Ergot

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Ergot
Claviceps purpurea - Köhler–s Medizinal-Pflanzen-185.jpg
Claviceps purpurea
Scientific classification edit
Kingdom: Fungi
Division: Ascomycota
Class: Sordariomycetes
Order: Hypocreales
Family: Clavicipitaceae
Genus: Claviceps
Tul., 1853
Species

About 50, including:
Claviceps africana
Claviceps fusiformis
Claviceps paspali
Claviceps purpurea
Claviceps sorghi
Claviceps zizaniae
Claviceps lutea

Ergot (pron. /ˈɜːrɡət/ UR-gət) or ergot fungi refers to a group of fungi of the genus Claviceps.[1]

The most prominent member of this group is Claviceps purpurea ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that can cause ergotism in humans and other mammals who consume grains contaminated with its fruiting structure (called ergot sclerotium).[2][3]

Claviceps includes about 50 known species, mostly in the tropical regions. Economically significant species include C. purpurea (parasitic on grasses and cereals), C. fusiformis (on pearl millet, buffel grass), C. paspali (on dallis grass), C. africana[4] (on sorghum), and C. lutea (on paspalum).[5] C. purpurea most commonly affects outcrossing species such as rye (its most common host), as well as triticale, wheat, and barley. It affects oats only rarely.

C. purpurea has at least three races or varieties, which differ in their host specificity:[6]

  • G1 — land grasses of open meadows and fields;
  • G2 — grasses from moist, forest, and mountain habitats;
  • G3 (C. purpurea var. spartinae) — salt marsh grasses (Spartina, Distichlis).

Life cycle[edit]

An ergot kernel, called a sclerotium, develops when a spore of fungal species of the genus Claviceps infects a floret of flowering grass or cereal. The infection process mimics a pollen grain growing into an ovary during fertilization. Infection requires that the fungal spore have access to the stigma; consequently, plants infected by Claviceps are mainly outcrossing species with open flowers, such as rye (Secale cereale) and ryegrasses (genus Lolium). The proliferating fungal mycelium then destroys the plant ovary and connects with the vascular bundle originally intended for seed nutrition. The first stage of ergot infection manifests itself as a white soft tissue (known as sphacelia) producing sugary honeydew, which often drops out of the infected grass florets. This honeydew contains millions of asexual spores (conidia), which insects disperse to other florets. Later, the sphacelia convert into a hard dry sclerotium inside the husk of the floret. At this stage, alkaloids and lipids accumulate in the sclerotium.

Claviceps species from tropic and subtropic regions produce macro- and microconidia in their honeydew. Macroconidia differ in shape and size between the species, whereas microconidia are rather uniform, oval to globose (5x3μm). Macroconidia are able to produce secondary conidia. A germ tube emerges from a macroconidium through the surface of a honeydew drop and a secondary conidium of an oval to pearlike shape is formed, to which the contents of the original macroconidium migrates. Secondary conidia form a white, frost-like surface on honeydew drops and spread via the wind. No such process occurs in Claviceps purpurea, Claviceps grohii, Claviceps nigricans, and Claviceps zizaniae, all from northern temperate regions.

When a mature sclerotium drops to the ground, the fungus remains dormant until proper conditions (such as the onset of spring or a rain period) trigger its fruiting phase. It germinates, forming one or several fruiting bodies with heads and stipes, variously coloured (resembling a tiny mushroom). In the head, threadlike sexual spores form, which are ejected simultaneously when suitable grass hosts are flowering. Ergot infection causes a reduction in the yield and quality of grain and hay, and if livestock eat infected grain or hay it may cause a disease called ergotism.

Black and protruding sclerotia of C. purpurea are well known. However, many tropical ergots have brown or greyish sclerotia, mimicking the shape of the host seed. For this reason, the infection is often overlooked.

Insects, including flies and moths, carry conidia of Claviceps species, but it is unknown whether insects play a role in spreading the fungus from infected to healthy plants.[7]

Evolution[edit]

The evolution of plant parasitism in the Clavicipitaceae dates back at least 100 million years, to the early-mid Cretaceous. An amber fossil discovered in 2014 preserves a grass spikelet and an ergot-like parasitic fungus. The fossil shows that the original hosts of the Clavicipitaceae could have been grasses. The discovery also establishes a minimum time for the conceivable presence of psychotropic compounds in fungi.[8][9] Several evolutionary processes have acted to diversify the array of ergot alkaloids produced by fungi; these differences in enzyme activities are evident at the levels of substrate specificity (LpsA), product specification (EasA, CloA) or both (EasG and possibly CloA).[10] The “old yellow enzyme,” EasA, presents an outstanding example. This enzyme catalyzes reduction of the C8=C9 double-bond in chanoclavine I, but EasA isoforms differ in whether they subsequently catalyze reoxidation of C8–C9 after rotation.[10] This difference distinguishes most Clavicipitaceae from Trichocomaceae, but in Clavicipitaceae it is also the key difference dividing the branch of classical ergot alkaloids from dihydroergot alkaloids, the latter often being preferred for pharmaceuticals due to their relatively few side effects.[10]

