BOLETIM TÉCNICO No. 22 - www.micotoxinas.com.br
Common mycotoxigenic species of Fusarium
Ailsa D. Hocking
Fusarium is one of the most important genera of plant pathogenic fungi on earth, with a record of devastating infections in many kinds of economically important plants. Fusarium species are responsible for wilts, blights, root rots and cankers in legumes, coffee, pine trees, wheat, corn, carnations and grasses. The importance of Fusarium species in the current context is that infection may sometimes occur in developing seeds, especially in cereals, and also in maturing fruits and vegetables. An immediate potential for toxin production in foods is apparent.
The very important role of Fusaria as mycotoxin producers appears to have remained largely unsuspected until the 1970s. Research has now unequivocally established the role of Fusaria as the cause of alimentary toxic aleukia (ATA). This was the previously mentioned human mycotoxicosis epidemic in the USSR which killed an estimated 100,000 people between 1942 and 1948 (Joffe, 1978). ATA is also known to have occurred in Russia in 1932 and 1913, and there is little doubt that outbreaks occurred in earlier years as well. Matossian (1981) has argued persuasively that ATA occurred in other countries, including England, in the 16th to 18th centuries at least.
Research since 1970 has shown that Fusarium species are capable of producing a bewildering array of mycotoxins. Foremost among these are the trichothecenes, of which at least 50 are known: the majority are produced by Fusaria. The most notorious is T-2 toxin, which was responsible for ATA (Joffe, 1978). Other Fusarium mycotoxins are known to be highly toxic to animals, and are suspected to be responsible for acute and chronic human diseases also.
The taxonomy of Fusarium was in disarray until recently, with several competing taxonomic schemes, recognising from 9 to 60 species in the genus. A determined attack on this problem by an international collaborative group has resolved most of the conflict, and the taxonomy of Nelson et al. (1983) has met with widespread approval. Nelson et al. (1983) accepted 30 species.
A direct consequence of confusion in taxonomy is confusion over species mycotoxin associations. Fusarium isolates producing a particular toxin have been given different names as a result of the different taxonomic systems used, or simply as a result of misidentification. Marasas et al. (1984) intensively studied more than 200 toxigenic Fusarium isolates, and provided accurate information on species identifications and the corresponding toxins produced. They listed 24 Fusarium species with confirmed toxigenicity. The four species judged to be most important from the viewpoint of human health, F. sporotrichioides, F. equiseti, F. graminearum and F. moniliforme, are discussed below.
Growth of Fusarium species is favoured by dilute, high aw (water acturty) media. Enumeration of fusaria can be effectively carried out on PDA (Booth, 1971) provided chloramphenicol or other broad spectrum antibiotics are added to suppress bacteria. However, acidified PDA, a frequently used antibacterial medium, is not recommended because it may inhibit sensitive cells (King et al., 1986). DCPA (Andrews and Pitt, 1986) is an effective enumeration and isolation medium for most food-borne Fusarium species. Recognition of Fusarium colonies on any of these media requires careful observation and experience. Presumptive identification to genus level can usually be made from colony appearance: low to floccose colonies, coloured white, pink or purple, with pale to red or purple reverses, are indicative of Fusarium. Confirmation requires microscopical examination, where the crescent-shaped macroconidia characteristic of the genus should be observed. These are not always produced on enumeration media, especially PDA, however. Differentiation of some species on enumeration media is possible, but also requires experience.
Identification of Fusarium species is ideally carried from growth on carnation leaf agar, an effective medium for macroconidium production (Nelson et al., 1983), but this medium is not readily available to the nonspecialist. Pitt and Hocking (1985a) provided keys and descriptions enabling identification of the species of interest in foods after growth on the readily available media CYA, MEA and PDA. Hocking and Andrews (1987) reported that DCPA, a medium that encourages production of macroconidia, is a practical alternative medium to carnation leaves for identifying most food-borne species.
As noted above, the current definitive taxonomy is that of Nelson et al. (1983). Burgess et al. (1988) have published a very useful and up to date guide to most species. Pitt and Hocking (1985a) give keys and descriptions of common food-borne species.
