| Trichothecenes are secondary fungal metabolites produced by food-borne and environmental molds including Fusarium, Stachybotrys, and Myrothecium. Human and animal exposure may occur via consumption of mold-contaminated grains, inhalation of fungal spores present on water-damaged building materials, or airborne exposure during suspected chemical warfare. Trichothecenes are potent translational inhibitors which bind to the ribosomes of actively dividing leukocytes of the immune system. Exposure to trichothecenes results in decreased leukocyte numbers and impaired resistance to pathogens. The overall hypothesis of this dissertation is that trichothecene-induced immune suppression is mediated in part by the induction of leukocyte death by apoptosis. The specific objectives of these studies were to compare apoptosis induction by trichothecenes and other naturally occurring translational inhibitors, determine the physico-chemical components of the trichothecenes critical for the induction of apoptosis, investigate the augmentation of trichothecene-induced cell death by inflammatory agents, and determine the signal transduction mechanisms critical for trichothecene-induced apoptosis. Comparisons of translational inhibitors suggested that trichothecenes were among the most potent inducers of leukocyte apoptosis when compared to other natural toxins. Multiple physico-chemical factors critical to transport and ribosomal binding contribute to the apoptotic actions of the trichothecenes including electrostatic interactions, and molecular shape. Trichothecene-induced leukocyte apoptosis may be augmented by signal components of stress and inflammation such as TNF-α and Fas ligand. Activation of mitogen activated protein kinases (MAPKs) appears to be an early, critical step in the development of leukocyte apoptosis induced by trichothecenes or potentiated by inflammatory agents. Taken together, these studies contribute to our knowledge of the mechanism of leukocyte apoptosis by the trichothecene mycotoxins and may facilitate risk assessment studies for this group of natural toxins. |