Effects on humans and other mammals[edit]

Ergot-derived drug to stop postnatal bleeding

The ergot sclerotium contains high concentrations (up to 2% of dry mass) of the alkaloid ergotamine, a complex molecule consisting of a tripeptide-derived cyclol-lactam ring connected via amide linkage to a lysergic acid (ergoline) moiety, and other alkaloids of the ergoline group that are biosynthesized by the fungus.[11] Ergot alkaloids have a wide range of biological activities including effects on circulation and neurotransmission.[12]

Ergot alkaloids are classified as:

  1. derivatives of 6,8-dimethylergoline and
  2. lysergic acid derivatives.[13]

Ergotism is the name for sometimes severe pathological syndromes affecting humans or other animals that have ingested plant material containing ergot alkaloid, such as ergot-contaminated grains. The Hospital Brothers of St. Anthony, an order of monks established in 1095, specialized in treating ergotism victims[14] with balms containing tranquilizing and circulation-stimulating plant extracts. The common name for ergotism is "St. Anthony's Fire",[14] in reference to this order of monks and the severe burning sensations in the limbs which was one of the symptoms.[15] There are two types of ergotism, the first is characterized by muscle spasms, fever and hallucinations and the victims may appear dazed, be unable to speak, become manic, or have other forms of paralysis or tremors, and suffer from hallucinations and other distorted perceptions.[16] This is caused by serotonergic stimulation of the central nervous system by some of the alkaloids.[16] The second type of ergotism is marked by violent burning, peripheral pulses and shooting pain of the poorly vascularized distal organs, such as the fingers and toes,[16] and are caused by effects of ergot alkaloids on the vascular system due to vasoconstriction, sometimes leading to gangrene and loss of limbs due to severely restricted blood circulation.

The neurotropic activities of the ergot alkaloids may also cause hallucinations and attendant irrational behaviour, convulsions, and even death.[11][12] Other symptoms include strong uterine contractions, nausea, seizures, high fever, vomiting, loss of muscle strength and unconsciousness. Since the Middle Ages, controlled doses of ergot were used to induce abortions and to stop maternal bleeding after childbirth.[17] Klotz offers a detailed overview of the toxicities in mammalian livestock, stating that the activities are attributable to antagonism or agonism of neurotransmitters, including dopamine, serotonin and norepinephrine. As well, he shares that the adrenergic blockage by ergopeptines (e.g., ergovaline or ergotamine) leads to potent and long-term vasoconstriction, and can result in reduced blood flow resulting in intense burning pain (St. Anthony’s fire), edema, cyanosis, dry gangrene and even loss of hooves in cattle or limbs in humans. Reduced prolactin due to ergot alkaloid activity on dopamine receptors in the pituitary is also common in livestock. Reduced serum prolactin is associated with various reproductive problems in cattle, and especially in horses, including agalactia and poor conception, and late-term losses of foals and sometimes mares due to dystocia and thickened placentas.[10] Although both gangrenous and convulsive symptoms are seen in naturally occurring ergotism resulting from the ingestion of fungus infected rye, only gangrenous ergotism has been reported following the excessive ingestion of ergotamine tartrate.[18] Ergot extract has been used in pharmaceutical preparations, including ergot alkaloids in products such as Cafergot (containing caffeine and ergotamine[17] or ergoline) to treat migraine headaches, and ergometrine, used to induce uterine contractions and to control bleeding after childbirth.[19] Clinical ergotism as seen today results almost exclusively from the excessive intake of ergotamine tartrate in the treatment of migraine headache.[18]

In addition to ergot alkaloids, Claviceps paspali also produces tremorgens (paspalitrem) causing "paspalum staggers" in cattle.[20] The fungi of the genera Penicillium and Aspergillus also produce ergot alkaloids, notably some isolates of the human pathogen Aspergillus fumigatus,[21] and have been isolated from plants in the family Convolvulaceae, of which morning glory is best known.The causative agents of most ergot poisonings are the ergot alkaloid class of fungal metabolites, though some ergot fungi produce distantly related indole-diterpene alkaloids that are tremorgenic.[10]

