The most commonly described mycotoxins associated with acute and chronic intoxication of animals are aflatoxins, ochratoxins, fumonisins, trichothecenes, zearalenone and the ergot alkaloids. The impact of the presence of mycotoxins in animals feeds has been reviewed by the European Food Safety Authority (EFSA), who summarized the available data on mycotoxin exposure and adverse effects in farm animals (EFSA, 2004a,b,c, 2005a,b,c).
Aflatoxins occur worldwide on peanuts, maize and numerous other important feed commodities (Scudamore et al, 1997; Galvano et al., 2001; Thirumala-Devi et al., 2002; van Egmond et al., 2007). As in laboratory animals and humans, aflatoxins affect liver function in all farm animal species. Following acute exposure, cellular necrosis of parenchymal cells in the liver, proliferation of the bile ducts and jaundice are the most prominent clinical signs of aflatoxicosis. The subsequent impairment of liver function results in loss of feed intake, reduced weight gain, and reduced productivity including reduced egg or milk pro duction. The liver lesions often can be diagnosed by visual inspection of the internal organs, as the liver is pale and enlarged and may show signs of neoplastic alterations. The animal species most sensitive to aflatoxins are poultry and fish. In poultry, the cooccurrence of cyclopiazonic acid, produced by the same fungal species, adds muscle weakness and signs of cardiotoxicity to the clinical presentations of exposed animals.
Aflatoxin exposure also results in effects on the immune system. Long-term exposure to low mycotoxin concentrations, which may produce no prominent signs of toxicity, can impair immune system functions. Subsequently, a lower immune response to vaccination programs and increased susceptibility to infectious diseases are noticed, as both, humoral and cellular immune responses are affected. Secondary effects include increased prevalence of Salmonella spp. and Campylobacter spp. infections in animals, unpredictable outbreaks of viral diseases and coccidiosis. Consequently, affected flocks require more medication, which in turn increases the risk for undesirable residues and the emergence of resistance to antimicrobials in poultry units and the products derived from the animals. The relationship between exposure to aflatoxins and the prevalence of hepatitis virus infections in human populations has been the subject of various epidemiological investigations, e.g., Groopman and Kensler (2005).
The primary target organ of aflatoxicosis is the liver, while ochratoxins, primarily ochratoxin A, which is produced by various Penicillium and Aspergillus spp. that occur on grains and cereals, usually affect kidney functions. The signs of ochratoxin intoxication often are mild, and the initial increase in water intake and excretion (polyuria - polydipsia syndrome), hypothermia and reduced weight gain is often not noted in large animals units. The most susceptible animal species are pigs, followed by poultry. In contrast to aflatoxins, mortality usually is low, but like aflatoxins, ochratoxins affect the immune system and reduce the health status of a herd.
Ochratoxin A has a short half-life in poultry, but a much longer half-life in pigs. Following exposure, ochratoxin A can be detected in pig blood serum where it is bound to proteins. The high serum protein binding is one of the explanations for the longer biological half-life. In addition to blood serum, high concentrations of ochratoxin A are found in the liver and the kidneys. The persistence of residues in these organs has resulted in many investigations of the contribution of residues in animal-derived tissues to overall human exposure to och-ratoxins. A recent overall exposure assessment of European consumers (EFSA, 2004a), however, concluded that the contribution from animal-derived products does not exceed 10%, as the major sources of human exposure are plant-derived products, including cereals, nuts, wines, grape juice, dried fruits and coffee.
In humans, ochratoxin A is excreted with mother's milk, resulting in exposure of the newborn. The same route of excretion also is expected in pigs. Various clinical case reports, describe general weakness, splay-leg and gangrene-like alterations in peripheral tissues, e.g., ears and tails, as associated with the presence of ochratoxin A in feeds, but experimental data confirming a causal relationship are lacking. Exposure of newborn piglets to ochratoxin A also is expected to affect the immune system and to result in increased susceptibility to infectious diseases (Stoev et al., 2000).
