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

Author
item GELINEAU-VAN WAES, JANEE - Creighton University
item RAINEY, MARK - Creighton University
item MADDOX, JOYCE - Creighton University
item Voss, Kenneth
item SACHS, ANDREW - Creighton University
item GARDNER, NICKI - Creighton University
item WILBERDING, JUSTIN - Kirksville College Of Osteopathic Medicine
item Riley, Ronald

Submitted to: Birth Defects Research Part A: Clinical and Molecular Teratology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/23/2012
Publication Date: 11/11/2012
Citation: Gelineau-Van Waes, J., Rainey, M.A., Maddox, J.R., Voss, K.A., Sachs, A.J., Gardner, N.M., Wilberding, J.D., Riley, R.T. 2012. Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720. Birth Defects Research Part A: Clinical and Molecular Teratology. 94(10):790-803.

Interpretive Summary: Fumonisin B1 (FB1) is a toxic chemical produced by a common mold which contaminates corn. Ingestion of FB1-contaminated food is associated with increased risk for neural tube defects (NTDs) in humans. FB1 induces NTDs in inbred LM/Bc mice. FB1 inhibits the synthesis of a group of fats known as sphingolipids. When their synthesis is inhibited, two chemicals known as sphinganine and sphinganine-1-phosphate (Sa1P) accumulate in tissues. Sa1P can bind to a family of cellular proteins known as S1PR receptors. Pregnant SWV and LM/Bc mice were treated with FB1 or a drug known to bind to S1P receptor known as FTY720. Analysis of cells and tissues showed that sphingoid base-1-phosphates accumulated in maternal blood spots, plasma, and embryonic tissue. Strain specific SWV and LM/Bc mouse embryonic cells were also treated with FB1 and they were also analyzed for sphingoid base-1-phosphates. 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 embryos that developed NTD. Sa1P was elevated in the embryonic cells treated with FB1, and Sa1P was higher in embryonic cells generated from the FB1-NTD susceptible LM/Bc mouse strain. Elevated sphingoid base-1-P after FB1 or FTY720 suggest a potential role for these bioactive fats and activation of S1P receptor signaling pathways in failure of neural tube closure after FB1 or FTY720. Sa1P may represent a specific indicator (biomarker) for FB1-NTD risk assessment.

Technical Abstract: 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. Pregnant SWV and LM/Bc mice were treated with FB1 (20 mg/kg/day ip on E7.5-E8.5) or the known S1P receptor agonist FTY720 (10mg/kg/day oral gavage on E6.5-E8.5). 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 M for 24h) and LC/MS was used to detect sphingoid base-1-phosphates. 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 E9.5 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. Elevated sphingoid base-1-P or FTY720-P after FB1 or FTY720, respectively, suggest a potential role for these bioactive lipid ligands and activation of S1P receptor signaling pathways in failure of neural tube closure after FB1 or FTY720. Sa1P may represent a biomarker for FB1-NTD risk assessment.