Ergot does not contain lysergic acid diethylamide (LSD) but instead contains lysergic acid as well as its precursor,[22] ergotamine. Lysergic acid is a precursor for the synthesis of LSD. Their realized and hypothesized medicinal uses have encouraged intensive research since the 1950s culminating on the one hand in development of drugs both legal (e.g., bromocriptine) and illegal (e.g., lysergic acid diethylamide= LSD), and on the other hand in extensive knowledge of the enzymes, genetics, and diversity of ergot alkaloid biosynthetic pathways.[10]

The January 4, 2007 issue of the New England Journal of Medicine includes a paper that documents a British study of more than 11,000 Parkinson's Disease patients. The study found that two ergot-derived drugs, pergolide and cabergoline, commonly used to treat Parkinson's Disease may increase the risk of leaky heart valves by up to 700%.[23]

History[edit]

Ergot on wheat stalks

Ergotism is the earliest recorded example of mycotoxicosis, or poisoning caused by toxic molds.[24] Early references to ergot poisoning (ergotism) date back as far as 600 BC, an Assyrian tablet referred to it as a 'noxious pustule in the ear of grain'.[25] In 350 BC, the Parsees described 'noxious grasses that cause pregnant women to drop the womb and die in childbed'.[25] In ancient Syria, ergot was called 'Daughter of Blood'.[26] In 1582 AD, Adam Lonicer, of Frankfort, describes the appearance of ergot in fields of rye grass and mentions its efficacy for women during childbirth.[26] Johannes Thallius, in 1588 AD, writes that it is called 'Mother of Rye', or rockenmutter, and is used to halt bleeding.[26] In 944 AD, a massive outbreak of ergotism caused 40,000 deaths in the regions of Aquitaine, Limousin, Perigord, and Angoumois in France.[24] In 944 AD, Radulf Glaber describes an ailment he calls 'hidden fire' or ignus ocultus, in which a burning of the limb is followed by its separation from the body, often consuming the victim in one night.[26] Human poisoning due to the consumption of rye bread made from ergot-infected grain was common in Europe in the Middle Ages. The first mention of a plague of gangrenous ergotism in Europe comes from Germany in 857 AD, following this France, Germany and Scandinavia experienced similar outbreaks.[27] England is noticeably absent from the regions affected by ergotism as their main source of food was wheat, which is resistant to ergot fungi.[26] Wendalin Thelius was one of the first to attribute ergotism poisoning to grain; in the Kingdom of Hesse in 1596 AD.[27] S Tessier, observing a huge epidemic at Sologne, France, in 1778 AD in which more than 8000 people died, recommended drainage of fields, compulsory cleaning of grain, and the substitution of potatoes for affected grain.[27] In 1722, the Russian Tzar Peter the Great was thwarted in his attack against the Ottoman Empire as his army travelling down the Terek steppe were struck by ergotism and he was forced to retreat to find edible grains for his soldiers. (Bennett 347) A diary entry from the time describes that as soon as people ate the poisoned bread they became dizzy, with such strong contractions of the nerves that those who did not die from the first day, find their hands and feet falling from them, as from frostbite.[28] The epidemic was known as Saint Anthony's fire,[14] or ignis sacer, and some historical events, such as the Great Fear in France during the Revolution have been linked to ergot poisoning.[29] St. Anthony was a 3rd century Egyptian ascetic who lived by the Red Sea and was known for long fasting in which he confronted terrible visions and temptations sent from the Devil.[27] His name was taken by an Order of Hospitalers founded in 1095 AD by a wealthy Frenchman who, whilst praying for his ill son, received a vision of St. Anthony asking that he dedicate his life to healing the sick and injured.[26] St. Anthony was a popular subject for art in the middle ages and his symbol is a large blue T sewn onto the shoulder of the monks of the order which symbolizes the crutch used by the ill and injured.[30] The Order of St. Anthony grew quickly and hospitals spread through France, Germany, and Scandinavia and gained wealth and power as grateful patrons bestowed money and charitable goods to the hospitals.[26] By the end of the Middle Ages, there were 396 settlements and 372 hospitals owned by the Order of St. Anthony.[30] Pilgrimages to St. Anthony's hospitalers became popular as well as the donation of limbs lost to ergotism which were displayed near shrines to the Saint.[26] These hagiotherapeutic centers were the first specialized European medical welfare systems and the friars of the order were knowledgeable about treatment of ergotism and the horrifying effects of the poison.[30] The sufferers would receive ergot-free meals, wines containing vasodilating and analgesic herbs, and applications of Antonites balsalm, which was the first transdermal therapeutic system (TTS) in medical history.[25] Their medical recipes have been lost to time, though some recorded treatments still remain.[30] After 1130 AD, the monks were no longer permitted to perform operations, and so barber surgeons were employed to remove gangrenous limbs and treat open sores.[30] Three barbers founded a hospital at Memmingten in 1214 and accepted those who were afflicted with the gangrenous form of ergotism, for the remainder of their days they were fed and housed with the more bodily abled acting as orderlies and assistants. Patients with the convulsive form of ergotism, or ergotismus convulsivus were welcomed for only nine days before they were asked to leave. The convulsive form of ergotism was seen as less detrimental though the sufferers often experienced irreversible effects, they most often returned to their families and resumed their livelihoods.[30] An important aspect to the Order of St. Anthony was the exclusion of rye bread and other ergot containing edibles which halted the progression of ergotism.[26] There is no known cure however there is treatment of the symptoms of ergotism which is notable for blood constriction, nervous disorder, and/or hallucinations; if the sufferer survived the initial poisoning, his limbs would often fall off and he or she would continue to improve in health if they halted consumption of ergot.[27] The trunk of the body remained relatively untouched by the disease until its final stages and the victims, not understanding the cause of their ailment, would continue to imbibe ergot laden food for weeks until the condition reached their digestive system.[30] It is believed that the peasantry and children were most susceptible to ergotism though the wealthy were afflicted as well, as at times entire villages relied on tainted crops for sustenance and during times of famine, ergotism reached into every house.[25] Ergot fungus is impervious to heat and water, thus it was most often baked into bread through rye flour though other grasses can be infected it was uncommon in Europe to consume grasses other than rye.[26] The physiological effects of ergot depended upon the concentration and combinations of the ingested ergot metabolites, as well as the age and nutritional status of the afflicted individual.[28] The Order of St. Anthony began to decline after physicians discovered the genesis of ergotism and recommended methods for removing the sclerotium from the rye crops. In 1776 AD, the cloisters of St. Anthony were incorporated into the Order of the Knight Hospitaller (Maltese), losing much of their medical histories in the process and losing the ergotism cures and recipes due to lack of use and lack of preservation.[30] Linnda R. Caporael posited in 1976 that the hysterical symptoms of young women that had spurred the Salem witch trials had been the result of consuming ergot-tainted rye.[31] However, Nicholas P. Spanos and Jack Gottlieb, after a review of the historical and medical evidence, later disputed her conclusions.[32] Other authors have likewise cast doubt on ergotism as the cause of the Salem witch trials.[33]

