title: Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720.
abstract: BACKGROUND
  Fumonisin B(1) (FB(1)) is a mycotoxin produced by a common fungal contaminant of corn. Ingestion of FB(1)-contaminated food is associated with increased risk for neural tube defects (NTDs). FB(1) induces NTDs in inbred LM/Bc mice. FB(1) 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 FB(1) (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 FB(1) (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 FB(1) or FTY720, respectively. FTY720-P was elevated in ED 9.5 exencephalic embryos. Sa1P was elevated in SFME and MEF cells treated with FB(1), and Sa1P was higher in MEFs generated from the FB(1)-NTD-susceptible LM/Bc strain.
  
  
  CONCLUSIONS
  Elevated sphingoid base-1-P after FB(1) 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 FB(1) or FTY720. Sa1P may represent a biomarker for FB(1)-NTD risk assessment.
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA. JaneeVanwaes@creighton.edu
authors.forename: Janee
authors.initials: J
authors.lastname: Gelineau-van Waes
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rainey
authors.forename: Joyce R
authors.initials: JR
authors.lastname: Maddox
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Voss
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sachs
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Gardner
authors.forename: Justin D
authors.initials: JD
authors.lastname: Wilberding
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Riley
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D000068876:Fingolimod Hydrochloride; D037341:Fumonisins / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000139:chemically induced; D011409:Propylene Glycols / Q000009:adverse effects* / Q000494:pharmacology; D013110:Sphingosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D037341:Fumonisins; D011409:Propylene Glycols; C060504:dihydrosphingosine 1-phosphate; C056933:fumonisin B1; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; C005682:safingol