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Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720

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  • Portions of the data in this manuscript were presented at the 7th International Conference on Neural Tube Defects held in Austin, Texas, on November 6–9, 2011.

    The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The authors have no conflicts of interest to declare.

Abstract

BACKGROUND: Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Ingestion of FB1-contaminated food is associated with increased risk for neural tube defects (NTDs). FB1 induces NTDs in inbred LM/Bc mice. FB1 inhibits ceramide synthase in de novo sphingolipid biosynthesis, resulting in accumulation of sphinganine and sphinganine-1-phosphate (Sa1P). Sa1P functions as a ligand for a family of G protein-coupled S1P receptors. METHODS: Pregnant SWV and LM/Bc mice were treated with FB1 (20 mg/kg/day intraperitoneally on embryonic day (ED) 7.5–8.5) or the known S1P receptor agonist FTY720 (10 mg/kg/day oral gavage on ED 6.5–8.5). LC/MS was used to detect sphingoid base-1-phosphates in maternal blood spots, plasma, and embryonic tissue. Strain-specific SWV and LM/Bc mouse embryonic fibroblasts (MEFs) and serum free mouse embryo (SFME) neural progenitor cells were treated with FB1 (40 μM for 24 hr) and LC/MS was used to detect sphingoid base-1-phosphates. RESULTS: FTY720 induced NTDs in both the SWV and the LM/Bc strains of mice. Sphinganine-1-P (Sa1P) and FTY720-P were elevated in the blood spots and plasma of mice treated with FB1 or FTY720, respectively. FTY720-P was elevated in ED 9.5 exencephalic embryos. Sa1P was elevated in SFME and MEF cells treated with FB1, and Sa1P was higher in MEFs generated from the FB1-NTD–susceptible LM/Bc strain. CONCLUSIONS: Elevated sphingoid base-1-P after FB1 or FTY720 suggest a potential role for these bioactive lipid ligands and activation of S1P receptor signaling pathways in the failure of neural tube closure after FB1 or FTY720. Sa1P may represent a biomarker for FB1-NTD risk assessment. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc.

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