Midwives and doctors have used extracts from ergots to hasten childbirth or to induce abortions for centuries.[34] "Ergot of rye", wrote Francis Ramsbotham, founder of the Obstetrical Society of London, in 1841, "has been known to possess deleterious and poisonous qualities for more than 800 years, and it has been used on the continent by female midwives as a promoter of labour pains for nearly 150 years"[27] The first reference to use of ergot in childbirth seems to be from 1582 AD, when a German physician, A Lonicer, recommended use of three sclerotia of ergot to speed contractions of prolonged labour; in 1688 AD, another German physician, R J Camerarius, wrote that midwives would give it to accelerate parturition; and in France, A.A. Parmentier wrote in his Journal de Physique of 1774 AD that ergot was frequently used by midwives as "a childbed remedy".[27] F. Paulisky, a german physician labels the use of ergot as ‘pulvis ad partum’ or a powder to aid birth, in 1787.[27]

Previous research has shown that the prophylactic use of uterotonic agents in the third stage of labour reduces both postpartum blood loss and postpartum haemorrhage.[35][needs update] In 1808 John Stearns of upper New York State learned from an immigrant German midwife of a new means to effect the mechanics of birth. This was ergot, a powerful natural drug that stimulates uterine muscles when given orally. It causes unremitting contractions. Stearns stressed its value in saving doctors time and relieving women of the agony of long labor. The 1836 Dispensatory of the United States recommended 15 to 20 grains (sclerotia) to induce uterine contractions and in 1839 the French Codex required ergot to be kept in all pharmacies.[24] Though ergot was known to cause abortions in cattle and women, it was not a recognized use for it as abortion was illegal in most countries thus evidence for its use in abortion is unknown.[24] Most often ergot was used to speed the process of parturition or delivery, and was not used for the purpose of halting postpartum bleeding, which is a concern of childbirth.[27] However, until anesthesia became available, there was no antidote or way of controlling the effects of ergot. So if the fetus did not move as expected, the drug could cause the uterus to mold itself around the child, rupturing the uterus and killing the child. David Hosack, an American physician, noted the large number of stillbirths resulting from ergot use and stated that rather than pulvis ad partum, it should be called pulvis ad mortem.[27] He began advocating for its use to halt postpartum bleeding. Eventually, doctors determined that the use of ergot in childbirth without an antidote was too dangerous. They ultimately restricted its use to expelling the placenta or stopping hemorrhage. Not only did it constrict the uterus, ergot had the ability to increase or decrease blood pressure, induce hypothermia and emesis, and influence pituitary hormone secretions.[24] In 1926, Swiss psychiatrist Hans Maier suggested to use ergotamine for the treatment of vascular headaches of the migraine type.[16]

