Oh

0H\ CH3 OH

Deoxynivalenol

Zearalenone

O COOH

O OH OH

O COOH

O OH OH

il I

O COOH

il I

O COOH

Fumonisin Bi Figure 11. Representative Fusarium mycotoxins.

alterations at 8 month posttreatment; the majority of treated animals lacked corpus lutea and uterine glands and exhibited squamous metaplasia of the uterine luminal epithelium. Ovarectomized, ZEN-treated animals showed none of these ovary-dependent alterations.

The mechanism of the estrogenic effect of ZEN appears to be mediated via binding of ZEN or metabolite(s) to the cytoplasmic estrogen receptor. In rat uterine tissue, transand e/s-ZEN and two ZEN derivatives compete with 17/?-estradiol for binding with the cytosolic receptor, but with a lesser affinity that that of estradiol. Accordingly, ZEN appears to have a greater affinity for estrogen receptors from animals that are more susceptible to the estrogenic effects of the mycotoxin. The affinity of ZEN to uterine and oviduct estrogen receptors follows the pattern pig, rat, and then chicken.

Fumonisins

Fumonisins are a group of recently discovered mycotoxins that have been associated with toxicity and mortality in horses and pigs following ingestion of F«sarta-contami-nated corn-based feeds. Fumonisin Bj (FBj) is the most toxic representative of the fumonisins (Fig. 11). One such animal disease is the neurotoxic syndrome Equine Leu-koencephalomalacia (ELEM), which is characterized by facial paralysis, nervousness, lameness, ataxia, and an inability to eat or drink. The principal pathologic lesions include severe cerebral edema, focal malacia, and liquefaction of cerebral white matter. The onset of such severe symptoms can be as short as a few hours. ELEM syndrome often is epizootic and nearly always is associated with ingestion of moldy corn.

Several studies have positively linked fumonisins to ELEM. A majority of horses fed a corn-based feed contaminated with 37 to 122 ppm FBj developed fatal ELEM (30). Hepatic involvement is often coincident with central nervous involvement in horses and swine. Intravenous or dietary administration of FBj causes both pulmonary edema and hydrothorax in swine (31). In swine, lower doses of FBj result in a slowly progressive hepatic necrosis, whereas higher doses result in acute pulmonary edema coincident with hepatic toxicity. That fumonisins are potent inhibitors of sphingosine biosynthesis in cultured hepatocytes has been postulated to account for both the hepatotoxic and central nervous system effects of this toxin.

Besides the neurotoxic and hepatotoxic effects, FBi is a potent rodent carcinogen. Initial studies showed that a diet containing culture material inoculated within moniliforme was carcinogenic in rats. Dietary FB: not only initiates y-glutamyltranspeptidase-positive (y-GT +) hepatic foci, but also promotes those induced by compounds such as dieth-ylnitrosamine (32). Long-term dietary FBj (50 ppm) induces a high incidence (66%) of HCC along with metastases to the heart, lungs, or kidneys (33). Symptoms of hepatic involvement such as macronodular cirrhosis and cholangiofibrosis are also observed. Later studies have led to the conclusion that FBi is probably only a modest initiator of liver tumors, because y-GT+ foci and hepatocellular nodules were observed only after prolonged feeding of very high (0.1%) FBX in rats. It was postulated that the carcinogenic effect of FBX likely involves promotion and the selection of initiated hepatocytes, events that occur during the postinitiation phase of hepatocarcinogenesis. Additionally, FBj carcinogenicity does not appear to involve interaction with DNA. Neither FB2 nor FB2 elicits unscheduled DNA repair in primary rat hepatocyte cultures treated either in vitro or in vivo (34). It is therefore possible that the carcinogenic activity of fumonisins is mediated via epige-netic mechanisms, such as is the case of peroxisome pro-liferators.

Research on the health effects of fumonisins is relatively modest, and information on the mechanism of fu-monisin toxicity or on the mechanisms underlying species sensitivity is only beginning to be compiled. Obviously, more information is needed to provide a fuller understanding of the extent of the adverse effects of fumonisins on human and animal health. Because corn is a staple in many parts of the world, and because Fusarium contamination of corn is nearly universal, it is likely that fumonisins may be involved in human toxicoses and other health effects. .FMsanwm-contaminated corn has been epidemi-ologically associated with human esophageal cancer in some regions of South Africa.

Ergot Alkaloids

Documented since the Middle Ages, the fungus Claviceps purpurea has caused periodic outbreaks of mycotoxicoses in many parts of the world. This mold, which grows in grasses and cereal products, is especially prevalent in overwintered rye and wheat. Growth of the fungus takes the form of hard, black-purple sclerotia (or ergots) that germinate in the spring. Claviceps produces several ergot alkaloids, which are derivatives of lysergic acid (ergotamine; Fig. 12). The major effect of these compounds is vasoconstriction, resulting in a reduction of blood flow and subsequent gangrene in the feet, legs, and hands. Symptoms of ergot poisoning include a burning sensation in the arms and legs, gangrene, abortion, vomiting, diarrhea, weakness, and sometimes hallucinations.

Ochratoxins

Ochratoxins are produced by Aspergillus ochraceus and selected Penicillium species. Ochratoxin A (Fig. 12), which is the most toxicologically significant of the ochratoxins, is produced in a variety of cereal grains (wheat, barley, oats, corn), dry beans, peanuts, and cheese. Ochratoxin A is a potent nephrotoxin in nearly all animals studied and is a probable etiologic agent for Balkan endemic nephropathy (BEN), a fatal chronic renal disease. The syndrome, which is associated with nephritis and associated urinary tumors, is especially prevalent in Bulgaria, Romania, and Yugoslavia. Pigs exposed to ochratoxin A experimentally present a nephropathy strikingly similar to BEN.

Surveys have repeatedly shown that a significant percentage of food supplies from several Balkan countries are contaminated with ochratoxin. In addition to the aforementioned cereal and other products, ochratoxin is often found in animal products such as sausage, bacon, and ham.

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