Trichothecene Toxicosis in Animals

Trichothecene mycotoxins contain a large number of compounds classified as tetracyclic sesquiterpenoids with a 12,13-epoxytrichothec-9-ene core structure. The 12–13 epoxy ring structure is responsible for the toxicological action. Although numerous fungi can produce these mycotoxins, the most important are Fusarium trichothecenes. The trichothecenes are easily absorbed and rapidly affect proliferating tissues, causing inhibition of protein synthesis.

The main clinical signs of trichothecene toxicosis are feed refusal, immunological challenges, vomiting, skin dermatitis, and hemorrhage. Diagnosis of trichothecene toxicosis is based on typical clinical signs and analytical identification of the trichothecene at significant concentrations associated with causing adverse effects in that species. Deoxynivalenol (DON or vomitoxin) is probably the most common trichothecene detected in animal feeds. Replacement of the contaminated feed with clean feed or feed with lower concentrations of trichothecenes not associated with adverse effects in that animal species (age and production type) is important for control. The use of agents that bind trichothecene mycotoxins in animal feed have not been approved by the US FDA, and those agents are generally sold as free flow compounds. The efficacy of these agents can vary with the mycotoxin and animal species and should be evaluated as to the potential benefit and cost of product. Also, potential conflicts of interest should be considered between the agency testing the feed, advocate of the free flow compound in animal feed, and company manufacturing the free flow compound.

The trichothecene mycotoxins are a group of closely related secondary metabolic products of several families of imperfect or plant pathogenic fungi. Those of most importance in much of the world are produced species of Fusarium, but also from genera of Trichothecium, Myrothecium, Cephalosporium, Stachybotrys, Trichodesma, Cylindrocarpon, and Verticimonosporium. Trichothecenes are classified as nonmacrocyclic (eg, deoxynivalenol [DON] or vomitoxin and its acetylated derivatives, nivalenol, T-2 toxin, diacetoxyscirpenol [DAS], and others) or macrocyclic (eg, satratoxin, roridin, verrucarin). The trichothecenes are small molecules, known as tetracyclic sesquiterpenoids, with a common 12,13-epoxytrichothec-9-ene core structure. The 12-13 epoxy ring structure is critical for toxicity of the compound. For livestock, the most important trichothecene mycotoxin is DON, which is commonly a contaminant of corn, wheat, and other commodity grains. Lesser amounts of T-2 and HT-2 toxin are found sporadically in the same sources under generally wet and cool conditions.

The trichothecene mycotoxins are highly toxic at the subcellular, cellular, and organic system level. Trichothecenes inhibit protein synthesis by affecting ribosomes to interfere with protein synthesis and covalently bond to sulfhydryl groups.

Toxicity of T-2 toxin and DAS is based on direct cytotoxicity and is often referred to as a radiomimetic effect (eg, bone marrow hypoplasia, gastroenteritis, diarrhea, hemorrhages). Direct contact with skin and oral cavity causes irritation and ulceration. Stomatitis, hyperkeratosis with ulceration of the esophageal portion of the gastric mucosa, and necrosis of the GI tract have been noted after ingestion of trichothecenes. Systemic effects of T-2 and DAS are often self-limiting because of oral irritation and feed refusal, although, if the contaminated feed is the sole source of nutrition, animals will consume the feed. Poultry and cats are very sensitive to the adverse effects of T-2 toxin in feed, with poultry displaying beak lesions and often a dramatic reduction in laying.

Administered in sublethal toxic doses via any route, the trichothecenes are immunosuppressive in mammals; however, longterm feeding of high levels of T-2 toxin does not seem to activate latent viral or bacterial infections. The toxins may affect function of helper T cells, B cells, or macrophages, or the interaction among these cells.

Irritation of the skin and mucous membranes and gastroenteritis are another set of clinical signs typical of trichothecene toxicosis. Hemorrhagic diathesis can occur, and the radiomimetic injury (damage to dividing cells) is expressed as lymphopenia or pancytopenia. Eventually, hypotension may lead to death. Many of the severe effects described for experimental trichothecene toxicosis are due to dosing by gavage. From a practical perspective, high concentrations of trichothecenes often cause feed refusal and therefore are typically self-limiting as a toxic problem.