Fumonisin Bi was first described as the causal agent of equine leukoencephalomalacia, a fatal disease in horses (Kellerman et al., 1990). In pigs, the clinical signs of fumonisin intoxication are entirely different, and comprise pulmonary hypertension and severe pulmonary edema that may result in acute mortality (Harrison et al., 1990). In poultry, exposure to fumonisins has been described to cause a toxic feed syndrome (spiking mortality) characterized by poor performance, multifocal hepatic necrosis and paralysis. In ruminants, as well as in laboratory animal species, the earliest signs of fumonisin exposure are renal lesions. The diversity of target organs of toxicity is incompletely understood, although inhibition of the enzyme ceramide synthetase (a N-acetyl transferase) is commonly assumed to underlie the diverse adverse effects of fumonisin (Merrill et al., 2001). The rate of absorption of fumonisin B1, following ingestion with feed, is very limited. The concentrations in feed materials, particularly in maize and products thereof, however, are much higher than that of other toxins, and a commonly accepted tolerable threshold level is 1000 ng/g in products for human consumption. Fumonisins also are known as immunomodulating agents that can decrease the vaccinal antibody titers in pigs (Taranu et al., 2005).
Fumonisins are produced primarily by Fusarium verticillioides [formerly termed Fusa-rium moniliforme (Seifert et al., 2003)] and Fusarium proliferatum. These Fusarium species are common in tropical and subtropical areas and temperate regions with warm growing seasons. In temperate climatic zones with cooler growing seasons, however, other Fusarium species such as Fusarium graminearum, Fusarium culmorum, F. proliferatum and Fusarium subglutinans are more prevalent. In these cooler regions, fumonisin B1 contamination is reduced and toxins produced by other Fusarium spp. become more important and more prominent. For example, F. graminearum is an important pathogen of maize, wheat, barley and oats, and is responsible for the production of both deoxynivalenol and zearale-none in these grains (D'Mello and Macdonald, 1997).
Deoxynivalenol is the most prominent toxin of a large group of epoxy-trichothecenes that share an epoxide group at position C12-C13. More than 180 trichothecenes have been described (Desjardins, 2006), and are produced not only by Fusarium species, but also by members of other fungal genera such as Trichoderma, Stachybotrys, Verticimonosporium and Myrothecium. Trichothecenes are divided into three broad classes based on their chemical characteristics. Group A trichothecenes include T-2 toxin, HT-2 toxin, neosolaniol, monoacetoxy scirpenol and diacetoxyscirpenol, whereas type B trichothecenes include deoxynivalenol, nivalenol, 3- and 15-acetyl-deoxynivalenol and fusarenon X. A third group, the macrocyclic trichothecenes, contains toxins such as satratoxins, verrucarins and roridins, which usually are produced by Stachybotrys species.
Type A trichothecenes, e.g., T-2 toxin, were first detected as dermatotoxins that cause mucosal and skin lesions due to the reactivity of their epoxide moiety. They also inhibit protein and DNA synthesis and hence are associated with reduced cell proliferation in the bone marrow (resulting in pancytopenia), the lymphatic system (resulting in reduced immune competence through inhibition of the cellular and humoral immune response), as well as in the gastrointes tinal tract, where primary necrosis and reduced cell proliferation result in hemorrhages and a non-specific inflammatory response that affect nutrient transport and utilization (Glenn, 2007).
These effects are exerted to a varying degree by all trichothecenes. A specific effect of deoxynivalenol is its obvious interaction with the dopaminergic system of the central nervous system, which can induce nausea and vomiting. This interaction resulted in the now rarely used term vomitoxin being given to deoxynivalenol to describe this clinically prominent effect. Deoxynivalenol is one of the most frequently occurring mycotoxins in cereal grains in Northern Europe, and appears to occur most frequently in common wild grasses, and products thereof, e.g., hay and silage. Thus, next to pigs, which are the most sensitive animal species, cattle and wild ruminants, e.g., red deer, are exposed to large quantities of this mycotoxin, due to their high consumption of grass. Under these circumstances, the ability of the rumen to degrade deoxynivalenol into less toxic metabolites is exhausted, and intact deoxynivalenol reaches the small intestines, where it is rapidly absorbed. Following absorption, deoxynivalenol has biphasic effects on the immune system, where it acts as an immune stimulant and pro-inflammatory agent at low concentrations, and as an immuno-suppressant at higher levels. The balance between activation and suppression of the immune system depends on the health status of the animal. Thus, various reports have focused on the interaction between pathogens or products therefrom, e.g., the bacterial lipopolysac-charide (LPS), with deoxynivalenol (Pestka et al., 2004).
