Verrucarin B

Trichothecenes (TCNs) are the mycotoxins produced by many fungal species such as Fusarium, Myrothecium, and Stachybotrys and pose a considerable health risk. Based on their characteristic functional moieties, they are divided into four categories: Type A (T-2, HT-2, diacetoxyscirpenol (DAS), harzianum A, neosolaniol (NEO) and trichodermin), Type B (deoxynivalenol (DON), nivalenol (NIV), trichothecin and fusarenon X), Type C (crotocin) and Type D (satratoxin G & H, roridin A and verrucarin A) with types A and B being the most substantial. TCNs cause growth retardation in eukaryotes, suppress seedling growth or regeneration in plants and could be a reason for animal reproductive failure. Due to the increased frequency of occurrence and widespread distribution of TCNs in food and feed, knowledge of their sources of occurrence is essential to strategise their control and management. Hence, this review provides an overview of various types and sources of TCNs, the associated biosynthetic pathways and genes responsible for production in food and feed. Further, various processing and environmental effects on TCNs production, detection techniques and management strategies are also briefly outlined.

Straw is the main by-product of grain production, used as bedding material and animal feed. If produced or stored under adverse hygienic conditions, straw is prone to the growth of filamentous fungi. Some of them, e.g. Aspergillus, Fusarium and Stachybotrys spp. are well-known mycotoxin producers. Since studies on mycotoxins in straw are scarce, 192 straw samples (wheat n = 80; barley n = 79; triticale n = 12; oat n = 11; rye n = 12) were collected across Germany within the German official feed surveillance and screened for the presence of 21 mycotoxins. The following mycotoxins (positive samples for at least one mycotoxin n = 184) were detected: zearalenone (n = 86, 6.0-785 μg/kg), nivalenol (n = 51, 30-2,600 μg/kg), deoxynivalenol (n = 156, 20-24,000 μg/kg), 15-acetyl-deoxynivalenol (n = 34, 20-2,400 μg/kg), 3-acetyl-deoxynivalenol (n = 16, 40-340 μg/kg), scirpentriol (n = 14, 40-680 μg/kg), T-2 toxin (n = 67, 10-250 μg/kg), HT-2 toxin (n = 92, 20-800 μg/kg), T-2 tetraol (n = 13, 70-480 μg/kg). 15-monoacetoxyscirpenol (30 μg/kg) and T-2 triol (60 μg/kg) were only detected in one barley sample. Macrocyclic trichothecenes (satratoxin G, F, roridin E, and verrucarin J) were also found in only one barley sample (quantified as roridin A equivalent: total 183 μg/kg). The occurrence of stachybotrylactam was monitored for the first time in four samples (n = 4, 0.96-7.4 μg/kg). Fusarenon-X, 4,15-diacetoxyscirpenol, neosolaniol, satratoxin H and roridin-L2 were not detectable in the samples. The results indicate a non-negligible contribution of straw to oral and possibly inhalation exposure to mycotoxins of animals or humans handling contaminated straw.

Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated. Moreover, trichothecenes may generate an "immune evasion" milieu that allows pathogens to escape host and vaccine immune defenses. Some trichothecenes, especially macrocyclic trichothecenes, also potently kill cancer cells. T-2 toxin conjugated with anti-cancer monoclonal antibodies significantly suppresses the growth of thymoma EL-4 cells and colon cancer cells. The type B trichothecene diacetoxyscirpenol specifically inhibits the tumor-promoting factor HIF-1 in cancer cells under hypoxic conditions. Trichothecin markedly inhibits the growth of multiple cancer cells with constitutively activated NF-κB. The type D macrocyclic toxin Verrucarin A is also a promising therapeutic candidate for leukemia, breast cancer, prostate cancer, and pancreatic cancer. The anti-cancer activities of trichothecenes have not been comprehensively summarized. Here, we first summarize the data on the immunomodulatory effects of trichothecenes and discuss recent studies that shed light on the underlying cellular and molecular mechanisms. These mechanisms include autophagy and major signaling pathways and their crosstalk. Second, the anti-cancer potential of trichothecenes and the underlying mechanisms will be discussed. We hope that this review will show how trichothecene bioactivities can be exploited to generate therapies against pathogens and cancer.