Because of the immunosuppressive action of trichothecenes, secondary bacterial, viral, or parasitic infections may mask the primary injury. The lymphatic organs are smaller than normal and may be difficult to find on postmortem examination.

Refusal to consume contaminated feedstuffs is the typical clinical sign, which limits development of other clinical signs. If no other food is offered, animals may eat reluctantly, but in some instances, excessive salivation and vomiting may occur. In the past, the ability to cause vomiting had been ascribed to DON only (hence the common name vomitoxin). However, other members of the trichothecene family also can induce vomiting.

In North America and many other parts of the world, DON is a substantial concern because of its common occurrence in feed grains and its well-known ability to cause feed refusal. Swine appear to be most sensitive to feed refusal, with greater tolerance by horses and dogs and even higher acceptance by ruminants, with a functional rumen critical for the metabolism of DON to less toxic metabolites. The pre-ruminal calf is susceptible to adverse effects of DON, and the young, immature animal or bird is susceptible to trichothecenes in the diet.

In swine, reduced feed intake may occur at dietary concentrations as low as 1 ppm, and refusal may be complete at 10 ppm. Ruminants generally will readily consume as much as 10 ppm dietary vomitoxin, and beef cattle have tolerated 12–20 ppm in some circumstances. Poultry may tolerate as much as 100 ppm. Horses may accept as much as 35–45 ppm dietary DON without feed refusal or adverse clinical effects. Dogs also will refuse foods containing DON, usually at concentrations >5 ppm. Related effects of weight loss, hypoproteinemia, and weakness may follow prolonged feed refusal. There is little evidence that DON causes reproductive dysfunction in domestic animals. Experimental studies suggest that DON may cause variable effects of immunosuppression or immunostimulation, but research is continuing to identify whether DON has a practical role in disease susceptibility in field conditions. Many counties have established regulatory guidelines for trichothecenes, particularly DON or deoxynivalenol, in animal feed and human food and the EU has for T-2 and HT-2 in feed.

Feed refusal caused by DON is a learned response known as taste aversion. The major effect of DON is feed refusal; it is rarely, if ever, a cause of the trichothecene effects described above. It appears related to brain neurochemical changes in serotonin, dopamine, and 5-hydroxyindoleacetic acid. Feed refusal response to DON varies widely among species. In swine, DON causes conditioned taste aversion, and swine appear to recognize new flavors (eg, flavoring agents) added to DON-containing feed and thus develop aversion to the new taste as well. Once uncontaminated feed is provided, animals usually resume eating within 1–2 days. A less well-known mycotoxin, fusaric acid, appears to interact with DON in the neurochemical response, leading to feed refusal.

Chemical identification of increased levels of DON by analysis in a ration is often used to confirm DON-related feed refusal or to judge the fitness of a feed ingredient. However, some mycotoxins may be modified or undetected by routine assay methods. These conjugated mycotoxins (thermally modified during processing or fungal, plant, or animal metabolites) may escape detection and not provide adequate warning of feed refusal levels. Use of binders for DON mycotoxin is currently an active area of research, but to date no mycotoxin binder agent has been approved by the US FDA. Currently, the aluminosilicates effective for aflatoxins appear not to be useful against DON. Glucomannan yeast-derived adsorbents may have potential to improve some aspects of DON feed refusal in swine, but work is ongoing to clarify use of this category of detoxicants. For barley, an abrasive pearling procedure removes two-thirds of DON with loss of only 15% of the grain mass. This and other forms of cleaning grain may prove useful to decrease DON when alternative grain is not available. In addition, grain may be diverted from swine to the more tolerant ruminants.

The best known macrocyclic trichothecene-related disease is stachybotryotoxicosis of horses, cattle, sheep, pigs, and poultry, first diagnosed in the former USSR but also occurring in Europe and South Africa. Cutaneous and mucocutaneous lesions, panleukopenia, nervous signs, and abortions have been noted. Death may occur in 2–12 days.

Myrotheciotoxicosis and dendrodochiotoxicosis have been reported from Russia and other post-Soviet states and New Zealand. The signs resemble those of stachybotryotoxicosis, but death may occur in 1–5 days.