Fumonisin inhibition of ceramide synthase: A possible risk factor for human neural tube defects

Abstract

Fumonisins are carcinogenic mycotoxins that cause farm animal diseases. They commonly contaminate maize and are suspected, but not proven, to cause human disease. Their mode of action involves inhibition of the enzyme (ceramide synthase) that controls the formation of sphingolipids, important regulators of pathways involved in cell death and survival. Sphingolipids are needed for the proper function of receptors associated with lipid rafts (for example, the high affinity folate-binding protein). Fumonisin disruption of folate transport interferes with neural tube closure in animal models in vitro, and this effect is reduced by folate supplementation. In vivo studies in the LMBc mouse strain have shown that maternal fumonisin administration during pregnancy causes a dose-related increase in the frequency of neural tube defects (NTDs) in the embryos. Co-exposing the dams to folate or ganglioside GM1 is protective, suggesting that fumonisin alters sphingolipid-dependent lipid raft function. In addition, altered expression of cytokines, inducible nitric oxide synthase, elevated levels of sphinganine and sphinganine 1-phosphate and several genes involved in redox homeostasis are observed in affected embryos. NTDs are the second most common birth defect in humans. The etiology of human NTDs is complex. Increased risk has been associated with genetic predisposition, dietary exposure to environmental contaminants, and reduced intake of folate and other vitamins/nutrients. Human clinical and epidemiological studies show folate supplementation reduces the risk for NTDs. While there is no direct evidence for fumonisin as a cause of NTD in humans, the incidence of NTD is higher where maize consumption is high, and both fumonisin exposure and folate deficient diets are likely. Thus, it has been hypothesized that fumonisin inhibition of ceramide synthase is a risk factor for NTDs in humans with folate deficient diets who consume large quantities of low quality maize. © Springer-Verlag Tokyo 2006. All rights reserved.