Toxins, toxicity and symptoms: General
Trichothecenes, the principal toxins produced by Fusaria, are sesquiterpenes with a basic 12,13-epoxytrichothec-9-ene ring system. Trichothecenes are often produced in mixtures even under pure culture conditions, and are very difficult to separate, so the toxicity of many of these compounds remains uncertain. Some are known to be highly toxic: none appear to be benign (Cole and Cox, 1981).
Because of the variable quality of the available data, trichothecene toxicity will not be considered in detail. However, as an example, the acute LD50 values for T-2 toxin are of the order of 8-4 mg/kg in rats, pigs and mice. LD50 values for the much less toxic deoxynivalenol have been reported as at least 70 mg/kh in mice; however, only 5 mg/kg in feed causes vomiting in pigs.
The biochemical basis of trichothecene toxicity is noncompetitive inhibition of protein synthesis (Cole and Cox, 1981; Ueno, 1983). Points of attack at the molecular level differ: some trichothecenes attack initiation of protein synthesis, others inhibit elongation or termination. Differences in toxicity and symptoms result.
It is difficult indeed to catalogue the symptoms of trichothecene poisoning. Vomiting, diarrhoea, anorexia and gastro-intestinal inflammation are rapid responses, which sometimes occur, but less immediate effects such as skin necrosis, leukopenia, ataxia, hemorrhaging of muscular tissue, and degeneration of nerve cells are all known (Cole and Cox, 1981; Ueno, 1983). Mortalities may result not only from injection or oral ingestion, but sometimes also from topical application. With the possible exception of the hepatocarcinogenicity of the aflatoxins, trichothecenes constitute the greatest known mycotoxin threat to human and animal health, the more insidious because the symptoms are so variable.
Some other mycotoxins are also produced by Fusarium species: zearalenone, in fact an oestrogen rather than a true mycotoxin; moniliformin, which has a unique four carbon ring structure; fusaric acid, better known as a phytotoxin involved in plant pathogenicity; and, from obviously toxic isolates, toxic principles which have defied isolation or characterisation (Marasas et al., 1984). The most notable of these, produced by F. moniliforme, eluded investigators for 15 years (Marasas et al., 1984). It has recently been isolated, characterised, and named fumonisin B (Bezuidenhout et al., 1988).
Most Fusarium toxins have been shown to possess only acute toxicity. However, strong circumstantial evidence suggests that some may be involved in human cancer. Fumonisin B. which is a bizarre molecule believed to cause leukoencephalomalactia in horses, is also reported to induce liver cancer in rats (Gelderblom et al., 1988). Involvement of this compound in oesophageal cancer in southern Africa appears likely.
Finally, the possible implication of trichothecenes in the controversial "yellow rain" episode in Laos must be mentioned (Mirocha et al., 1983; Nowicke and Meselson, 1984). The discussions of this controversy show strong political bias and the facts about the alleged use of mycotoxins as a biological warfare agent remain obscure. However, the fact that trichothecene toxins could have caused many of the reported symptoms is beyond dispute (Marasas et al., 1984).
Distribution in nature and in foods
Fusarium species are primarily plant pathogens, and occur mostly in association with plants and cultivated soils. In many cases, particular plant species associations are known or can be predicted. Such associations will be described under the individual species which follow.
Unlike most Aspergillus and Penicillium species, Fusaria grow in crops before harvest, and grow only at high aw levels. Mycotoxins are therefore usually only produced before or immediately after harvest.
In the years 1942-1948, at least 100,000 Russian people died from a mysterious epidemic. Illness and death occurred mostly but not exclusively in the Orenburg district near the Caspian Sea. In some localities, up to 60% of the population were affected, and up to 10% died (Joffe, 1978). The disease, now called Alimentary Toxic Aleukia (ATA), has since been shown to have occurred in Russia twice previously in this century, in 1932 and 1913, and perhaps elsewhere in Europe, including England, in earlier centuries (Matossian, 1981).
ATA is an exceptionally unpleasant disease. Symptoms include fever, haemorrhagic rash, bleeding from nose, throat and gums, necrotic angina, extreme leukopenia, agranulocytosis, sepsis and exhaustion of the bone marrow (Joffe, 1978). These symptoms more closely resemble those of radiation sickness than bacterial or other fungal toxicoses.
