Chronic,including teratogenic and carcinogenic effects of trichothecenes: A short review

Trichothecenes are toxic sesquiterpenes, produced as secondary metabolites by certain soil microfungi in agricultural products harvested during wet and cold weather, and/or stored inappropriately. When present in the ingested food they can cause haemorrhagic diathesis, acute and chronic disorders in many animal species, including man. Animals experimentally treated with T-2 toxin, one of the common, very toxic and immunosuppressive trichothecenes, develop gastrointestinal, skin, and neurological disorders. T-2 toxin given to pregnant animals can lead to abortion and fetal abnormalities. Rats surviving many months after several sublethal doses of T-2 toxin can develop cardiovascular lesions, high blood pressure and tumours, benign and malignant, of the brain, the pancreas, stomach, and certain other organs. The possibility has to be considered that trichothecenes may be involved in some similar idiopathic disorders and tumours in livestock and in man.     

Mycotoxins and mycoflora in animal feedstuffs in western Canada.

Feed samples associated with 51 cases of suspected or potential mycotoxicoses of farm animals in western Canada were examined during a three year study. Ochratoxin A was detected in four cases, T-2 toxin and diacetoxyscirpenol in one, and sterigmatocystin in one. Samples examined for microflora associated with production of these mycotoxins contained Penicillium spp., Aspergillus ochraceus, Fusarium spp. and fungi of the Aspergillus glaucus group. Samples were analyzed for T-2 toxin and diacetoxyscirpenol only if Fusarium spp. were present. The first known incidence of suspected sterigmatocystin poisoning of poultry through feed ingestion has been encountered.     

Comparison of the effect of T-2 toxin with that of dexamethasone or cyclophosphamide on resistance to Babesia microti infection in mice

The effect of T-2 toxin on host resistance to acute and latent Babesia microti infections was evaluated in mice and was compared with the effects of the immunosuppressive drugs dexamethasone and cyclophosphamide. Mice with acute or latent B microti infection were treated with 2 mg of T-2 toxin/kg of body weight, 0.2 mg of dexamethasone/kg, or 30 mg of cyclophosphamide/kg daily for 5 days. Treatment with dexamethasone or cyclophosphamide caused significant (P less than 0.05) increases in Babesia parasitemia during acute infection and significantly (P less than 0.05) prolonged the duration of parasitemia during acute babesiosis. Treatment with T-2 toxin caused a transient significant (P less than 0.05) increase in Babesia parasitemia on day 10 after acute infection and numerical, though statistically nonsignificant, increases in the maximal level and duration of parasitemia during acute babesiosis. Significant (P less than 0.005) recrudescence of parasitemia was observed in the dexamethasone- and cyclophosphamide-treated mice with latent Babesia infection. Treatment with T-2 toxin did not cause recrudescence of parasitemia in mice with latent Babesia infection.     

T-2毒素和HT-2毒素检测方法的研究进展

T-2毒素和HT-2毒素属于单端孢霉烯族毒素。T-2毒素是A类单端孢霉烯族毒素中毒性最强的一种真菌毒素,HT-2毒素为T-2毒素在体内与体外最为主要的代谢产物,二者在自然界中分布广泛。对T-2毒素和HT-2毒素检测方法的研究进展进行综述,对二者常见检测方法的优点和缺点进行分析,以期为T-2毒素和HT-2毒素检测方法的科学选择提供参考。     

The fungal T-2 toxin alters the activation of primary macrophages induced by TLR-agonists resulting in a decrease of the inflammatory response in the pig