In the 1930s, abortifacients drugs were marketed to women by various companies under various names such as Molex Pills and Cote Pills. Since birth control devices and abortifacients were illegal to market and sell at the time, they were offered to women who were "delayed". The recommended dosage was seven grains of ergotin a day. According to the FTC[36] these pills contained ergotin, aloes, Black Hellebore, and other substances. The efficacy and safety of these pills are unknown. The FTC deemed them unsafe and ineffective and demanded that they cease and desist selling the product. Currently, over a thousand compounds have been derived from ergot ingredients.[16]

British author John Grigsby contends that the presence of ergot in the stomachs of some of the so-called 'bog-bodies' (Iron Age human remains from peat bogs N E Europe such as Tollund Man) is indicative of use of ergot in ritual drinks in a prehistoric fertility cult akin to the Eleusinian Mysteries cult of ancient Greece. In his book Beowulf and Grendel, he argues that the Anglo-Saxon poem Beowulf is based on a memory of the quelling of this fertility cult by followers of Odin. He writes that Beowulf, which he translates as barley-wolf, suggests a connection to ergot which in German was known as the 'tooth of the wolf'. Beowulf is alternatively theorized to be translated at 'bee-wolf', a kenning for 'bear', to reference his berserker (bear shirt) state.[37]

Kykeon, the beverage consumed by participants in the ancient Greek cult of Eleusinian Mysteries, might have been based on hallucinogens from ergot,[38] and lysergic acid diethylamide (LSD) is a potent hallucinogen, which was first synthesized from ergot alkaloids by the Swiss chemist, Albert Hofmann, in 1938, while he was searching for a respiratory and circulatory stimulant. He discovered its effect on the nervous system accidentally in 1943 when he ingested the substance and mentioned a hallucinogenic reaction.[16]

Claviceps purpurea[edit]

Mankind has known about Claviceps purpurea for a long time, and its appearance has been linked to extremely cold winters that were followed by rainy summers.[citation needed]

The sclerotial stage of C. purpurea conspicuous on the heads of ryes and other such grains is known as ergot. Favorable temperatures for growth are in the range of 18–30 °C. Temperatures above 37 °C cause rapid germination of conidia.[citation needed] Sunlight has a chromogenic effect on the mycelium, with intense coloration.[citation needed] Cereal mashes and sprouted rye are suitable substrates for growth of the fungus in the laboratory.[citation needed]

Claviceps africana[edit]

Claviceps africana infects sorghum. In sorghum and pearl millet, ergot became a problem when growers adopted hybrid technology, which increased host susceptibility.[16] It only infects unfertilized ovaries, so self-pollination and fertilization can decrease the presence of the disease, but male-sterile lines are extremely vulnerable to infection.[citation needed] Symptoms of infection by C. africana include the secretion of honeydew (a fluid with high concentrates of sugar and conidia), which attracts insects like flies, beetles, and wasps that feed on it. This helps spread the fungus to uninfected plants.

C. africana caused ergot disease that caused a famine in 1903-1906 in Northern Cameroon, West Africa, and also occurs in eastern and southern Africa, especially Zimbabwe and South Africa. Male sterile sorghums (also referred to as A-lines) are especially susceptible to infection, as first recognized in the 1960s, and massive losses in seed yield have been noted. Infection is associated with cold night temperatures that are below 12 °C occurring two to three weeks before flowering.[citation needed]

Sorghum ergot caused by Claviceps africana Frederickson, Mantle and De Milliano is widespread in all sorghum growing areas, whereas the species was formerly restricted to Africa and Asia where it was first recorded more than 90 years ago, it has been spreading rapidly and by the mid-1990s it reached Brazil, South Africa, and Australia. By 1997, the disease had spread to most South American countries and the Caribbean including Mexico, and by 1997 had reached Texas in the United States.[16]

See also[edit]

References[edit]

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