The direct cause of ATA in Russia in the 1940s was consumption of bread and other cereal products made from grains, which were left in fields over winter due to wartime labour shortages. This became clear about 1950. However the fact that ATA was a mycotoxicosis was not finally established until the mid 1970s, when it was proved that T-2 toxin was produced by Fusarium sporotrichioides and the closely related species F. pose during growth in freezing and thawing cycles (Yagen et al., 1977; Joffe, 1978).
F. sporotrichioides has also been implicated in a variety of very serious animal diseases, including scabby grain intoxication and bean hull poisoning in Japan, mouldy corn toxicosis in the USA, and fescue foot in the USA, Australia and New Zealand (Marasas et al., 1984).
Fusarium sporotrichioides, classified in Fusarium Section Sporotrichiella, is now a well circumscribed species (Nelson et al., 1983). However, many literature reports have misidentified this species as F. tricinctum sensu Snyder and no boldface currently accepted species. F. tricinctum sensu stricto is in fact a species of low toxicity. Much of this confusion has been rectified by Marasas et al. (1984).
Colonies of F. sporotrichioides grow rapidly on CYA, MEA, PDA or DCPA, are deep and floccose, with mycelium coloured pale pink or salmon, and reverse on PDA grayish rose to burgundy. Macroconidia and microconidia are abundant on DCPA: micro conidia are both fusiform and pear-shaped, and are borne from phialides with more than one fertile pore.
Toxins and toxicity
As well as T-2 toxin, some isolates of F. sporotrichioides are known to produce butenolide, fusarenon-X, neosolaniol and nivalenol. Zearalenone, deoxynivalenol and some less well characterised trichothecenes occur less frequently (Marasas et al. 1984).
The patterns of toxicity shown by isolates of this species depend on the relative production of these various toxins. All animal species studied are affected by them, in various ways.
T-2 toxin, produced by F. sporotrichioides, is the most important human food poison which can result from ingestion of mouldy grain. The symptoms of this intoxication have been described above.
Distribution in nature and food
Fortunately, Fusarium sporotrichioides is not a commonly occurring species. It is found mainly in temperate regions on cereal crops, although it has also been isolated from peanuts and soybeans (Pitt and Hocking, 1985a). Indications are that T-2 production is favoured by growth at low temperatures, but experimental evidence remains incomplete.
A broad spectrum plant pathogen and soil saprophyte of widespread distribution, F. equiseti has a long history of association with animal disease, and a possible implication in human leukaemia. Conclusive evidence of the latter is lacking. However, given its widespread distribution and the long list of mycotoxins produced (Marasas et al., 1984), the potential for this species to cause human and animal disease cannot be ignored. Confusion over the name of this species in earlier years precludes any detailed discussion of its history.
F. equiseti is classified by Nelson et al. (1983) in Fusarium Section Gibbosum. It has a teleomorph (sexual state) called Gibberella intricans, which has been recorded from nature quite rarely (Booth, 1971). Consequently, use of the Fusarium name for this species is to be preferred.
Much of the earlier literature on F. equiseti is located under the names F. roseum sensu Snyder and Hansen (1940), F. roseum 'Gibbosum', F. roseum 'Avenaceum', F. roseum 'Culmorum', or F. roseum 'equiseti' and several other distinct species as well. Hence it is now frequently impossible to determine which of the names used by earlier authors actually refers to F. equiseti (Marasas et al., 1984).
Colonies of F. equiseti on CYA, MEA and PDA usually cover the whole Petri dish, while those on DCPA are smaller. Mycelium and colony reverses are not strongly coloured, but white or pale salmon to brown. Macroconidia are distinctly curved ("hunch backed"); microconidia are not produced.
Toxins and toxicity
Mycotoxins produced by F. equiseti include nivalenol, fusarenon X, T-2, diacetoxyscirpenol, butenolide, zearalenone and several others less well characterised: an impressive list (Marasas et al., 1984). Several of these may be produced simultaneously. Suzuki et al. (1980) reported production of nivalenol, diacetoxyscirpenol and fusarenon-X by 16 of 25 isolates of F. equiseti in Japan. T-2, zearalenone and butenolide occur less commonly.