T-2 toxin is known to be one of the most toxic trichothecene mycotoxins. Exposure to T-2 toxin induces many hematologic and immunotoxic disorders and is involved in immuno-modulation of the innate immune response. The objective of this work was to evaluate the effects of T-2 toxin on the activation of macrophages by different agonists of Toll-like receptors (TLR) using an in vitro model of primary porcine alveolar macrophages (PAM). Cytotoxic effects of T-2 toxin on PAM were first evaluated. An IC₅₀ of 19.47 ± 0.9753 nM was determined for the cytotoxicity of T-2 toxin. A working concentration of 3 nM of T-2 toxin was chosen to test the effect of T-2 toxin on TLR activation; this dose was not cytotoxic and did not induce apoptosis as demonstrated by Annexin/PI staining. A pre-exposure of macrophages to 3 nM of T-2 toxin decreased the production of inflammatory mediators (IL-1 beta, TNF-alpha, nitric oxide) in response to LPS and FSL1, TLR4 and TLR2/6 agonists respectively. The decrease of the pro-inflammatory response is associated with a decrease of TLR mRNA expression. By contrast, the activation of TLR7 by ssRNA was not modulated by T-2 toxin pre-treatment. In conclusion, our results suggest that ingestion of low concentrations of T-2 toxin affects the TLR activation by decreasing pattern recognition of pathogens and thus interferes with initiation of inflammatory immune response against bacteria and viruses. Consequently, mycotoxins could increase the susceptibility of humans and animals to infectious diseases.     

Effect of acute oral doses of T-2 toxin on tissue concentrations of biogenic amines in the rat

T-2 toxin [3 alpha-hydroxy-4 beta, 15-diacetoxy-8 alpha-(3-methylbutyryloxy)-12,13-epoxytrichotec-9-ene] is an emetic Fusarium trichothecene mycotoxin known to cause lethargy, ataxia and feed refusal in economically important animals. Experiments were conducted to determine the effect of acute oral doses of T-2 toxin on tissue concentrations of neurotransmitters thought to play some role in regulation of feed consumption. Sixty-seven male weanling rats were intubated with a few grams of diet in a liquid slurry with or without 2.0 mg T-2 toxin per kilogram of body weight. At 1, 2, 4, 6, 8, 12, 24 and 48 h following dosing, rats were killed, and brains, spleens, hearts and adrenal glands were excised and analyzed for concentrations of neurotransmitters and metabolites using high-performance liquid chromatography with electrochemical detection. Administration of T-2 toxin caused increases in brain concentrations of tryptophan and serotonin at the early time intervals after dosing. Brain concentrations of dopamine increased, whereas concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) decreased at the later time interals following dosing. Concentrations of dopamine were increased in adrenal glands, whereas epinephrine concentrations decreased. Epinephrine was detected in spleen and heart after administration of T-2 toxin. It was concluded that the increase in brain indoleamines induced by T-2 toxin could contribute to feed refusal in animals suffering from T-2 toxicosis.     

The effect of T-2 toxin on the bovine immune system: Cellular factors

The effect of T-2 toxin, a Fusarium metabolite, on the bovine cellular defense (immune) system was evaluated during high level, chronic administration. The administration of T-2 toxin to calves at the rate of 0.6 mg/kg/day was associated with significant depression of lymphocyte responses to mitogens and significant decreases in chemotaxic migration of neutrophils.     

Determination of the acute 50% lethal dose T-2 toxin in adult bobwhite quail: additional studies on the effect of T-2 mycotoxin on blood chemistry and the morphology of internal organs

Three experiments were conducted to assess mortality rate, blood chemistry, and histologic changes associated with acute exposure to T-2 mycotoxin in adult bobwhite quail. In Experiment 1, adult quail were orally dosed with T-2 toxin to determine the lethal dose that resulted in 50% mortality of the affected population (LD50), and that dose was determined to be 14.7 mg of T-2 toxin per kilogram of body weight (BW). A second experiment was performed to study the effects of 12-18 mg/kg BW T-2 toxin on blood chemistry and liver enzyme profiles. Posttreatment uric acid, aspartate aminotransferase, lactic dehydrogenase, and gamma glutamyltransferase increased as compared with pretreatment values. In contrast, posttreatment plasma total protein, cholesterol, and triglyceride levels numerically decreased as compared with pretreatment values. Changes in blood chemistry values were consistent with liver and kidney damage after T-2 toxin exposure. In Experiment 3, histologic analyses of bone marrow, spleen, liver, small intestine, kidney, and heart were conducted on birds dosed in Experiment 2. Marked lymphocyte necrosis and depletion throughout the spleen, thymus, bursa, and gut-associated lymphoid tissue in the small intestine were observed in birds dosed with 15 and 18 mg/kg BW T-2 toxin. Necrosis of liver and lipid accumulation as a result of malfunctioning hepatocytes were also observed. Little or no morphologic change was observed in bone marrow and heart tissue. The LD50 for adult bobwhite quail as found in this study is two to three times higher than that reported for other species of commercial poultry. Results from these data confirm previous reports of immunosuppressive and/or cytotoxic effects of T-2 toxin in other mammalian and avian species. T-2 toxin may have a negative impact on the viability of wild quail populations.     

