|Gelineau-Van Waes, Janee - MED.CEN./U. NEBRASKA|
Submitted to: Toxicological Sciences
Publication Type: Abstract Only
Publication Acceptance Date: November 1, 2005
Publication Date: March 1, 2006
Citation: Gelineau-Van Waes, J., Riley, R.T. 2006. Gene-nutrient-environment interactions as risk factors for birth defects: fumonisin, folate, genetic variation and neural tube defects [abstract]. Toxicological Sciences 90(1):305. Technical Abstract: The second most common birth defect is neural tube defects (NTDs). In Guatemala, parts of China and Africa, NTD risk is estimated to be higher than that observed in the USA. The etiology of NTD in these areas 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. 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 folate-binding protein (Folbp1). Fumonisin disruption of folate transport via Folbp1 interferes with neural tube closure in animal models in vitro and can be prevented by folate supplementation. In vivo studies in LM/Bc and CD1 mouse strains have found that maternal fumonisin administration during pregnancy increases the frequency of NTD in exposed embryos. Supplementation with folate or ganglioside GM1 is protective, suggesting altered sphingolipid-dependent lipid raft function. In addition, altered expression of cytokines, inducible nitric oxide synthase, and several genes involved in redox homeostasis are observed in affected embryos. 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. Epidemiological studies and further experimentation with animal models will be necessary to assess the teratogenic potential and impact of fumonisin as a human health hazard.