title: Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts.
abstract: Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Administration of FB1 to pregnant LM/Bc mice induces exencephaly in embryos, and ingestion of FB1-contaminated food during early pregnancy is associated with increased risk for neural tube defects (NTDs) in humans. FB1 inhibits ceramide synthase enzymes in sphingolipid biosynthesis, causing sphinganine (Sa) and bioactive sphinganine-1-phosphate (Sa1P) accumulation in blood, cells, and tissues. Sphingosine kinases (Sphk) phosphorylate Sa to form Sa1P. Upon activation, Sphk1 associates primarily with the plasma membrane, while Sphk2 is found predominantly in the nucleus. In cells over-expressing Sphk2, accumulation of Sa1P in the nuclear compartment inhibits histone deacetylase (HDAC) activity, causing increased acetylation of histone lysine residues. In this study, FB1 treatment in LM/Bc mouse embryonic fibroblasts (MEFs) resulted in significant accumulation of Sa1P in nuclear extracts relative to cytoplasmic extracts. Elevated nuclear Sa1P corresponded to decreased histone deacetylase (HDAC) activity and increased histone acetylation at H2BK12, H3K9, H3K18, and H3K23. Treatment of LM/Bc MEFs with a selective Sphk1 inhibitor, PF-543, or with ABC294640, a selective Sphk2 inhibitor, significantly reduced nuclear Sa1P accumulation after FB1, although Sa1P levels remained significantly increased relative to basal levels. Concurrent treatment with both PF-543 and ABC294640 prevented nuclear accumulation of Sa1P in response to FB1. Other HDAC inhibitors are known to cause NTDs, so these results suggest that FB1-induced disruption of sphingolipid metabolism leading to nuclear Sa1P accumulation, HDAC inhibition, and histone hyperacetylation is a potential mechanism for FB1-induced NTDs.
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, United States. Electronic address: nicolegardner@creighton.edu.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Gardner
authors.affiliation: USDA-ARS, Toxicology and Mycotoxin Research Unit, Athens, GA 30605, United States.
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Riley
authors.affiliation: USDA-ARS, Toxicology and Mycotoxin Research Unit, Athens, GA 30605, United States.
authors.forename: Jency L
authors.initials: JL
authors.lastname: Showker
authors.affiliation: USDA-ARS, Toxicology and Mycotoxin Research Unit, Athens, GA 30605, United States.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Voss
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sachs
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, United States.
authors.forename: Joyce R
authors.initials: JR
authors.lastname: Maddox
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, United States.
authors.forename: Janee B
authors.initials: JB
authors.lastname: Gelineau-van Waes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D037341:Fumonisins / Q000633:toxicity*; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D009436:Neural Tube Defects / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D021241:Spectrometry, Mass, Electrospray Ionization; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D004785:Environmental Pollutants; D037341:Fumonisins; C060504:dihydrosphingosine 1-phosphate; C056933:fumonisin B1; D006655:Histone Deacetylases; D013110:Sphingosine
keywords: Fumonisin B1; Histone acetylation; Histone deacetylase (HDAC); Neural tube defect (NTD); Sphinganine-1-phosphate (Sa1P)