Mycotoxins.

Horses consume feed grains and forages that can produce a range of mycotoxins resulting from mold invasion. Toxicosis of horses often occurs from fumonisins or aflatoxin in grains, from the tremorgenic mycotoxins in dallis grass, or from slaframine in red clover. Fumonisin toxicosis often is severe and fatal, and aflatoxin can be acute or chronic and debilitating. Other mycotoxins reported in horses may cause moderate to mild signs that regress when the contaminated feedstuff is removed. Overall, horses appear to have a relatively low prevalence of reported mycotoxicoses among domestic animals, but they are extremely sensitive to the fumonisins. Since there are no good therapies for mycotoxin poisoning, attention to providing high quality grains and forages to prevent mycotoxicoses is the most effective means for reducing the risk of mycotoxins in horses.     

Inhibitory effect of trichothecene mycotoxins on bovine platelets stimulated by platelet activating factor.

Several species of fungi, which infect cereals and grains, can produce a class of compounds, known as trichothecene mycotoxins, which is characterized by a substituted epoxy-trichothecene ring structure. Cattle are susceptible to intoxication from feeds contaminated with T-2 toxin, one of the more potent trichothecene mycotoxins, while swine refuse to ingest feed contaminated with T-2 toxin. The bovine platelet has been used as a model cell system to evaluate the effects of T-2 toxin and its natural metabolites, HT-2 toxin and T-2 tetraol, on cell function in vitro. Due to the lipophilic nature of these mycotoxins, a biologically active phospholipid was used to stimulate the platelets in the presence and absence of the toxins. The mycotoxin T-2 toxin and its major metabolite HT-2 toxin inhibited platelet activating factor-stimulated bovine platelets, suspended in homologous plasma, in a concentration but not time dependent manner. Significant inhibition of platelet function (p less than 0.01) occurred with 135 ng T-2 toxin per 10(6) platelets and with 77 ng HT-2 toxin per 10(6) platelets. These mycotoxins exerted an additive inhibitory effect on the platelet aggregation response. In contrast, the minor metabolite T-2 tetraol had no inhibitory effect on platelet function and had no influence on the responses of T-2 toxin or HT-2 toxin when the mycotoxins were present together in the platelet suspensions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Embryotoxic effects of prenatal T-2 toxin exposure in mice.

Pregnant CD-1 mice were administered T-2 toxin by gastric intubation on day 11 of gestation at dosages of 0, 0.75 and 1.5 mg/kg. The T-lymphocyte dependent antibody response against sheep red blood cells which was evaluated in the offspring at six weeks of age was not affected by T-2 toxin exposure. Individual birth and weaning weights were not influenced by T-2 toxin, but the litter size was reduced in the high dose group, without affecting the number of implantation sites per dam. The number of female offspring produced by dams exposed to 1.5 mg/kg T-2 toxin was less compared to other treatment groups, suggesting that the female fetus was more susceptible to embryolethal effects of prenatal T-2 toxin exposure. These results suggest that prenatal T-2 toxin exposure is unlikely to be a significant health problem with respect to primary humoral immunity. At the dosages given, T-2 toxin produced substantial embryotoxicity without alteration in antibody production. The embryolethal effects are a primary limiting factor which may preclude the expression of any immunoteratological manifestations associated with humoral immunity under natural field conditions.     

Mycotoxins: Their implications for human and animal health

Abstract

Mycotoxins contaminate various feed and food commodities, due to the global occurrence of toxinogenic molds. They exert adverse health effects in human and animals. The nature of these toxic effects varies depending on the chemical structure of the toxin. The degree of these adverse effects is not only determined by the toxin concentration present in foods and feeds, but also by the time of exposure. Whilst in animals, next to acute intoxication, losses in productivity, reduced weight gain and immunosuppression are considered as most important feature of mycotoxicoses, genotoxic effects and the involvement of certain mycotoxins such as aflatoxin, ochratoxins and fumonisins in the etiology of human cancers have obtained particular attention. This implies that recent research activities concentrate on mechanistic aspects of mycotoxin‐ induced pathologies, rather than compiling analytical measures of mycotoxin concentrations in food and feeds.     

