Morphological and toxicological studies on experimental T-2 mycotoxicosis
Hayes, Michael Anthony
T-2 toxin, a trichothecene mycotoxin produced by some Fusarium fungi, is possibly the cause of several mycotoxicoses of humans and livestock. Several studies were conducted to characterize the "dermatitic" and the "radiomimetic" properties of T-2 toxin, and to determine their effects on animals fed T-2 toxin in the diet. The dermatitic responses to T-2 toxin and a similar trichothecene, diacetoxyscirpenol (DAS), were examined by applying the toxins to the skin of rats. The resulting acute non-specific dermal inflammatory reactions were, at all stages of development, histologically similar to reactions produced by croton oil. The skin of rabbits treated with T-2 toxin reacted in the same way. Variation in sensitivity among rats was responsible for poor correlation between dose and visible signs of cutaneous inflammation, measured either by subjective rating of the intensity of inflammation, or by frequency-response. However, variation in sensitivity among test rats had little influence on the dose-response relationship when reactions were rated in units of equivalent concentration of T-2 toxin by comparison with reactions to a graded series of standard solutions of T-2 toxin applied to the same rat. This novel method of evaluating reactions improved the skin-irritation bioassay for trichothecenes such that test solutions in the range of 5 to 60 pg/ml were measured accurately and precisely to within 13% of actual concentrations. Intragastric administration of a single sublethal dose of T-2 toxin (2.0 or 2.5 mg/kg) to juvenile Swiss mice caused necrosis of lymphoblasts in lymphoid follicles, of lymphocytes in the intestinal mucosa, of lymphocytes in the thymic cortex, of epithelial cells in intestinal crypts, and of hematopoietic cells in splenic red pulp and bone marrow within 6 hours. The severity of injury in these tissues was dose-dependent. Ultrastructurally and histologically, lesions resembled those reported in response to various anti-neoplastic chemicals. Cells in damaged target tissues regenerated during a 96-hour period after treatment. The subacute toxic effects of dietary T-2 toxin on the hematopoietic, lymphopoietic, and alimentary systems were examined in Swiss mice and Wistar rats. Attempts were made to identify factors that potentiated the toxicity of dietary T-2 toxin to the hematopoietic system. Dietary T-2 toxin at levels of 10 or 20 ppm, in either natural-ingredient diets or in semipurified diets of various protein levels, consistently caused dose-dependent thymic atrophy, lymphopenia, gastric hyperkeratosis and gastric ulceration in juvenile mice. Similar, but less severe effects occurred in adult mice and in young rats fed these levels of T-2 toxin in natural-ingredient diets. Juvenile mice fed 20 ppm of T-2 toxin also developed aplastic anemia due to suppression of erythropoiesis in splenic red pulp and in bone marrow. Hypoplastic hematopoietic and lymphopoietic tissues began to regenerate within 7 days in mice transferred from toxic diets to control diets. Suppression of hematopoiesis in juvenile mice fed T-2 toxin was probably a subacute manifestation of the toxicity of T-2 toxin to rapidly dividing cells. This effect was transient during continuous dietary exposure because suppression was gradually overcome and hematopoietic cells regenerated after several weeks. Such recovery may have been due to biotransformation of T-2 toxin into a non-toxic metabolite by the liver because recovery occurred more slowly in.mice housed in suspension cages than in mice housed on softwood bedding, a known inducer of microsomal enzyme activity. Perioral dermatitis, gastritis, and hyperplasia of the gastric and duodenal mucosa, all of which were attributed to direct irritant toxicity of T-2 toxin to the upper alimentary tract, persisted in mice that overcame the suppression of hematopoiesis. Thus, mice eventually exhibited similar toxic effects as were observed in rats, and as have been reported in swine and poultry fed dietary T-2 toxin. Diets of low protein content (8%) potentiated the toxicity of dietary T-2 toxin to juvenile mice by prolonging the period of suppression of hematopoiesis and lymphopoiesis. These results supported the hypothesis that the normally low susceptibility of animals to the hematopoietic-suppressive or immunosuppressive effects of dietary T-2 toxin is increased under conditions of suboptimal protein nutrition.