Trichothecenes responses

Ex vivo studies have revealed that trichothecenes can both inhibit and stimulate leukocyte function.12 For example, trichothecenes are toxic to alveolar macrophages,13 but drive differentiation of human myeloid leukemic cells.14 Dose-dependent decreases or increases in B- and T-cell mitogen responses are observable in lymphocytes from animals exposed to T-2 toxin, DON, or various macrocyclic trichothecenes these toxins similarly impair or enhance mitogen-induced lymphocyte proliferation in vitro.12 Rank order of inhibitor potency in rodent and human lymphocyte proliferation assays is Type D > Type A group > Type B group and is dependent on degree of acylation as well as of uptake and metabolism. 

What are the mechanisms by which trichothecenes exert their transcriptional and post-transcriptional effects The 60S ribosomal subunit is a well-known molecular target of trichothecenes in leukocytes and other actively proliferating eukaryotic cells,3 whereas attempts to demonstrate alternative receptors have not been successful.37 38 Translational inhibitors that bind to ribosomes rapidly activate mitogen-activated protein kinases (MAPKs) and apoptosis via a mechanism termed the ribotoxic stress response. 39-40... 

Zhou, H. R., Yan D., and Pestka J.J. Differential cytokine mRNA expression in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol) Dose response and time course. Toxicol. Appl. Pharmacol. 144, 294, 1997. 

Shifrin, V. I. and Anderson P. Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J. Biol. Chem. 274, 13985, 1999. 

Trichothecenes are potent inhibitors of protein synthesis due to binding to the 60S ribosomal unit and this is believed to be the main mechanism of toxicity. However, recent experimental data suggest that activation of the mitogen-activated protein kinases (MAPKs) through the ribosomal stress response could be another mechanism that operates via apoptotic and proinflammatory processes. 

Trichothecenes inhibit synthesis of protein, RNA and DNA as well as mitochondrial and electron transport chain function stimulate lipid peroxidation alter cell membrane function induce apoptosis modulate immune responses activate mitogen-activated protein kinases (MAPKs) and induce gene expression of numerous chemokines and cytokines and alter neurotransmitter levels. 

LD50 values, which may differ based on route of exposure and species exposed, can be used to compare the toxicity of trichothecenes (Table 26.1). For example, the LD50 values for i.p. exposure in the mouse are 5.2 mg/kg for T-2 toxin and 23 mg/kg for DAS, while for i.v. exposure in the pig they are 1.21 mg/kg for T-2 toxin and 0.37 mg/kg for DAS (Ueno, 1985). For T-2 toxin, oral LD50 values are not markedly different across species (Ueno, 1985) however, T-2 toxin was 10- to 50-fold more toxic when inhaled than when administered orally (Marrs et al, 1986). For DON, pigs are the most sensitive, followed by mice then rats. For DON in pigs, the main clinical effect at high levels is vomiting and at low levels reduced food intake or food refusal. Such responses apparently limit exposure and thus toxic manifestations. 

Trichothecene toxicosis is manifested by a broad spectrum of clinical disorders, which vary according to the specific causative toxin or mixture of toxins. Species differences in response are generally related to severity of the response, and young animals are more susceptible than adults. Toxicosis can be acute or chronic, with clinical signs remaining fairly similar. A comprehensive review of the pathophysiology of spontaneous and experimentally induced trichothecene mycotoxicosis is available (Beasley, 1989). 

Zhou, H.R., Jia, Q., Pestka, J.J. (2005b). Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase hck. Toxicol. Sci. 85 916-26. 

In all these cases the responses observed in plants are, upon treatment with the trichothecenes, very similar to those seen in plants. Among those genera that have been claimed to produce trichothecenes are Acremonium (11), Cylindrocarpon (11), Dendrostilbella (12), Fusarium (11), Myrothecium (11), TrichoTerma (11), Trichothecium (11), and of these Cylindrocarpon, Fusarium, Myrothecium, and Trichothecium are plant pathogens ... 

The strucure-activity response is even more subtly expressed in the etiolated wheat coleoptile (Triticum aestivum L. Wakeland) that has been described in detail elsewhere (13) Subtle modifications in structure cause marked changes in the inhibitory responses induced (Table I). With the exception of 15-acetoxy-T- 2-tetraol, neosolaniol and isoneosolaniol which are inactive at lO M (Fig. 2l, all of the trichothecenes so far tested are active at 10" M. A further one-third are active at 10"°M and the most potent, which are active at 10" M, are verrucarins A and J, and trichoverrin B, Neosolaniol, which inhibits 100% at 10" and 61% at 10" M has an acetate at C15 while isonesolaniol, which has an hydroxyl group at C15 inhibits coleoptiles 80 and 51% at 10" and 10"3, respectively. 

A detailed study of the effects of exogenously applied macrocylic trichothecenes on intact bean, corn, and tobacco plants recalls that they may induce a variety of responses that are tissue dependent and range from no effect to complete phytotoxicity (H). Initial experiments have conclusively shown that in the etiolated wheat coleoptile bioassay verrucarin A, verrucarin J, and trichoverrin B are exception-... 

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