benzofurans and Plant-Poisoning

Rayless goldenrod (RG; Isocoma pluriflora) poisons livestock in the southwestern U.S., west Texas, and northern Mexico. The putative toxin(s) have historically been thought to be benzofuran ketones. Goats have been used successfully as a model of RG poisoning. The transmammary transfer of toxicity to offspring from lactating goats has not been studied, thus the objective of this study was to determine if nursing kids would become poisoned via mother's milk when the dams were dosed with RG. Twelve lactating goats (6 controls and 6 treated; all with twin kids) were dosed via oral gavage with alfalfa or rayless goldenrod at 2% of BW per day for 14 days. Two kids showed overt clinical signs near the end of the study; however, no dams showed clinical signs, and none developed exercise intolerance or muscle weakness. After day 11 of treatment, the RG kids showed increased (P < 0.05) serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine kinase (CK) activities until exposure to the plant via mothers' milk ended. Serum CK activity of kids declined rapidly over 7 days after transmammary exposure ended. Histopathology revealed that one kid had extensive myonecrosis that involved both myocardium and skeletal muscles. The other kids from RG-treated does had minimal myocyte degeneration and necrosis characterized by individual myofiber swelling, hypereosinophilia and loss of striation. Benzofuran ketones were not detected in the milk of lactating goats; further, dosing with RG did not alter milk composition. In summary, milk ingestion from does dosed with >300 mg/kg BW of benzofuran ketones from RG over 14 days increased mean CK concentrations in treated kids compared to controls; however kids rapidly recovered when exposure ended. Additional work is needed to better define benzofuran ketone metabolism, toxicity, and animal susceptibility.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Asteraceae; Benzofurans; Creatine Kinase; Female; Goat Diseases; Goats; Ketones; Lactation; Milk; Muscular Diseases; Necrosis; Plant Poisoning; Plants, Toxic

Rayless goldenrod (Isocoma pluriflora) sporadically poisons livestock in the southwestern United States. Similarities with white snakeroot (Ageratina altissima) poisoning and nearly identical chemical analyses led early researchers to conclude that tremetol, a mixture of benzofuran ketones, is the rayless goldenrod toxin. The toxicity of these ketone toxins have not been fully characterized nor are the pathogenesis and sequelae of poisoning completely understood. The objective of the current study was to characterize and describe the clinical and pathologic changes of rayless goldenrod toxicity in goats. Fifteen goats were gavaged with rayless goldenrod to obtain benzofuran ketone doses of 0, 10, 20, 40, and 60 mg/kg/day. After 7 treatment days, the goats were euthanized, necropsied, and tissues were processed for microscopic studies. After 5 or 6 days of treatment, the 40-mg/kg and 60-mg/kg goats were reluctant to move, stood with an erect stance, and became exercise intolerant. They had increased resting heart rate, prolonged recovery following exercise, and increased serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatinine kinase activities. All treated animals developed skeletal myopathy with dose-related distribution and severity. The goats dosed with 20 mg/kg and higher also developed myocardial degeneration and necrosis. Although skeletal myonecrosis was patchy and widely distributed, the quadriceps femoris was consistently damaged, even in low-dosed animals. Myocardial lesions were most severe in the papillary muscles of 60-mg/kg-dosed animals. This indicates that goats are highly susceptible to rayless goldenrod poisoning, and that the characteristic lesion of poisoning is skeletal and cardiac myonecrosis.

Topics: Animals; Asteraceae; Benzofurans; Dose-Response Relationship, Drug; Female; Goat Diseases; Goats; Heart; Ketones; Muscular Diseases; Necrosis; Plant Poisoning; Plants, Toxic

Tremetone and possibly other benzofuran ketones are believed to be the toxic compounds in white snakeroot. However, disease has not been reproduced with purified toxins and the concentrations of the benzofuran ketones in white snakeroot populations that cause toxicosis have not been documented. The objectives of this study were to compare the toxicity of seven plant populations, better characterize the clinical and pathologic changes of poisoning, and correlate intoxication with benzofuran ketone content. Four of the seven white snakeroot collections were toxic at the dose and duration used in the study. Affected goats became exercise intolerant, had significant serum enzyme changes and histological lesions in the large appendicular muscles. The incidence and severity of poisoning was not correlated with total doses of tremetone or total benzofuran ketone concentrations suggesting they may not be closely involved in producing toxicity and the possible involvement of an unidentified toxin. The results also demonstrate that white snakeroot populations vary chemically and toxicologically.

Topics: Ageratina; Animals; Benzofurans; Dose-Response Relationship, Drug; Female; Goat Diseases; Goats; Plant Extracts; Plant Poisoning; Random Allocation

Isocoma pluriflora, a plant prevalent on land used for livestock production and native to Arizona, New Mexico, West Texas, and Northern Mexico, is poisonous and causes trembles in livestock. Tremetone and dehydrotremetone have been suggested as the toxic compounds in I. pluriflora. In this study several different Isocoma spp., including I. pluriflora, I. tenuisecta, I. azteca, I. acradenia, and I. rusbyi, that are native to land used for grazing livestock in the southwestern United States were analyzed by high performance liquid chromatography (HPLC) for tremetone, dehydrotremetone, and other structurally related compounds. This is the first report of tremetone, dehydrotremetone, and 3-oxyangeloyltremetone in I. tenuisecta, I. azteca, I. acradenia, I. rusbyi, and several other Isocoma spp. In addition, this is the first report of 4-hydroxy-3-(3-methyl-2-butenyl)acetophenone and 7-isopentenyloxycoumarin in Isocoma spp.

