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Chemical Analysis of Plants that Poison Livestock: Successes, Challenges, and Opportunities Kevin D. Welch,* Stephen T. Lee, Daniel Cook, Dale R. Gardner, and James A. Pfister Poisonous Plant Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, 1150 E. 1400 N., Logan, Utah 84341, United States ABSTRACT: Poisonous plants have a devastating impact on the livestock industry as well as human health. To fully understand the effects of poisonous plants, multiple scientific disciplines are required. Chemical analysis of plant secondary compounds is key to identifying the responsible toxins, characterizing their metabolism, and understanding their effects on animals and humans. In this review, we highlight some of the successes in studying poisonous plants and mitigating their toxic effects. We also highlight some of the remaining challenges and opportunities with regards to the chemical analysis of poisonous plants. KEYWORDS: poisonous plants, plant toxins, plant secondary compounds
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conomic losses from poisonous plants in western North America, and across the world, have a significant impact on the livestock industry. It is estimated that the poisoning of livestock by plants results in over $500 million in losses to the livestock industry annually in the 17 western United States (U.S.) states.1 Consequently, research is performed each year to understand and characterize the toxic nature of plants and the compounds responsible for their toxicity. Research at the USDA/ARS Poisonous Plant Research Laboratory (PPRL) and other laboratories around the world have provided successes for the livestock industry in dealing with poisonous plants. The objective of this review is to highlight some of the successes of chemical analyses of plant toxins and the impact of plant toxin analysis on managing poisonous plants in livestock, along with some remaining challenges and opportunities for poisonous plant research.
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Figure 1. Picture of selected plants that are poisonous to livestock and/or humans. (A) V. californicum, (B) Astragalus lentiginosus, (C) Delphinium barbeyi, (D) Lupinus argenteus, (E) Pinus ponderosa, (F) Senecio crassulus, and (G) Palicourea marcgravii. Photos A, B, C, D, and F were provided courtesy of Al Schneider, Southwest Colorado Wildflowers.
SUCCESSES
Veratrum. During the late 1950s and early 1960s, approximately 25% of pregnant ewes in central Idaho gave birth to cyclopic or “monkey-faced” lambs.2 Field studies were conducted, and it was determined that the plant, Veratrum californicum (Figure 1A), was responsible. Subsequent feeding trials determined that when pregnant ewes ingested Veratrum on gestation days 13−15, the lambs were born with craniofacial deformities. Subsequently, the steroidal alkaloid in the plant responsible for causing the birth defects was identified and named cyclopamine, 1, (Figure 2, Table 1). Additional defects can occur when pregnant ewes are exposed to Veratrum on gestation days 27−33, including limb defects and tracheal stenosis. Now that Veratrum-induced toxicities are understood and characterized, management recommendations have been instituted which have dramatically reduced the incidence of Veratrum-induced malformations. More recently, cyclopamine was found to inhibit the hedgehog signaling pathway, which plays a critical role in embryonic development and cell division.3 Aberrant hedgehog signaling has been implicated in several types of cancer. Inhibitors of the hedgehog signaling pathway, including © XXXX American Chemical Society
cyclopamine derivatives, have been targeted by pharmaceutical companies as potential treatments for certain cancers and other diseases associated with the hedgehog signaling pathway. Locoweeds. In the late 1800s and early 1900s, USDA scientists conducted research in response to livestock producers dealing with locoweed (i.e., Oxytropis and Astragalus spp., Figure 1B) poisoning in their herds. The toxin in locoweeds, the indolizidine alkaloid swainsonine, 2, (Figure 2, Table 1), was first reported in Swainsona,4 a related legume in Australia, which also poisons livestock. Subsequently, swainsonine was identified as the toxin in U.S. locoweeds.5 In addition, swainsonine has been found in two other plant families, the Convolvulaceae and the Malvaceae, as a result of investigations into livestock poisoning cases. Recent work has shown that swainsonine is produced by fungal endophytes growing within Received: Revised: Accepted: Published: A
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Figure 2. Chemical structures of the primary toxins from numerous poisonous plants.