Mycotoxins: their implications for human and animal health

Mycotoxins contaminate various feed and food commodities, due to the global occurrence of toxinogenic molds. They exert adverse health effects in human and animals. The nature of these toxic effects varies depending on the chemical structure of the toxin. The degree of these adverse effects is not only determined by the toxin concentration present in foods and feeds, but also by the time of exposure. Whilst in animals, next to acute intoxication, losses in productivity, reduced weight gain and immunosuppression are considered as most important feature of mycotoxicoses, genotoxic effects and the involvement of certain mycotoxins such as aflatoxin, ochratoxins and fumonisins in the etiology of human cancers have obtained particular attention. This implies that recent research activities concentrate on mechanistic aspects of mycotoxin-induced pathologies, rather than compiling analytical measures of mycotoxin concentrations in food and feeds.     

Effect of T-2 toxin on resistance to systemic Salmonella typhimurium infection of newly hatched chickens

Newly hatched chickens were treated with the trichothecene mycotoxin, T-2 toxin, during the first day of life. Control chickens were treated with other agents known to cause immunosuppression--cyclosporine, cyclophosphamide, and aflatoxin. Chickens were infected on day 6 (5 days after treatment with T-2 toxin) by intraperitoneal inoculation with Salmonella typhimurium. Blood samples were collected from treated chickens (noninfected) and used to assess the responsiveness of blood lymphocytes to T-cell or B-cell mitogens, phytohemagglutinin, or lipopolysaccharide, respectively. The T-2 toxin had a profound negative effect on the ability of the chickens to resist salmonellosis, as measured by survival. However, the toxin effect in reducing phytohemagglutinin- and lipopolysaccharide-stimulated mitogenesis, though significant (P greater than 0.05), was not severe. Our data indicate a direct effect of T-2 toxin on native resistance to systemic salmonellosis, which was not accompanied by marked alteration in T- or B-cell responses to mitogenic stimulation.     

T-2毒素的毒性作用及其诱导细胞凋亡机制概述

T-2毒素是一种毒性作用很强的霉菌毒素,是以镰刀菌属为主要产毒菌株所产生的一种A类单端孢霉烯族毒素,在多种谷物中的污染水平较高,通过食物摄入后在人类和动物机体内产生一系列毒性作用,严重威胁人类和动物的健康。论文从T-2毒素的理化性质、产毒菌株、毒性作用及对细胞凋亡的作用机制进行了简述,重点介绍了T-2毒素在免疫系统、消化系统和肝脏毒性、神经和皮肤毒性、血液毒性、生殖毒性方面的研究进展,以及T-2毒素通过线粒体信号通路介导细胞凋亡机制的研究进展,为T-2毒素的深入研究提供参考。     

Interaction of T-2 fusariotoxin and monensin in broiler chickens infected with Coccidia

Field observations suggest that coccidiosis is a common cause of death in broiler chicken flocks fed diets containing sufficient amounts of ionophore antibiotics (monensin, narasin, etc.) and contaminated with mycotoxins, particularly with T-2 fusariotoxin. To study this phenomenon, broiler chickens fed diets containing different amounts of T-2 toxin and free from monensin, or containing a preventive dose (100 mg/kg of feed) of monensin, were infected experimentally with coccidian oocysts. In all groups fed a diet containing monensin plus T-2 toxin severe clinical symptoms of coccidiosis (blood-stained faeces etc). occurred. Deaths and retarded growth depended on the toxin dose and were considerable. The body mass gain of chicks fed a diet containing monensin and T-2 toxin but not infected with coccidia was inferior to that of groups fed diets which contained either monensin or T-2 toxin (experiment 2). On the basis of these findings a negative interaction of the two compounds is assumed. This seems to be supported by the results of experiment 3, i. e. the finding that the lethal dose of narasin, a compound closely related to monensin both in chemical structure and mechanism of action, proved to be much lower (LD50 = 102 mg/kg body mass) for chickens fed a diet supplemented with T-2 toxin than for the control chickens (LD50 = 176 mg/kg body mass). The present results suggest that the feeding of diets severely contaminated with T-2 toxin may alter the anticoccidial efficacy of monensin.     