Association of F. equiseti with human leukaemia has been reported, and diacetoxyscirpenol is suggested as a possible cause. F. equiseti was isolated from dust in a house in the United States where two people had developed leukaemia, and the isolate was capable of depressing the immune response of guinea pigs (Wray et al., 1979). Previous work by the same authors had suggested a Fusarium species was the cause of leukaemia in a U.S. house where four cases had occurred (Wray and O'Steen, 1975).
Associations have been reported linking F. equiseti with animal diseases such as degnala, a disease of buffalo eating rice straw in Pakistan and India, bean hull poisoning of horses in Japan, and tibial dyschondroplasia, a bone disease of poultry (Marasas et al., 1984). Clear evidence of causation remains elusive in each case
As with other intoxications caused by Fusaria, symptoms of poisoning caused by F equiseti are very varied, reflecting the insidious nature of trichothecene toxicoses, the range of toxins produced by a single species and the proportion of each toxin formed under the influence of substrate, temperature and water activity.
F. equiseti has been reported from several types of grains, and no doubt toxins produced by this species are consumed in human food in many places from time to time. The wide range of diseases produced in animals, as indicated above, provide little clue to the recognition of symptoms in humans.
Distribution in nature and foods
A cosmopolitan soil fungus, F equiseti has a distribution extending from Alaska to the tropics (Domsch et al., 1980). It has also been isolated from a wide variety of plants, where it causes stem and root rots in particular (Booth, 1971; Nelson et al., 1983). F equiseti has been reported from a variety of cereal grains, especially maize and barley (Marasas et al., 1979) but relatively from other foods (Pitt and Hocking, 1985a).
As with most Fusarium species, the history and toxicological importance of F graminearum is obscured by the confusion over its identity. Now that the taxonomic problems have been clarified, it is recognised that F. graminearum causes oestrogenic syndromes, feed refusal and emetic syndromes in pigs and sometimes other animals, and is very likely to be the cause of human Akakabi-byo (scabby grain intoxication) in Japan (Yoshizawa, 1983).
In the classification of Nelson et al. (1983), F graminearum is placed in the Section Discolor. This species has a well recognised teleomorph (sexual state), Gibberella zeae. Literature references to G. zeae are frequent, and usually correct. Choice of the Fusarium or Gibberella name for this species ultimately depends on the individual author's preference, but should also reflect the predominant state being isolated or studied.
Two quite distinct biotypes of this species have been encountered in Australia. F. graminearum Group I, the cause of crown rot of wheat, produces the Gibberella state only when isolates are mated in compatible pairs. However, F. graminearum Group II, which causes diseases in aerial parts and grains of cereals, readily forms the Gibberella state in single isolate (and single spore) culture (Burgess et al., 1988).
As with F. equiseti, the name F. roseum sensu Snyder and Hansen (1940) has caused great confusion in the literature related to F. graminearum.
Colonies of F. graminearum fill the Petri dish when grown on CYA, MEA or PDA for 7 days; colonies on DCPA are somewhat smaller. On CYA and MEA, colonies are floccose, in muted or pastel shades of greyish red or yellow. On PDA, colonies are usually highly coloured, with dense to floccose greyish rose to golden brown mycelium and a dark ruby reverse, while on DCPA, colony appearance is dominated by salmon to orange clusters of macroconidia, often in concentric rings. Macroconidia are relatively straight and thick walled, with a foot-shaped basal cell. Microconidia are not produced.
Toxins, toxicity and symptoms
The principal toxins produced by F. graminearum are well defined: deoxynivalenol (DON; also known as vomitoxin), nivalenol ad zearalenone (Marasas et al., 1984). Reports of the occurrence of diacetoxyscirpenol, fusarenon-X and butenolide are accepted by Marasas et al. (1984), but the frequency of production appears to be much lower. Production of T-2 remains equivocal. Some minor toxins are also produced (Marasas et al., 1984).
