Selected Trichothecenes TCTCs

3.4.1 General Considerations

Several species of Fusaria infect corn, wheat, barley, and rice. Under favorable conditions, they elaborate a number of different types of tetracyclic sesquiterpenoid mycotoxins that are composed of the epoxytrichothecene skeleton and an olefinic bond with different side chain substitutions (Figure 4). Based on the presence of a macrocyclic ester or ester-ether bridge between C-4 and C-15, trichothecenes (TCTCs) are generally classified as macrocyclic (Type C) or nonmacro-cyclic (Types A and B) (Figure 4). Although more than 100 TCTCs have been identified, only a few frequently found in foods and feeds are potentially hazardous to human and animal health. Other fungal genera are Myrothecium, Trichoderma, Trichothecium, Cephalosporium, Verticimono-sporium, and Stachybotrys. In addition to fungi, extracts from a Brazilian shrub, Baccharis megapotamica, also contain macrocyclic TCTCs. The term TCTCs is derived from trichothecin, the first compound isolated in this group (Chu 1997; Jarvis et al. 1995; Miller and Trenholm 1994; Vesonder and Golinski 1989).

Similar to other sesquiterpenes, TCTCs are biosynthesized via the mevalonate pathway: the TCTC skeleton is formed by cyclization of farnesyl pyrophosphate via the intermediate trichodiene by an enzyme trichodiene synthase. The isovaleroxy side chain in T-2 toxin is derived from leucine. Several key enzymes in the TCTC biosynthetic pathway have been identified. At least six genes (Tril to Tri6) involved in the biosynthesis of these mycotoxins have been cloned, and these genes are clustered together on a chromosome. Genes Tri3, Tri4, and Tri5, which encode a transacetylase (15-O-acetyltransferase), a cytochrome P-450 monooxy-genase, and trichodiene synthase, respectively, are contained within a 9-kb region, while Tri5 and Tri6 (a regulatory gene) are in a 5.7kb region (Proctor 2000).

The structural diversity of TCTCs results in a variety of toxic effects in animals and humans [reviewed in Bhatnagar et al. (2002)]. The TCTC mycotoxicoses affect many organs, including the gastrointestinal tract, hemato-poietic, nervous, immune, hepatobiliary, and cardiovascular systems. Outbreaks of several types of mycotoxicoses in humans and animals, including moldy corn toxicosis, scabby wheat toxicosis (or red-mold, or akakbi-byo disease, or scabby barley poisoning), feed refusal and emetic syndrome (swine), fusaritoxicoses, hemorrhagic syndrome, and alimentary toxic aleukia (ATA) have been reported. Mechanistically, inhibition of protein synthesis is one of the earlier events in manifestation of TCTC toxic effects and they act at different steps in the translation process. Inhibitory effects of these mycotoxins vary considerably with the chemical structure of the side chain [see review in Chu (2002)].

3.4.2 T-2 Toxin and Related Type A TCTCs

T-2 toxin, a highly toxic type A TCTC, is produced by F. tricinctum, F. sporotrichioides (major), F. poae, F. sulphureum, F. acuminatum, and F. sambucinum. Unlike most mycotoxins, which are usually synthesized near 25°C, the optimal temperature for T-2 toxin production is around 15°C. Higher temperatures (20-25°C) are needed for the production of related metabolites, such as H-T2 toxin. Although T-2 toxin occurs naturally in cereal grains, including barley, corn, corn stalk, oats, wheat, and mixed feeds, contamination with T-2 toxin is less frequent than with deoxynivalenol (DON). However, T-2 toxin (LD50 in mice: 2-4 mg/kg mice) is much more toxic to animals, perhaps also to humans, than DON (LD50 in mice: 50-70 mg/kg).