Subacute toxicity of Dietary T-2 toxin in mice: influence of protein nutrition.

The subacute toxic effects of dietary T-2 toxin (20 ppm) incorporated in semipurified diets of 8%, 12% or 16% protein, were examined in young Swiss mice after one, two, three and four weeks. Dietary T-2 toxin caused substantial reductions in growth and food consumptaion, the degrees of which were greatest in mice fed the diets of reduced protein content. T-2 toxin consistently caused similar degrees of nonregenerative anemia, lymphopenia, thymic atrophy and gastric hyperkeratosis irrespective of the dietary protein level. However, erythroid hypoplasia was temporary in mice fed T-2 toxin in the 16%-protein diet such that erythroid precursors regenerated in splenic and bone marrow and were hyperplastic after four weeks. Liver to body weight ratios of mice fed T-2 toxin in the 16%-and 12%-protein diets increased during the four week trial in comparison to control mice fed at a similar rate. These observations indicated that suppression of erythropoiesis in mice by dietary T-2 toxin was temporarty and that the interval before regeneration was prolonged by diets of reduced protein content.     

The Failure of Purified T-2 Mycotoxin to Produce Hemorrhaging in Dairy Cattle

A Holstein cow was intubated with 182 mg of 97% pure T-2 toxin (0.44 mg/kg of body weight) for 15 days. A dairy ration containing 50 mg/kg (50 ppm) of T-2 toxin was refused. A calf, born four days after onset of maternal treatment, was intubated with 26.2 mg of purified T-2 toxin (0.6 mg/kg of body weight) for seven consecutive days and then on alternate days for a total of 16 days. The calf was severely affected clinically by the T-2 toxin. The T-2 toxin failed to cause bovine hemorrhagic syndrome in either animal. Unspecific gastrointestinal lesions were noted in the cow but none were detected in the calf. In the calf, severe depression, hindquarter ataxia, knuckling of the rear feet, listlessness and anorexia were caused by the T-2 toxin.     

电化学生物传感器在真菌毒素检测中的研究进展

真菌毒素是真菌在食品或饲料中生长所产生的代谢产物,这些低分子质量化合物既是天然存在的,同时也是无法避免的。真菌通过两种途径进入食物链,一方面可以直接从受真菌毒素污染的植物性食品成分进入食物链;另一方面也可以通过食物中产毒真菌生长的间接污染进入食物链。真菌毒素广泛存在于成熟的玉米、谷物、大豆、高粱、花生和饲料作物中。食用受真菌毒素污染的食物或饲料会对人和动物造成急性或慢性毒性。真菌毒素除了有直接食用受霉菌毒素污染的食物和饲料造成的不良影响外,还有因为摄入动物源性食品,如肉类、牛奶或鸡蛋,含有真菌毒素的残留物或代谢物而引起的公众健康问题。目前虽然已经鉴定出超过400种真菌毒素,但食物中广泛存在的6种毒素：黄曲霉毒素、赭曲霉毒素、玉米赤霉烯酮、伏马菌素、呕吐毒素及T-2毒素,已在世界范围内引发了持续的食品安全问题。该论文总结了6种真菌毒素的毒性,重点分析了近年来电化学生物传感器在这几种真菌毒素检测中的研究进展,旨在通过一系列的总结分析去展望其在真菌毒素检测方面的发展前景。     

The effect of administration of a single dose of T-2 toxin on blood coagulation in the rabbit.

The single intravenous administration of T-2 toxin to rabbits at a dosage of 0.5 mg per kg body weight produced an alteration in several blood coagulation parameters. The activities of factors VII, VIII, IX, X and XI were decreased by approximately 40% six hours after T-2 toxin administration. Plasma fibrinogen concentration became elevated within 24 hours after T-2 toxin exposure. Circulating platelet numbers were unaffected by T-2 toxin administration. The similarity of coagulation parameter changes induced by T-2 toxin in animals receiving daily subcutaneous injections of vitamin K (0.5 mg per kg body weight) and those in nonvitamin K supplemented animals suggests that T-2 toxin does not function as a vitamin K antagonist.