The toxicity of the major F. graminearum toxins is undoubted, but until recently the picture has been clouded by the fact that some isolates identified as this species can produce T-2. Even low levels of this very toxic compound, difficult to separate out or often even to detect, can cause symptoms, which have been wrongly attributed to the other toxins. The recent production of gram quantities of pure DON (Miller et al., 1984) will shortly result in much more accurate toxicity studies.
One point is clear: DON causes vomiting and feed refusal in pigs at levels near 5 mg/kg of feed. Although very low limits have been set for DON in human foods in the USA, Canada and Japan, its toxicity to species other than pigs remains to be defined, and appears unlikely to be high.
The oestrogenic effect of zearalenone in animals is a well-defined syndrome. Corn, barley and wheat grains infected with F. graminearum and producing zearalenone cause genital problems in domestic animals, especially pigs. Symptoms include hyperemia and edematous swelling of the vulva in prepubertal gilts, or in more severe cases prolapse of the vagina and rectum. Reproductive disorders in sows include infertility, foetal resorption or mummification, abortions, reduced litter size and small piglets. Male pigs are also affected: atrophy of testes, decreased libido and hypertrophy of the mammary glands are all well documented (Marasas et al., 1984).
At present, F. graminearum isolates, which produce nivalenol, are known only from Japan, and the significance of this mycotoxin in the environment is not clear. However, in Japan, sporadic epiphytotics of "akakabi-byo" (red mould disease) occur, most probably due to the common occurrence of F. graminearum on wheat, barley, oats, rye and rice in Japan. Symptoms include anorexia, nausea, vomiting, headache, abdominal pain, diarrhoea, chills, giddiness and convulsions (Yoshizaw, 1983). Deoxynivalenol and zearalenone appear unlikely to be the prime causes of this range of symptoms: nivalenol is a more likely candidate (Yoshizawa, 1983; Marasas et al., 1984).
Metabolites of F. graminearum enter the human diet through cereal consumption in other parts of the world also. Deoxynivalenol, nivalenol and zearalenone have all been reported from corn, corn meal and other corn products, wheat and breakfast cereals in the USA, Canada and Africa. Possible effects in humans remain undefined.
Distribution in nature and food
F. graminearum is primarily a pathogen of gramineous plants, particularly wheat, causing crown rot at the base of the stem, and head scab in developing grain. It also causes cob rot of corn in many countries, including the wetter areas of Europe, North America, Africa and Australia (Marasas et al., 1984) It is uncommon in other situations, or other foods (Pitt and Hocking 1985a).
Fusarium moniliforme Sheldon, also known as verticillioides (Sacc.) Nirenberg, was described more than a century ago as a species occurring on corn. Reports of its possible involvement in human or animal disease date back almost as far, coming from Italy, Russia and the United States by 1904 (Marasas et al., 1984).
The only animal disease for which the causal role of F. moniliforme has been established beyond doubt is the disease of horses and related animals known as equine leukoencephalomalacia (LEM). This disease was known as early as 1850 in the corn belts in the United States, with epidemics involving hundreds or thousands of horses in 1900, the 1930s and as recently as 1978/79. It also occurs in other parts of the world, including Argentina, China, Egypt, New Caledonia and South Africa (Marasas et al., 1984). However, F. moniliforme was not positively identified as the cause of LEM until 1971 (Wilson, 1971).
F. moniliforme has been suggested to be the cause of a variety of other animal diseases, including bean hull poisoning of horses in Japan, abnormal bone development or rickets in chickens and pigs in the U.S.A., France and Germany, and a toxicosis due to mouldy sweet potatoes in the U.S.A. (Marasas et al., 1984).
The high rate of human oesophageal cancer which occurs in some parts of Transkei in southern Africa appears to be associated with corn consumption, ad perhaps, therefore, with F. moniliforme (Marasas et al., 1984).
Unlike other species considered here, F. moniliforme has been recognised as a distinct entity for many years. Disagreement still exists over the correct name: the name F. verticillioides (Sacc.) Nirenberg undoubtedly has nomenclatural priority, but has not been accepted by Nelson et al. (1983), their grounds being that the provisions of the International Code of Botanical Nomenclature are difficult to apply to Fusarium species in the absence of type material. Eventual conservation of F. moniliforme seems likely.