locoweed plants.6 Locoweed populations can be classified into two chemotypes. One chemotype contains sufficient swainsonine to poison livestock, while the second chemotype contains very little or no swainsonine and thus would not likely pose a risk to poison livestock. A quantitative assay to determine concentrations of endophyte within plants was developed, and it was found that the chemotype of the plant is directly related to the amount of fungal endophyte producing swainsonine,6 providing other potential avenues for research and control. Recently, numerous Astragalus, Oxytropis, and Swainsona
species were screened to identify and document species that contain swainsonine. Understanding the distribution of the different chemotypes and their potential risk is an important management tool to reduce the risk of livestock losses. The capability of swainsonine and related compounds to disrupt normal glycoprotein processing and cell function has lead biomedical researchers to investigate swainsonine and related toxins for their potential as therapeutic agents for various diseases, including cancer, diabetic treatments, and as antiviral and antiparasitic drugs.3 B
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Journal of Agricultural and Food Chemistry Table 1. Brief List of Plants Reviewed in This Perspective and Some of the Active Compounds Identified group veratrum locoweeds larkspur lupine pine needle abortions pyrrolizidine alkaloids monofluoroacetatecontaining plants poison hemlock wild tree tobacco
plantsb
compounds identifiedc
Veratrum californicum cyclopamine, cycloposine, jervine, veratramine, muldamine Astragalus spp., Oxytropis spp., (aSida spp., Ipomoea swainsonine spp., Swainsona spp.) Delphinium spp. methyllycaconitine (MLA), deltaline, lycoctonine, anthranoyllycoctonine, nudicauline, 14-deacetylnudicauline (14-DAN), dictyocarpine, brownine, geyerline Lupinus spp. anagyrine, sparteine, lupanine, ammodendrine, N-acetylhystrine, angustifoline, gramine, Pinus ponderosa, Juniperus occidentalis, Juniperus isocupressic acid, agathic acid, dihydroagathic acid, imbricataloic acid utahensis Crotalaria spp., Senecio spp., Amsinckia spp., Echium riddelline, senecionine, lycopsamine, intermedine, heliosupine, echimidine, heliotrine, spp., Heliotropium spp., Symphytum spp. lasiocarpine, indicine, monocrotaline Gastrolobium spp., Palicourea spp., Amorimia spp., monofluoroacetate Dichapetalum spp. Conium maculatum coniine, gamma coniceine, N-methylconiine Nicotiana glauca anabasine
a Additional swainsonine containing plants. These are not considered locoweeds. bThere are numerous species of plants from many genera and in some instances several families of plants that contain the associated toxins. The following are some of the more common or problematic plants. cThe following are some of the more toxic and more abundant compounds identified from the associated plants. For many of the plant species, there are many more known compounds and likely many unknown.
Larkspur. Larkspurs (Delphinium spp., Figure 1C) are known to poison cattle on foothill and mountain rangelands of western North America.7 The primary toxic larkspur species are D. barbeyi and D. occidentale (tall larkspurs) and D. nuttallianum and D. andersonii (low larkspurs). The toxicity of larkspurs is due to norditerpene alkaloids, including two predominant types, a N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type, including methyllycaconitine, 3, (MLA) and a 7,8-methylenedioxylycoctonine (MDL)-type, including deltaline, 4, (Figure 2, Table 1), with the MSAL-type alkaloids being several fold more toxic. These alkaloids are antagonists of the nicotinic acetylcholine receptors, causing a flaccid muscle paralysis in poisoned animals. Various larkspur alkaloids have been identified and isolated, providing purified compounds for toxicity testing, which has allowed for the determination of structure−activity relationships.8 Research has demonstrated that larkspur alkaloids change as a function of plant phenology and that cattle consume the majority of tall larkspur (D. barbeyi and D. occidentale) after elongation of flowering stalks and subsequent flowering. These range studies, coupled with chemical analyses, have resulted in the “toxic window” management recommendation, whereby cattle can be grazed on tall larkspur (D. barbeyi and D. occidentale)-infested rangelands for 4 to 6 weeks early in the grazing season with little risk, removed during the time of greatest danger (i.e., the toxic window), then grazed again with little risk later in the season.7 This management recommendation has significantly reduced cattle losses in tall larkspur-infested rangelands. Different tall larkspurs species, and even different populations of the same species, often have unique alkaloid profiles allowing classification using chemotaxonomy.9 Some species such as D. occidentale and D. ramosum are represented by two chemotypes where populations of each chemotype have distinct geographical distributions.9 Understanding the distribution of the different chemotypes and their potential risk is an important management tool to enable utilization of the larkspur-infested rangelands while reducing the risk of livestock losses. Lupine. Cattle producers began reporting incidences of deformed calves in the 1950s and 1960s when their pregnant cattle were grazed on lupine-infested ranges.10 The high occurrence of these deformed calves resulted in naming the condition “crooked calf syndrome”, which is used to describe
