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Deciphering the Link Between Genetic Variants and Sphingolipid Metabolites in Fumonisin B1- and FTY720-Induced Neural Tube Defects

出版	Creighton University, 2015
URL	http://books.google.com.hk/books?id=MyN_tAEACAAJ&hl=&source=gbs_api

註釋Neural tube defects (NTDs) are birth defects that affect approximately 1/1000 babies annually worldwide and are thought to result from complex interactions between genetics, maternal nutrition, and environmental factors. Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Ingestion of FB1-contaminated food during early pregnancy is associated with increased risk for having a child with anencephaly/exencephaly, a lethal NTD. FB1 treatment of pregnant mice results in 79% exencephaly in LM/Bc mice, but less than 1% NTDs in SWV mice. FB1 inhibits ceramide synthase (CerS1-6) enzymes involved in de novo sphingolipid biosynthesis, causing increased accumulation of sphinganine and its phosphorylated bioactive metabolite sphinganine-1-phosphate (Sa1P). CerS1 is the primary isoform found in the brain and has a unique bicistronic mRNA structure with Gdf1 (growth differentiation factor 1). Exome sequencing of the LM/Bc strain identified a single nucleotide polymorphism (SNP) in Gdf1 that may contribute to enhanced genetic susceptibility to FB1-induced NTDs; AKR/J mice have the same Gdf1 SNP and are also susceptible to FB1-NTDs. FTY720 (Fingolimod, Gilenya®) is an FDA-approved drug used for treating multiple sclerosis. FTY720 treatment in pregnant mice caused NTDs in 40-60% of SWV and LM/Bc embryos and results in an accumulation of the bioactive ligand FTY720-P. Cytoplasmic Sa1P and FTY720-P function as agonists for sphingosine-1-phosphate (S1P) receptors, whereas nuclear Sa1P and FTY720-P inhibit histone deacetylase (HDAC) activity. FB1 treatment in LM/Bc MEFs caused significant accumulation of nuclear Sa1P, decreased HDAC activity, and increased histone acetylation, suggesting that HDAC inhibition may represent a novel mechanism for FB1-induced NTDs. FB1 treatment also results in increased Gdf1 mRNA expression and increased miR-574-5p expression, a known regulator of CerS1 mRNA stability in the bicistronic transcript. Detection of the Gdf1 SNP and enhanced mir-574-5p expression may represent new genetic and epigenetic biomarkers for identifying individuals at risk for FB1-induced NTDs. FTY720 treatment in LM/Bc MEFs resulted in elevated nuclear and cytoplasmic FTY720-P, suggesting that both HDAC inhibition and S1P receptor activation may play a role in FTY720-induced NTDs. As pharmacological applications for FTY720 expand, these studies provide mechanistic insight into the potential risks for use in pregnant women.