenously in a 10–20% solution may be effective. Intramuscular injection of dimercaprol 1.5–5 mg/kg i.m. two to four times daily for 10 consecutive days should also be administered if over 4 hours have elapsed since time of exposure. Additional treatment with sodium thiosulfate 30–40 mg/kg i.v. two to four times daily until recovery (typically 2–4 days) is also recommended.61 Cadmium (Cd) is a divalent transition metal with chemical properties similar to those of zinc.63 Unlike many minerals, cadmium has no essential physiologic or biochemical function in the body and is highly toxic to animals and humans.59 Cadmium compounds are widely utilized in industrial applications. They are used in iron and steel plating and can be found in batteries, semiconductors, solders, plastic stabilizers, and solar cells. Environmental contamination of water and soil is often secondary to industrial pollution. Cadmium may enter the environment from steel and iron production, zinc refining and smelting, mine wastes, coal combustion, improper battery disposal, and the use of sewage sludge and rock phosphate as fertilizers.63 Batteries are considered to be one of the most common sources of cadmium intoxications in cattle in the United States. However, phosphate fertilizers and sewage sludge are also important sources of cadmium toxicosis in cattle.64 Some plants readily accumulate cadmium from contaminated soil making it available for consumption by grazing animals.59,63 Cadmium, once ingested, is primarily absorbed through the respiratory system and digestive tract and accumulates mainly within the liver and kidneys. Gastrointestinal absorption of cadmium is much less than other divalent cations (zinc and iron). However, intestinal absorption can be increased in animals with iron deficiency. Following absorption, the metal circulates either in red blood cells or bound to albumin in the plasma. Cadmium interacts with the metabolism of essential minerals such as calcium, zinc, iron, copper, and selenium. Cadmium ions can displace divalent metals such as zinc from their binding sites on metallothionein (major metal-binding protein).63,64 Metallothionein functions in cadmium detoxification through high-affinity binding with the mineral that results in a toxicologically inert compound.59,64 Cadmium along with other heavy metals (Cu, Zn, and toxic mercury) induces metallothionein synthesis in multiple organs including the liver and kidneys. However, because metallothionein’s action is limited, excessive amounts of cadmium ingested acutely or over time can exceed metallothionein’s ability to bind it and significant multiorgan damage can develop.59 In the liver, cadmium toxicity results in hepatocellular apoptosis and necrosis.63 High levels of dietary cadmium can cause decreased feed intake, poor weight gain, anemia, decreased bone absorption, and abortions.64 There is no specific treatment for cadmium poisoning in livestock and therefore exposure should be minimized or prevented in the environment and in feeds.63 Lead poisoning in cattle often results from environmental contamination. Cattle may become acutely intoxicated from the ingestion of large quantities of lead-containing materials, licking old storage batteries, licking or ingesting lead-containing paint chips on outbuildings or from discarded paint cans, eating lead-containing lubricants, and drinking water from lead-containing water pipes.6 Chronic exposure most often occurs from ingesting forages grown on polluted pastures in the vicinity of mines or industrial sites. Only about 2–10% of ingested lead is absorbed by the digestive tract and distributed throughout the body.6 Absorbed lead is slowly excreted in bile, milk, and urine and is deposited in tissues, predominantly in the kidney, liver, brain, and bone. Lead induces toxic effects via multiple mechanisms including combining with calcium- and zinc-binding proteins, random hydrolysis of nucleic acids, and by inducing RNA catalysis via activation of ribosomal 5S RNA.65 Lead interferes with protein/hemoprotein biosynthesis, inhibits mitochondrial and membrane enzymes, and causes deficits in cholinergic, dopaminergic, and glutamatergic functions.40 Lead disrupts calcium homeostasis, causing the accumulation of calcium in lead-exposed cells and mitochondrial release of calcium inducing apoptotic cell death. In adult cattle acute toxicity typically causes death within 12–24 hours. When poisoning is less acute animals may survive 4–5 days. Clinical signs may include cortical blindness, delayed menace response, delayed withdrawal reflex, decreased glossal tone, ptyalism, frothing at the mouth, champing of the jaws, respiratory difficulty, tachycardia, ataxia, head pressing, convulsions, circling, and recumbency. Signs of subacute poisoning may include depression, anorexia, bruxism, colic, diarrhea, and rumenal atony, and central nervous system (CNS) signs and abortion.40,65 Lead readily crosses the placenta and can pass through the immature blood–brain barrier of developing fetuses where it concentrates in the CNS.6,40,65 Lead can also accumulate in the placenta during times of fetal stress. The toxicity of lead is primarily attributed to its ability to mimic and substitute calcium. Effects of lead