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Title: Fumonisin B1 (FB1) and Fingolimod (FTY720): Tortilla Toxin and Oral Therapeutic Target Sphingolipid Pathways During Neural Tube Closure

Author
item GELINEAU-VAN WAES, JANEE - Creighton University
item GARDNER, NICOLE - University Of Iowa
item MOSELEY, ARTHUR - Duke University School Of Medicine
item SODERLOM, ERIC - Duke University School Of Medicine
item Voss, Kenneth
item GREGORY, SIMON - Duke University
item ASHLEY-KOCH, ALLISON - Duke University Medical Center
item SACHS, ANDREW - Creighton University
item MADDOX, JOYCE - University Of Nebraska
item RILEY, RONALD - Retired ARS Employee

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 2/21/2018
Publication Date: 5/18/2018
Citation: Gelineau-Van Waes, J.B., Gardner, N., Moseley, A.M., Soderlom, E., Voss, K.A., Gregory, S., Ashley-Koch, A., Sachs, A., Maddox, J., Riley, R.T. 2018. Fumonisin B1 (FB1) and Fingolimod (FTY720): Tortilla Toxin and Oral Therapeutic Target Sphingolipid Pathways During Neural Tube Closure. Meeting Abstract. vol 110(9):34

Interpretive Summary:

Technical Abstract: Gestational exposure to environmental toxins or pharmaceuticals may increase the risk for neural tube defects (NTDs) by altering cell signaling pathways and/or inducing epigenetic modifications that affect gene regulation. Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, a common contaminant of corn. FB1 inhibits ceramide synthase, leading to increased levels of sphinganine and sphinganine-1-P (Sa1P) in human and mouse blood and tissues. Consumption of FB1-contaminated food is associated with increased risk for birth defects in humans, and experimental administration of FB1 causes NTDs in LM/Bc mice. The sphingoid base analog FTY720 is an oral prodrug that is phosphorylated in vivo by sphingosine kinase to form bioactive FTY720-P. Experimental administration of FTY720 results in elevation of FTY720-P in blood and tissues and causes NTDs in LM/Bc and SWV mice. Sa1P and FTY720-P formed in the cytoplasm are exported from the cell to act as ligands for a family of G protein-coupled sphingosine-1-P (S1P) receptors, whereas nuclear Sa1P and FTY720-P bind and inhibit histone deacetylases (HDACs). In order to determine the potential mechanism(s) underlying FB1 and FTY720-induced NTDs, serum free mouse embryo (SFME) neural progenitor cells (NPCs) were treated with FB1 or FTY720 and the relative accumulation of Sa1P or FTY720-P in the cytoplasm vs. the nucleus was determined. HDAC activity was measured in the nuclear fraction, and histones were purified and analyzed using multidimensional liquid chromatography – tandem mass spectrometry for treatment-induced changes in histone post-translational modifications (PTMs). After FB1 treatment, Sa1P accumulated primarily in the nucleus, whereas after FTY720 treatment, FTY720-P accumulated primarily in the cytoplasm. HDAC activity in SFME cells decreased in a dose-responsive manner following treatment with either FB1 or FTY720. Significant changes in histone PTMs (acetylation, oxidation) were observed for histone H2B, H3 and H4 in response to FB1, and dimethylation of H4K91 and H4R92 increased significantly after exposure to either FB1 or FTY720. Alterations in subcellular levels of bioactive sphingolipid metabolites during embryonic development may contribute to failure of neural tube closure by affecting S1P receptor-mediated signaling pathways and/or inducing epigenetic modifications that alter gene regulation in neural progenitor cells.