the skeletal malformations in newborn calves that typically includes a twisted spine, neck, and one or both forelimbs as well as a cleft palate. These deformities may prevent the calf from walking or nursing normally, and consequently most die or are euthanized. In the 1960s, scientists confirmed that ingestion of lupine (Figure 1D) was the cause of the syndrome.10 Research demonstrated that the quinolizidine alkaloid anagyrine, 5, and the piperidine alkaloid ammodendrine, 6, (Figure 2, Table 1) are responsible for the deformities.11 Further research demonstrated that these alkaloids are not found in all lupine species or populations within a species, leading to the conclusion that taxonomic classification is not sufficient to determine toxic risk. When ingested by the dam, these alkaloids reduce fetal movement during the critical stage of pregnancy (gestation days 40−100 in cattle) and are hypothesized to result in the skeletal malformations of the offspring without injuring the mother. Research has also shown that Conium and Nicotiana spp. also contain teratogenic piperidine alkaloids (Table 1), with a similar effect in livestock when eaten during critical periods of gestation.11 Using these teratogenic plants, a goat model was developed and is used as an important tool in understanding the mechanism of cleft palate induction. This model has also been extensively used in biomedical research to develop new surgical techniques to repair cleft palates, including an in utero procedure, as potential interventions for cleft palate repair in humans.12 Pine Needle Abortions. Cattle grazing ponderosa pine needles (Figure 1E) are known to abort their calves, especially when grazed in the last trimester of pregnancy.13 Using bioassay-guided fractionation in cattle, the labdane resin acid isocupressic acid, 7, (Figure 2, Table 1) was identified and isolated from ponderosa pine needles and determined to be the putative abortifacient compound. Other derivatives and metabolites, including agathic acid, have now been identified with known abortifacient activity. Many other trees and shrub species found throughout the world have been analyzed for isocupressic acid and related labdane acids.14 Significant levels (>0.5% dry weight of the needles) were detected in numerous species, including other conifer and juniper species from around the world, indicating a risk for causing late term abortions. Research has also demonstrated that there is C
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Figure 3. Profile of isocupressic acid metabolism. (A) Concentration of isocupressic acid (ICA) metabolites in serum after intravenous dosing of isocupressic acid: agathic acid (AA) and dihydroagathic acid (DHAA). (B) Possible mechanistic pathway by which isocupressic acid causes abortions in cattle.
spp., Figure 1F), and Boraginaceae (Amsinckia, Borago, Cynoglossum, Echium, Heliotropium, and Symphytum). There are over 1200 Senecio spp. throughout the world with many containing toxic PAs.15 PA poisoning is a worldwide problem in animals and humans and is a significant impediment to international trade because of contaminated or potentially contaminated animal feeds and human foods. PAs can enter the human food chain via contaminated grains, milk, honey, eggs, and other foods or herbal products. The developing fetus and young children are especially susceptible to PA toxicity.
variation in the concentration of labdane acids in both ponderosa pine and western juniper trees between different geographical locations and even within the same location. Identifying which trees are potentially toxic and highlighting the risks of grazing these rangelands during late gestation or adverse weather has helped livestock managers reduce the incidences of the abortions. Pyrrolizidine Alkaloids. Pyrrolizidine alkaloids (PAs) such as riddelline, 8 (Figure 2, Table 1), are common in three plant families, i.e., Fabaceae (Crotalaria spp.), Asteraceae (Senecio D
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strated that there is in fact a difference in the toxicity of the coniine enantiomers. Additionally, the alkaloids ammodendrine, N-methylammodendrine, and anabasine from lupine and tobacco plants are chiral compounds (Table 1). However, currently very little is known regarding the importance of the stereochemical differences of plant toxins on the toxicity in mammalian systems. Multiple Toxins. In many plants, the putative toxin is known; however, most often there is more than one active compound in the plant (Table 1). For example, there are more than 18 different toxic larkspur alkaloids, and some larkspur plants can contain many different toxic alkaloids, all of which can elicit adverse effects, albeit at different potencies.7 The toxicity of many of these compounds has been tested individually, however, the interaction of multiple toxins dosed together is not well understood. Recent studies of simple mixtures of larkspur toxins have shown additive or synergistic effects occur when animals are exposed to multiple larkspur alkaloids.21 Similarly, livestock grazing in rangelands do not only eat one plant but eat a variety of plants, all of which contain a unique suite of potentially toxic compounds. As a result, when livestock are in a range setting, they are exposed to multiple toxins from multiple plants. There is evidence that livestock can “selfmedicate” by altering their plant preferences in response to adverse effects of prior plant exposures. The highly dynamic nature of toxin intake, absorption, and elimination further complicates the situation with multiple plant secondary compounds. Understanding the interactions of various toxins whether they are additive, synergistic, antagonistic, or therapeutic merits further investigation. Climate Change. The severity of problems from poisonous plants on rangelands is sensitive to changes in climatic conditions (i.e., precipitation and temperature); global climate change will influence the interaction of poisonous plants and grazing livestock. Climate change will result in changes that may influence the size and density of plants as well as the toxin concentrations. Recent studies have shown that populations of low larkspurs (D. nuttallianum and D. andersonii) are influenced by winter and spring climatic conditions.22 Studies have shown that elevated atmospheric CO2 increases the biomass of some plants23 and may influence the concentrations of