Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts

Nicole M. Gardner, Ronald T. Riley, Jency L. Showker, Kenneth A. Voss, Andrew J. Sachs, Joyce R. Maddox, Janee Gelineau-van Waes

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)56-65
Number of pages10
JournalToxicology and Applied Pharmacology
Volume298
DOIs
StatePublished - May 1 2016

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Histone Deacetylases
Fibroblasts
Phosphates
Neural Tube Defects
Histones
Acetylation
Sphingolipids
Defects
Enzyme inhibition
fumonisin B1
dihydrosphingosine 1-phosphate
Histone Deacetylase Inhibitors
Mycotoxins
Biosynthesis
Cell membranes
Metabolism
Lysine
Zea mays
Blood Cells
Blood

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Toxicology

Cite this

Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts. / Gardner, Nicole M.; Riley, Ronald T.; Showker, Jency L.; Voss, Kenneth A.; Sachs, Andrew J.; Maddox, Joyce R.; Gelineau-van Waes, Janee.

In: Toxicology and Applied Pharmacology, Vol. 298, 01.05.2016, p. 56-65.

Research output: Contribution to journalArticle

Gardner, Nicole M. ; Riley, Ronald T. ; Showker, Jency L. ; Voss, Kenneth A. ; Sachs, Andrew J. ; Maddox, Joyce R. ; Gelineau-van Waes, Janee. / Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts. In: Toxicology and Applied Pharmacology. 2016 ; Vol. 298. pp. 56-65.
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AU - Gelineau-van Waes, Janee

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