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

Janee Gelineau-van Waes, Mark A. Rainey, Joyce R. Maddox, Kenneth A. Voss, Andrew J. Sachs, Nicole M. Gardner, Justin D. Wilberding, Ronald T. Riley

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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.

Original languageEnglish (US)
Pages (from-to)790-803
Number of pages14
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume94
Issue number10
DOIs
StatePublished - Oct 1 2012

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All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Developmental Biology

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