toxins.24 However, other studies have shown that elevated CO2 does not influence toxin production within the plant.25 Another complicating factor is that climate change may influence the palatability and nutritional content (e.g., crude protein) of range plants, including poisonous plants. Ultimately, it is difficult to predict how changes in weather patterns and atmospheric CO2 will affect individual plant species or populations. Therefore, much remains to be understood regarding the impact of climate change on the toxicity of plants and the effect on the interaction with livestock species. Toxic Plants and Food Safety. A number of invasive weeds contain toxic PAs (Table 1). Most are not palatable to livestock and are only eaten when other forage is unavailable.15 However, if PA-containing plants are inadvertently harvested from hay meadows or grain fields, toxic PAs will contaminate prepared feeds, grains, and food, which will then be consumed by animals or humans.26 PAs can also contaminate eggs, milk, honey, and pollen products. Human poisonings may occur as a result of food contamination or when PA-containing plants are used for medicinal purposes.
Consequently, consumption of herbal products containing PAs by pregnant or lactating women is not recommended. Regulations in some parts of the world specify a maximum daily intake of 0.1 μg of hepatotoxic PAs and their N-oxides from herbal plants or plant extracts.16 Intake limitations and restrictions of use have created trade restrictions with various countries. Numerous methods have been developed to identify and quantitate PAs to provide safe feeds and foods for animals and humans. Additionally, research has been conducted to better understand the structure−activity relationships of the various PAs. Monofluoroacetate-Containing Plants. Numerous plant species worldwide cause sudden death syndrome in animals. Many of these plants contain monofluoroacetate, 9 (Figure 2, Table 1). Recently, HPLC−MS and GC−MS methods have been developed to detect and quantify monofluoroacetate in plants.17,18 Using these methods, monofluoroacetate has been detected in 18 plant species from 3 different families of plants, many of which are suspected to cause sudden death in livestock. Monofluoroacetate concentrations have been shown to differ greatly between various genera and within species of a genus, which helps explain the incidence of poisoning and the amount of plant material required to cause sudden death.
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CHALLENGES AND OPPORTUNITIES Plant Toxin Metabolism. One challenge in poisonous plant research is not only identifying the active constituent in the plant but also determining the biologically active form in the animal. For example, isocupressic acid is the compound in ponderosa pine needles that causes abortions.19 However, isocupressic acid is rapidly metabolized in the cow (Figure 3A) and is not the biologically active principle eliciting the physiological changes that cause the abortion (Figure 3B). Further research is needed to identify the metabolite(s) of isocupressic acid that is/are directly responsible for the physiological changes that result in abortion. In a related manner, preliminary mass balance studies of larkspur toxins have proven difficult. When larkspur was dosed to sheep, very little of the toxins was accounted for in the serum, urine, and feces of the sheep. This suggests the parent compounds were metabolized prior to elimination or were sequestered in tissues. Mass balance studies are challenging with natural products, as it is difficult to follow their metabolism in vivo, as one would do with a radiolabeled synthetic pharmaceutical. Thus, another challenge in poisonous plant research is to accurately characterize the absorption, distribution, metabolism, and elimination (ADME) of plant toxins in the target livestock species. Enantiomer Evaluation. Many plant toxins are ligands for mammalian receptors. Consequently, slight structural differences, including stereochemistry, could have profound impacts on the toxicological effects. Several plants are known to contain toxins with chiral carbons and thus possible enantiomers. For example, poison hemlock has been recognized as a poisonous plant for thousands of years. It is known to poison humans as well as livestock species. Poison hemlock contains three major toxic alkaloids (Table 1). The toxicity and teratogenic effects of the three major alkaloids from poison hemlock have been compared.20 The pharmacological activity is similar among these alkaloids but varies in potency because of structural differences. Pharmacological studies with the Conium alkaloids have demonstrated that they act as stereoselective nicotinic acetylcholine receptor agonists. Recent research has demonE
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all the drugs in clinical use today. However, there are still many unknown compounds awaiting discovery, characterization, and modification such that they can be used as potential therapeutics for medicine, to enhance human health through dietary benefits, or even as research tools for better understanding biological processes. 2018 International Symposium on Poisonous Plants. Every four years, scientists from around the world convene to present and discuss new discoveries and current knowledge regarding poisonous plants. This meeting is termed the International Symposium on Poisonous Plants (ISOPP). Previous meetings were held in Australia, United States, Brazil, China, and Scotland. The next ISOPP will be held in St. George, Utah, United States on September 16−20, 2018. An invitation is extended to all scientists with an interest in poisonous plants. This meeting will be a forum to learn from past successes, explore ways to resolve current challenges, and develop meaningful collaborations to tackle the plethora of opportunities that await discovery and understanding regarding poisonous plants and the toxins they produce.