on the developing fetus have been demonstrated in laboratory animals and may include growth retardation, reduced fertility, neural tube defects, brain defects, urogenital defects, and tail defects.39,65 Antemortem diagnosis of acute lead poisoning should be based on a history of exposure, clinical signs, and blood lead concentrations greater than 0.35 μg/mL. Hematologic abnormalities may also be indicative of lead toxicity and may include anemia, anisocytosis, poikilocytosis, polychromasia, basophilic stippling, metarubricytes, and hypochromia. Postmortem gross and histologic lesions in cattle are nonspecific and therefore definitive diagnosis relies on the clinical history and liver and kidney lead concentrations.2 Acid-fast positive lead inclusion bodies within nuclei of proximal renal tubular epithelial cells may be observed in some cases, although the presence of these inclusions is variable. Brain lesions are usually absent but mild to moderate brain swelling may be appreciated along with vascular congestion. In select cases of subacute lead poisoning laminar cortical necrosis may be observed.66 In cattle, chelation with calcium disodium edetate (Ca-EDTA) is the preferred option. It may be administered intravenously or subcutaneously at a dose of 110 mg/kg daily divided into two doses for 2–3 days and then repeated 2 days later. Thiamine may also be utilized as an adjunct to Ca-EDTA treatment in ruminants; in adult cattle a dose of 250–2500 mg/day is recommended and for calves 2 mg/kg daily. Cathartics such as magnesium sulfate (400 mg/kg p.o.) may be administered or a rumenotomy may be performed to remove larger ingested lead sources but is rarely successful in cases of particulate lead ingestion. Convulsions may be controlled by barbiturates or tranquilizers. Withdrawal times in cattle may be greater than 1 year and can be estimated by periodically monitoring blood lead concentrations.28 Selenium poisoning is most commonly attributed to (i) ingestion of selenium-concentrating plants grown in soils high in selenium content; (ii) accidental overdoses of selenium from ingestion of improperly mixed rations or injections; and (iii) from environmental contamination due to either plant accumulation or water contamination.67 Selenium is a nonmetallic element that is an important antioxidant but can be toxic in excessive amounts. Naturally occurring selenium toxicosis is most often a regional problem in the western United States between the Rocky Mountains and the Mississippi river. Grains and forages grown in high selenium regions may passively accumulate toxic levels of selenium causing chronic toxicosis in herbivores.68 The toxic dose of selenium in ruminants is unclear. References range from 2.2 to greater than 20 mg/kg body weight across species.67 Table 65.2 lists common obligate selenium-accumulating plants and potential secondary selenium-accumulating plants. Table 65.2 Selenium-accumulating plants of North America.
Bovine Abortifacient and Teratogenic Toxins
Introduction
Nitrate/nitrite-accumulating plants
Sorghum sudan (Sorghum vulgare)
Pigweed (Amaranthus spp.)
Button grass (Dactyloctenium radulans)
Sugar beet (Beta vulgaris)
Corn (Zea mays)
Soybean (Glycine max)
Pearl millet (Pennisetum typhoides)
Flax (Linum spp.)
Rye (Secale cereale)
Sunflower (Helianthus annuus)
Oats (Avena spp.)
Lamb’s-quarter (Chenopodium spp.)
Turnips and rape (Brassica spp.)
Canada thistle (Cirsium arvense)
Wheat (Triticum aestivum)
Goldenrod (Solidago spp.)
Nightshades (Solanum spp.)
Barley (Hordeum spp.)
Sorrel, curly leaf dock (Rumex)
Alfalfa (Medicago sativa)
Russian thistle (Salsola kali)
Johnson grass (Sorghum halepense)
Sweet clover (Melilotus spp.)
Tall fescue (Lolium arundinaceum)
Kochia weed (Kochia scoparia)
Timothy grasses (Phleum spp.)
Smart weed (Polygonum spp.)
Ragweed (Ambrosia spp.)
Jimsonweed (Datura stramonium)
Fireweed (Kochia spp.)
Field bindweed (Convolvulus arvense)
Docks (Rumex)
Barnyard grass (Echinochloa crus-galli)
Cheese weed (Malva spp.)
Pathogenesis/mechanism of action
Diagnosis of nitrate/nitrite poisoning
Treatment and management
Ponderosa pine
Management and treatment
Ateleia glazioviana, Tetrapterys acutifolia, and Tetrapterys multiglandulosa
Enterolobium spp. and Stryphnodendron spp.
Hairy vetch (Vicia villosa)
Diagnosis, mechanism of action, and clinical signs
Broom snakeweed
Sumpweed (Iva angustifolia)
Moldy sweet clovers
Teratogenic plants
Astragalus and Oxytropis (locoweeds)
Mechanism of action
Teratogenic effects
Management and treatment
Other swainsonine-containing plants
Other toxic effects of Astragalus spp.
Lupines
Management and treatment
Poison hemlock (Conium maculatum)
Mechanism of toxicity in acute poisoning
Mechanism of teratogenicity
Management and treatment
Tobacco poisoning
Veratrum californicum (false hellebore)
Mimosa spp.
Mycotoxins
Ergot alkaloids
Tall fescue
Mechanism of action
Reproductive effects
Management and treatment
Ergotism
Management and treatment
Aflatoxins
Treatment
Zearalenone
Treatment
Phytoestrogens
Management and treatment
Trace minerals and heavy metals
Arsenic
Mechanism of action
Diagnosis, treatment, and prevention
Cadmium
Lead
Diagnosis
Treatment
Selenium toxicosis
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