Fumonisins are mycotoxins produced by a common fungus Fusarium moniliforme, prevalent in corn. Fumonisin B1 and related toxins have been reported as a contributing factor in human esophageal and liver cancer. In livestock, fumonisins induce equine leukoencephalomalacia and porcine pulmonary edema. In these animals and laboratory animals fumonisins produce varying degrees of hepatic and renal lesions. The cause of species-specificity is unknown. An early biochemical lesion produced by fumonisin is inhibition of sphinganine-N-acyl transferase, causing accumulation of free sphingoid bases and altered lipid homeostasis. Fumonisin B1 causes apoptosis and alters cell proliferation in various cell types. In recent studies a short term exposure of mice to fumonisin B1 produced apoptotic cells in liver and kidney, the effect was associated with increased production of tumor necrosis factor-alpha (TNF) by systemic macrophages. Acute hematological effects of fumonisin B1 were prevented by anti-TNF antibodies. Fumonisin B1 also induced TNF in murine macrophage cells in vitro. Further studies of TNF involvement in fumonisin toxicity are proposed to: (1) Demonstrate the production of TNF after fumonisin B1 exposure in vivo in mice, using immunosorbent assay, histochemistry, and localization of specific mRNA, (2) Investigate the modification of fumonisin B1-response in mice by manipulating the TNF production by injecting lipopolysaccharide or TNF, along with anti-TNF, (3) Determine if target cells treated with fumonisin B1 have altered response to TNF, by comparing the apoptotic signaling pathway (i.e., protein kinase C, ceramide), and DNA damage (affected both by TNF and sphingoid bases), and (4) Determine if TNF production or increased sensitivity of cells to TNF is related to altered sphingolipid metabolism. Results will help in defining the mechanism(s) of fumonisin toxicity, causes of species-specificity, and provide a better appraisal of risk in humans, including modification of fumonisin response by gram-negative infections.
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