Colonies of F. moniliforme on PDA are white, sometimes tinged with purple. Macroconidia vary from slightly sickle shaped to almost straight. Microconidia are abundant, and are usually single celled, ellipsoidal to clavate with a flattened base, and formed in long chains.
Toxins and toxicity
Despite early warnings that F. moniliforme was a highly toxic fungus, the road to understanding of the toxins responsible has been long and difficult. The most important toxin produced by this species is undoubtedly fumonisin B. a mycotoxin only characterised very recently (Bezuidenhout et al., 1988). Fumonisin B is a bizarre molecule, consisting of a 20 carbon aliphatic chain with two ester-linked hydrophilic side chains.
F. moniliforme growing in corn is known to be responsible for LEM, a brain disease of horses. LEM has been as a serious problem in the United States corn belt for more than 100 years, and has caused the deaths of thousands of horses. Recent work indicates that fumonisins are the toxins most likely to be responsible for LEM.
The effect of fumonisins on humans is not known, but the fact that fumonisin B can induce cancer in rats suggests that this toxin may have a role in human oesophageal cancer. Corn is the major staple food in areas of the Transkei where oesophageal cancer is endemic, and the most striking difference between areas of low and high incidence was the much greater infection of corn by F. moniliforme in the high incidence areas (Marasas et al., 1981). Kriek et al (1981) showed that several isolates of F. moniliforme from high incidence areas were acutely toxic to ducklings, but did not produce other known toxins such as moniliformin. The discovery of the fumonisins should help in the elucidation of the role of moniliforme in human oesophageal cancer.
Because of the intense interest over the past two decades in the toxicity of F. moniliforme, which has recently culminated in the discovery of the fumonisins, other toxins produced by this species have been carefully studied. A few isolates of moniliforme produces moniliformin, a compound which is known to be toxic, but which lacks a known disease role. Other known compounds of greater or less toxicity include fusaric acid, fusarins and fusariocins (Marasas et al., 1984). The production of T-2 toxin, diacetoxyscirpenol and zearalenone by F. moniliforme have been reported, but are regarded as unlikely by Marasas et al. (1984).
The known toxicity of F. moniliforme to a wide variety of animals, and its probable role in human oesophageal cancer, may well result from the production of the newly discovered fumonisins. However, the diversity of the demonstrated toxicity of authentic isolates of F. moniliforme to a wide variety of animals (Marasas et al., 1984) is such that the possibility of other potent toxins cannot be ruled out.
Symptoms of F. moniliforme poisoning vary widely with animal type, dosage and toxigenic fungal isolate. The best-defined disease produced by F. moniliforme, LEM, is characterised by liquefactive necrotic lesions in the white matter of the cerebral hemispheres of horses and other equine species. Marked neurotoxicity is evident, with aimless walking and loss of muscle control followed by death, which usually occurs about 2 weeks after toxin ingestion. In baboons, F. moniliforme toxicity has been shown to lead to heart failure. Chickens and ducklings are sensitive to feed containing F. moniliforme, and there is some evidence that the toxin responsible is moniliformin (Cole et al., 1973).
The toxicity of one F. moniliforme isolate to rats was characterised by cirrhosis and hyperplasia in the liver, and thrombosis in the heart and other organs (Kriek et al., 1981). Of 20 other isolates, 15 showed mortalities and some symptoms, while 5 were non-toxic.
F. moniliforme may also be involved in abnormal bone development and diseases similar to rickets in chickens, sometimes with high mortalities.
The principal human disease with which F. moniliforme may be associated is oesophageal cancer, which has an abnormally high prevalence in the Transkei and in Henam Province, China. However, direct evidence that fumonisins or other known F. moniliforme toxins are causally related to this disease remains lacking.
Distribution in nature and foods
Like other Fusarium species, F. moniliforme is primarily a plant pathogen, causing both stalk and cob rot of corn, and diseases in rice, sorghum, sugar cane and other Gramineae. It is much more common in the tropics than temperate zones (Domsch et al., 1980; Pitt and Hocking, 1985a). By far its most common source in foods is corn, both under field and storage conditions, but it has also been isolated from nuts, yams and occasionally other commodities (Pitt and Hocking, 1985a).
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