Recent evidence (Miller, 2002; Promputtha et al, 2007) suggests an interaction between Fusarium species, and the presence of endophytes in grasses. This interaction might explain the increasing frequency of deoxynivalenol-contaminated small grains and seeds, and also provide a target for intervention strategies aimed at reducing the incidence of deox-ynivalenol in foods and feed materials.
Zearalenone, which also is produced by F. graminearum and related species, differs entirely in its chemical structure from the trichothecenes. The open lactone ring has many structural characteristics of the natural steroid estradiol. Zearalenone also is recognized by mammalian estrogen receptors. By acting as a mixed agonist/antagonist on these receptors, zearalenone induces a hyperestrogenic syndrome, with vulvovaginitis, enlarged uteri, enlarged nipples, and ovarian cysts. Young pigs are particularly sensitive and may be born with vulvovaginitis following intra-uterine exposure, and develop reproductive disorders at puberty. Co-exposure of animals to both zearalenone and deoxynivalenol seems to accelerate reproductive failure.
Zearalenone also interacts with the enzymes that are involved in steroid synthesis, e.g., hydroxysteroid dehydrogenases. The dual mode of action, receptor binding and interaction with the synthesis of steroids, qualifies zearalenone as an endocrine disruptor. More research is needed to understand the long-term and transgenerational effects of this toxin in animals and probably humans (Fink-Gremmels, 2007).
Ergot alkaloids were amongst the first mycotoxins associated with a human mycotoxicosis, cf., medieval reports of the Holy Fire or St. Anthony's Fire, a gangrenous disease in humans. Ergot alkaloids cause vasoconstriction, which reduces blood flow and oxygen trans port in the terminal circulation of legs, tail and ears, resulting in necrosis. These compounds also cause abortions by reducing the blood supply to a gravid uterus. Ergot alkaloids are produced by Claviceps spp. that transform developing kernels of cereal grains (and grasses) into enlarged dark sclerotia. Ergot alkaloids also are produced as secondary metabolites by many species of the genera Epichloe and Neotyphodium. These endophytes often invade cold season grasses, which they colonize symbiotically. These fungi provide the plant with peramines, a class of compounds that protects the seeds and the living plant from insect damage while increasing heat tolerance (Faeth et al, 2006). The most prominent animal diseases associated with endophytes are tall fescue toxicoses, which are associated with exposure to ergovaline and other alkaloids produced by Neotyphodium coenophialum in tall fescue (Festuca arundinacea), a grass species that covers millions of acres of farm land. In a similar way, the production of lolitrem B by Neotyphodium lolii, which colonizes rye grass (Lolium perenne) is responsible for a common neurotoxic syndrome in sheep, cattle and horses, generally referred to as rye grass staggers disease (Tor-Agbidye et al., 2001; Fink-Gremmels, 2005).
The aim of this very brief summary was to provide an indication of the type of mycotox-icoses that occur in farm animals, with special reference to Europe. However, even more important than these acute intoxications, which occur only incidentally and affect only a small percentage of the animal population, are chronic mycotoxicoses. In the absence of obvious clinical symptoms of intoxication, chronic exposure to mycotoxins via contaminated feed materials often goes undiagnosed, as the entire herd is affected with some degree of decreased performance and reproductive capacity. Exposure to these lower levels originates in many cases from on-farm products as well as from mixed feeds. Critical products are maize and maize products, e.g., maize-cob mix and silage, cereal grains, gluten, legumes, sorghum, peanuts, soybean products, cotton and sunflower seeds, straw, grass, hay and other forages that are given to animals in large quantities, very often without any control for the presence of mycotoxins. Chronic exposure is associated with two major effects: economic losses due to reduced performance and fertility, and increased risk to public health, due to higher disease prevalence in affected herds.
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