Livestock that graze poisonous plants but are not fatally affected are a source of concern if humans subsequently consume contaminated meat or milk products. For example, in the 19th century, poisoning in humans consuming milk from cows grazing white snakeroot (Ageratina altissima) may have been the leading cause of death and disability/disease in the midwestern United States.26 Future research related to food safety and possible contamination of food products or forages is critical. There is a simultaneous need to increase public understanding of plant secondary compounds with potential adverse as well as beneficial health effects. Diagnosis and Field Analyses. Animal losses are a traumatic and costly experience for livestock producers. To minimize or prevent future losses, it is often imperative to quickly determine the cause of death. Evaluation of stomach contents for identifiable plants is a valuable tool; however, plant material in the rumen or stomach is often difficult to visually identify. Detection of toxic plants or the toxic principles in the rumen contents of poisoned animals is therefore a potential diagnostic tool. For example, the toxic principle monofluoroacetate was detected in the rumen contents of a sheep poisoned by Gastrolobium species (Figure 1G).27 Similarly, metabolites of isocupressic acid have been detected in fetal fluid samples associated with calves aborted from ponderosa pine.28 A PCR-based diagnostic tool to determine whether a specific poisonous plant was ingested was recently developed.29 This method used oligonucleotide primers specific to several larkspur species. Using these primers, larkspur was detected in cattle rumen samples under controlled circumstances at biologically relevant amounts. Other factors to consider in the development of diagnostic tests include choice of animal tissues/fluids to sample, quantitating the toxic principle, and determining whether a toxic threshold has been exceeded. Detection of poisonous plants or toxins in rumen contents and other animal tissues/fluids are promising diagnostic tools. Additionally, the development of portable tests that can be performed in the field by veterinarians or livestock producers would provide an important advance in the diagnostics of poisoned animals. Genetic Selection of Animals. The identification and measurement of genomic features (e.g., DNA sequence and gene expression) is becoming less expensive and increasingly routine. For years, ranchers have selected and culled animals, seeking to emphasize specific traits to increase animal wellbeing and ranch profits. Genetic selection of livestock has the potential to further enhance production efficiency and animal welfare. Using a genetic research approach, studies on larkspur poisoning in cattle have shown substantial animal to animal variation among individuals and breeds of cattle for susceptibility to larkspur poisoning.30 Preliminary work suggests that an individual animal’s genetic predisposition for larkspur poisoning can be predicted from its DNA sequence. The goal of this research is to identify a gene marker that will allow producers to identify susceptible and resistant animals by submitting a saliva, blood, or hair sample to a genetic testing laboratory. Matching animal species, breeds, or genotypes to the proper grazing environment is one avenue to reduce the negative effects of poisonous plants. Biomedical Spin-Offs of Poisonous Plant Research. A number of plants highlighted in this review contain toxins that could be used or are being used for biomedical benefits for humans.3 The wealth of the natural pharmacopeia and derivatives has been studied for years, resulting in >50% of
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]; Phone: (435) 752-2941; Fax: (435) 753-5681. ORCID
Kevin D. Welch: 0000-0002-5552-4894 Stephen T. Lee: 0000-0002-0597-8353 Daniel Cook: 0000-0001-8568-113X Funding
This work was supported by direct congressional appropriations via the U.S. Department of Agriculture to the Poisonous Plant Research Laboratory, which is part of the Agricultural Research Service. Notes
The authors declare no competing financial interest.
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REFERENCES
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(29) Cook, D.; Pfister, J. A.; Constantino, J. R.; Roper, J. M.; Gardner, D. R.; Welch, K. D.; Hammond, Z. J.; Green, B. T. Development of a PCR-based method for detection of Delphinium species in poisoned cattle. J. Agric. Food Chem. 2015, 63, 1220. (30) Green, B. T.; Welch, K. D.; Pfister, J. A.; Chitko-McKown, C. G.; Gardner, D. R.; Panter, K. E. Mitigation of larkspur poisoning on rangelands through the selection of cattle. Rangelands 2014, 36, 10− 15.
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