5 research outputs found
Fumonisins-Occurrence, Toxicology and Mechanism of Action
[Synopsis] Fumonisins are fungal toxins commonly found on corn worldwide.They are produced by species of Fusarium, most notably Fusarium moniliforme. Typically, the fumonisin B_1 (FB_1) level in processed corn products averages 5 ppm sometimes occur in corn-products and home-grown corn. High levels of fumonisins in feed are correlated with outbreaks of equine leucoencephalomalacia and porcine pulmonary oedema syndrome. The liver is a target in most species and kidney is a target in some species. FB_1 is considered non-genotoxic but produced liver tumors in male BDIX rats and female B6C3F1 mice, and renal tumors in male F344N rats. Reproductive effects are secondary to maternal toxicity. FB_1 induces apoptosis and alters cell growth, can modify immune response, inhibit the biosynthesis of receptors for pathogens and toxins, can sensitize macrophages to endotoxins, and alters cytokine expression in vivo. FB_1 is an inhibitor of ceramide synthase, a key enzyme in sphingolipid biosynthesis. Inhibition results in an elevation in sphingoid bases and alters the amounts of the 1- phosphates and N-acetyl-derivatives of sphinganine. Disruption of sphingolipid metabolism is correlated with the animal toxicity and rodent carcinogenicity of FB_1. FB_1 also inhibits processes mediated by ceramide generated de novo. All of these changes must be considered when evaluating the effects of fumonisins
Fumonisins-Occurrence, Toxicology and Mechanism of Action
none[Synopsis] Fumonisins are fungal toxins commonly found on corn worldwide.They are produced by species of Fusarium, most notably Fusarium moniliforme. Typically, the fumonisin B_1 (FB_1) level in processed corn products averages < 1 ppm. Nonetheless, levels of FB_1 > 5 ppm sometimes occur in corn-products and home-grown corn. High levels of fumonisins in feed are correlated with outbreaks of equine leucoencephalomalacia and porcine pulmonary oedema syndrome. The liver is a target in most species and kidney is a target in some species. FB_1 is considered non-genotoxic but produced liver tumors in male BDIX rats and female B6C3F1 mice, and renal tumors in male F344N rats. Reproductive effects are secondary to maternal toxicity. FB_1 induces apoptosis and alters cell growth, can modify immune response, inhibit the biosynthesis of receptors for pathogens and toxins, can sensitize macrophages to endotoxins, and alters cytokine expression in vivo. FB_1 is an inhibitor of ceramide synthase, a key enzyme in sphingolipid biosynthesis. Inhibition results in an elevation in sphingoid bases and alters the amounts of the 1- phosphates and N-acetyl-derivatives of sphinganine. Disruption of sphingolipid metabolism is correlated with the animal toxicity and rodent carcinogenicity of FB_1. FB_1 also inhibits processes mediated by ceramide generated de novo. All of these changes must be considered when evaluating the effects of fumonisins
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Sphingolipid Perturbations as Mechanisms for Fumonisin Carcinogenesis
There is a great deal of evidence that altered sphingolipid metabolism is associated with fumonisin-induced
animal diseases including increased apoptotic and oncotic necrosis, and carcinogenesis in
rodent liver and kidney. The biochemical consequences of fumonisin disruption of sphingolipid
metabolism most likely to alter cell regulation are increased free sphingoid bases and their
1-phosphates, alterations in complex sphingolipids, and decreased ceramide (CER) biosynthesis.
Because free sphingoid bases and CER can induce cell death, the fumonisin inhibition of CER
synthase can inhibit cell death induced by CER but promote free sphingoid base-induced cell death.
Theoretically, at any time the balance between the intracellular concentration of effectors that
protect cells from apoptosis (decreased CER, increased sphingosine 1-phosphate) and those that
induce apoptosis (increased CER, free sphingoid bases, altered fatty acids) will determine the
cellular response. Because the balance between the rates of apoptosis and proliferation is important
in tumorigenesis, cells sensitive to the proliferative effect of decreased CER and increased
sphingosine 1-phosphate may be selected to survive and proliferate when free sphingoid base
concentration is not growth inhibitory. Conversely, when the increase in free sphingoid bases
exceeds a cell’s ability to convert sphinganine/sphingosine to dihydroceramide/CER or their
sphingoid base 1-phosphate, then free sphingoid bases will accumulate. In this case cells that are
sensitive to sphingoid base-induced growth arrest will die and insensitive cells will survive. If the
cells selected to die are normal phenotypes and the cells selected to survive are abnormal, then
cancer risk will increase.Keywords: Fumonisin, Carcinogenesis, Glycosphingolipids, Corn, Sphinganine, Sphingolipid, Sphingosine, Sphingosine 1-phosphate, Fusarium moniliforme, Ceramid