Topics: Animals; Asteraceae; Benzofurans; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Livestock; Magnetic Resonance Spectroscopy; Plant Poisoning; Southwestern United States

Rayless goldenrod (Isocoma pluriflora) sporadically poisons horses and other livestock in the southwestern United States. Similar to livestock poisoning by white snakeroot (Ageratina altissima) in the midwestern United States, previous research suggests that benzofuran ketones (BFK: tremetone, dehydrotremetone, 6-hydroxytremetone, and 3-oxyangeloyl-tremetone) are responsible for the toxicity of rayless goldenrod. However, experimental reproduction of rayless goldenrod-induced disease and detailed descriptions of poisoning in horses with known concentrations of tremetone and other BFK has not been documented. In this study four horses were fed increasing amounts of rayless goldenrod to obtain doses of approximately 0, 10, 30, and 60 mg BFK/kg BW for 14 days. After seven days of dosing the horse dosed with 60 mg BFK/kg BW horse developed depression, reluctance to eat, dehydration, trembling, and muscle fatigue. Biochemical alterations including increases in the serum enzyme activities of CK, AST, ALT, and LDH, and increased cardiac troponin I concentration, were also identified. Physiologically the clinically poisoned horse had decreased endurance seen as reluctance to perform on the treadmill with increased resting heart rate and a prolonged recovery of heart rate following treadmill exercise. The condition of the horse continued to decline and it was euthanized and necropsied on day 10. At necropsy the myocardium was pale and soft and many of the appendicular and large apical muscles were pale and moist. Histologically, the myocardium had extensive myocardial degeneration and necrosis with extensive fibrosis and multifocal mineralization. Several of the large appendicular muscles in this horse also had small foci of skeletal muscle degeneration and necrosis. Less severe myocardial changes were also identified in the horse dosed with 30 mg BFK/kg BW after 14 days of dosing. No clinical, biochemical or histologic changes were identified in the control horse and the horse dosed with 10 mg BFK/kg BW. These results suggest that doses of 60 mg BFK/kg BW for seven days produce extensive myocardial lesions in horses. The horse dosed with 30 mg BFK/kg BW developed less severe, but similar myocardial lesions over a longer duration, this suggests that poisoning may be cumulative and lower doses of longer duration are also toxic. Horses seem to be uniquely sensitive to rayless goldenrod-induced myocardial disease, therefore cardiac troponin I may be a useful marker o

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Asteraceae; Benzofurans; Cardiomyopathies; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Histological Techniques; Horses; Ketones; Plant Poisoning; Southwestern United States; Troponin I

Toxicity following ingestion of the vagrant, foliose lichen Xanthoparmelia chlorochroa was identified as the putative etiology in the death of an estimated 400-500 elk on the Red Rim-Daley Wildlife Habitat Management Area in Wyoming during the winter of 2004. A single, unsubstantiated report in 1939 attributed toxicity of X. chlorochroa in cattle and sheep to usnic acid, a common lichen secondary metabolite. To test the hypothesis that usnic acid is the proximate cause of death in animals poisoned by lichen, domestic sheep were dosed PO with (+)-usnic acid. Clinical signs in symptomatic ewes included lethargy, anorexia, and signs indicative of abdominal discomfort. Serum creatine kinase, aspartate aminotransferase, and lactate dehydrogenase activities were considerably elevated in symptomatic sheep. Similarly, only symptomatic ewes exhibited appreciable postmortem lesions consisting of severe degenerative appendicular skeletal myopathy. The median toxic dose (ED(50)) of (+)-usnic acid in domestic sheep was estimated to be between 485 and 647 mg/kg/day for 7 days.

Topics: Animals; Benzofurans; Female; Lichens; Muscle, Skeletal; Plant Poisoning; Sheep; Sheep Diseases

Of 10 horses in a heavily overgrazed pasture, 4 died within 1 week. Clinical signs included muscle tremors, ataxia, reluctance to walk, heavy sweating, and myoglobinuria. Serum creatine kinase, aspartate transaminase, and alkaline phosphatase activities were high. Histopathologic findings were nonspecific. On the basis of clinical signs, clinicopathologic findings, nonspecific histopathologic findings, the condition of the pasture, the identification of numerous white snakeroot plants from which trematone was extracted, and evidence that these plants had been heavily browsed, it was believed that the horses died from ingestion of Eupatorium rugosum.

Topics: Animals; Benzofurans; Horse Diseases; Horses; Male; Plant Extracts; Plant Poisoning; Plants, Medicinal