Abstract
Fumonisins are mycotoxins produced by the fungus Fusarium verticillioides, a common contaminant of maize (corn) worldwide. Maternal consumption of fumonisin B1-contaminated maize during early pregnancy has recently been associated with increased risk for neural tube defects (NTDs) in human populations that rely heavily on maize as a dietary staple. Experimental administration of purified fumonisin to mice early in gestation also results in an increased incidence of NTDs in exposed offspring. Fumonisin inhibits the enzyme ceramide synthase in de novo sphingolipid biosynthesis, resulting in an elevation of free sphingoid bases and depletion of downstream glycosphingolipids. Increased sphingoid base metabolites (i.e., sphinganine-1-phosphate) may perturb signaling cascades involved in embryonic morphogenesis by functioning as ligands for sphingosine-1-phosphate (S1P) receptors, a family of G-protein-coupled receptors that regulate key biological processes such as cell survival/proliferation, differentiation, and migration. Alternatively, fumonisin-induced depletion of glycosphingolipids impairs expression and function of the GPI-anchored folate receptor (Folr1), which may also contribute to adverse pregnancy outcomes. Impaired folate transport through inactivation of Folr1 or the reduced folate carrier (RFC1) in transgenic mouse models results in failure of neural tube closure. However, maternal folate supplementation can "rescue" the knockout embryos and restore normal development. Supplementation of pregnant dams with folic acid has been shown to protect against fumonisin-induced NTDs in a mouse model. Human clinical and epidemiological studies indicate that maternal periconceptional use of vitamin supplements containing folic acid can reduce the risk of having a child with an NTD, yet the precise mechanism of folate protection is currently unknown. Folic acid is a pteridine derived from plant sources that is structurally similar to tetrahydrobiopterin (BH4), an important cofactor for the nitric oxide synthase (NOS) enzymes. Nitric oxide (NO) has been shown to play a role in cell cycle regulation during neural tube closure. Insufficient levels of BH4 can lead to "uncoupling" of NOS and the production of damaging reactive oxygen species (ROS, i.e., superoxides, hydrogen peroxide) and/or reactive nitrogen species (RNS, i.e., peroxynitrite). Activation of inflammatory cytokines and inducible NOS (iNOS) subsequent to fumonisin exposure may lead to altered redox homeostasis and oxidative stress, a paradigm that has been implicated in other teratogen-induced malformations. Folic acid may function as an antioxidant to decrease intracellular ROS/RNS generation by preventing peroxynitrite-mediated BH4 oxidation and improving NOS coupling. Folate reportedly stimulates endogenous BH4 regeneration and enhances NO synthesis. NTDs appear to be multifactorial in origin, involving complex gene-nutrient-environment interactions; fumonisins may represent an environmental risk factor for birth defects, although other aspects of maternal nutrition, such as folic acid intake, play an interactive role in determining pregnancy outcome. Minimizing exposures to mycotoxins through enhanced agricultural practices, identifying biomarkers of exposure, characterizing mechanisms of toxicity, and improving maternal nutrition are all important strategies for reducing the NTD burden in susceptible human populations.