Almost all the major TCTCs, including T-2 toxin, are cytotoxic and cause hemorrhage, edema, and necrosis of skin tissues. Inflammatory reactions near the nose and mouth of animals are similar to some lesions found in humans suffering from ATA disease. The severity of lesions is also related to chemical structure. Compared with other types of TCTCs, group A toxins (T-2 toxin) are less toxic than macrocyclic toxins but more toxic than type B toxins. Neurologic dysfunctions, including emesis, tachycardia, diarrhea, refusal of feed/anorexia, and depression have also been observed. T-2 toxin and some TCTCs also induce pathological lesions in the gastrointestinal system. However, the major lesion of T-2 toxin is its devastating effect on the hematopoietic system in many mammals, including humans. T-2 toxin and related TCTCs are the most potent immunosuppressants of the known mycotoxins and cause significant lesions in lymph nodes, spleens, thymus, and the bursa of Fabricius (Bondy and Pestka 2000). The heart and pancreas are other target organs for T-2 toxin intoxication. Urinary and hepatobiliary lesions induced by T-2 toxin and DAS are secondary.

3.4.3 Deoxynivalenol (DON)

The DON is a major type B TCTC mycotoxin produced by F. graminearum (major) and other related fungi such as F. culmorum and F. crookwellense. Because DON causes feed refusal and emesis in swine, the name "vomitoxin" is also used for this mycotoxin. Although DON is considerably less toxic than most other TCTC mycotoxins, the level of contamination of this toxin in corn and wheat is generally high, usually above 1 ppm, sometimes greater than 20 ppm. Contamination of DON in other commodities, including barley, oats, sorghum, rye, safflower seeds, and mixed feeds has also been reported. Worldwide frequent natural occurrence of DON in cereal grains has been reported (Miller and Trenholm 1994). Although inadequate storage may lead to the production of some TCTC mycotoxins, infestation of fusaria in wheat and corn in the field is of most concern for the DON problem. With wet and cold weather during maturation, grains are especially susceptible to F. graminearum infection, which causes so-called "scabby wheat" and simultaneously produces the toxin. The optimal temperature for DON production is about 24°C. Outbreaks of DON in winter wheat in the United States, Finland, and Canada usually occur when continental chilly and humid weather favoring the fungal infection is followed by a humid summer favorable for toxin production.

Toxicologically, DON induces anorexia and emesis both in humans and animals [reviewed in Bhatnagar et al. (2002); Chu (2002)]. Swine are most sensitive to feed contaminated with DON. Whereas most TCTCs are immunosuppressors, DON is a hyperinducer of cytokines and IgA. Induction of expression of mRNA of Ils-2, 4, 5, 6 in a T-cell model EL4.IL-2 by DON was found at levels required for partial or maximal protein synthesis inhibition. A single oral gavage with DON was sufficient to induce these mRNA levels in Peyer's patches and spleen (Bondy and Pestka 2000).

3.4.4 The Impact of TCTC on Human and Animal Health

Because of their toxicity and their frequent presence in foods and feeds, TCTCs are potentially hazardous to human and animal health. Among the many types of TCTC myco-toxicoses, only ATA and scabby wheat toxicosis have been demonstrated in human populations. ATA, which has symptoms including skin inflammation, vomiting, damage to hematopoietic tissues, leukocytosis, and leukopenia, was attributed to the consumption of overwintered cereal grains colonized by F. sporotrichioides and F. poae; it caused the deaths of hundreds of people in the USSR between 1942 and 1947 (Ueno 1986). TCTCs may also be involved in the so-called "sick building syndrome (SBS)" in humans (Mahmoudi and Gershwin 2000; Vesper et al. 2000). S. atra and S. chartarum were isolated from a badly water-damaged home or building where the occupants complained about headaches, sore throats, hair loss, flu symptoms, diarrhea, fatigue, dermatitis, and general malaise as well as pulmonary hemorrhage cases. Several TCTCs were found in these cases, but other molds and mycotoxins were also found in the mold damaged buildings (Toumi et al. 1993).

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