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ARS Home » Southeast Area » Athens, Georgia » U.S. National Poultry Research Center » Toxicology & Mycotoxin Research » Research » Publications at this Location » Publication #295073
Title: Gene-environment interactions in susceptibility to fumonisin-induced neural tube defects

Author
item GELINEAU-VAN WAES, JANEE - Creighton University
item GARDNER, NICOLE - National Institute Of Public Health (INSP)
item MADDOX, JOYCE - Creighton University
item KRUPP, DIEDRE - Duke University Medical Center
item GREGORY, SIMON - Duke University Medical Center
item ASHLEY-KOCH, ALLISON - Duke University Medical Center
item Riley, Ronald

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 7/4/2013
Publication Date: 10/7/2013
Citation: Gelineau-Van Waes, J., Gardner, N.M., Maddox, J.R., Krupp, D., Gregory, S.G., Ashley-Koch, A.E., Riley, R.T. 2013. Gene-environment interactions in susceptibility to fumonisin-induced neural tube defects. 8th International Conference on Nearal Tube Defects. October 7-10, 2013 Austin, Texas.

Interpretive Summary: Abstract - no summary required.

Technical Abstract: Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. In populations that rely on maize-based foods as a dietary staple, consumption of FB1-contaminated food during early pregnancy is associated with increased risk for neural tube defects (NTDs). Administration of FB1 (20 mg/kg ip, E7.5-E8.5) to pregnant dams of the inbred LM/Bc mouse strain produces exencephaly in 79% of exposed embryos, whereas the same treatment results in <1% exencephaly and a significant increase in resorptions (15%) in the inbred SWV strain, suggesting differences in genetic susceptibility to FB1-NTDs. FB1 inhibits the enzyme ceramide synthase (CerS) in de novo sphingolipid biosynthesis. The predominant isoform of ceramide synthase expressed in neural tissue (CerS1), has an unusual bicistronic transcript containing Gdf1 (growth differentiation factor 1) that is highly conserved in mouse, rat, and human brain (CerS1-Gdf1). Gdf1 is a member of the TGF-Beta superfamily best known for its interaction with Nodal during gastrulation to establish left-right asymmetry. DNA sequencing of the CerS1-Gdf1 gene in LM/Bc and SWV mice identified a unique SNP in the coding region of Gdf1 in each mouse strain, both of which result in amino acid changes likely to impact stability and/or signaling partners of the mature GDF1 protein. The AKR/J mouse strain is the only other commercially available mouse strain with the same Gdf1 SNP as the LM/Bc mouse strain. Administration of FB1 to pregnant AKR/J mice results in exencephaly in exposed offspring, implicating a role for this Gdf1 variant in enhanced susceptibility to FB1-NTDs. FB1 inhibition of ceramide synthase results in increased accumulation of sphinganine and its phosphorylated metabolite sphinganine-1-phosphate (Sa1P). In pregnant LM/Bc mice exposed to FB1, Sa1P is significantly elevated in blood, amniotic fluid, and maternal and embryonic tissues. Sa1P is a bioactive lipid mediator that functions as a ligand for a family of five G protein-coupled ‘S1P’ receptors (sphingosine-1-phosphate receptors). Inactivation of the Gdf1 portion of the CerS1-Gdf1 gene in Gdf1 knockout mice results in increased expression of the remaining part of the transcript (CerS1) in a Gdf1 gene dosage-dependent manner. Conversely, whole mount in situ hybridization (WM-ISH) demonstrates increased expression of Gdf1 in the cranial neural tube of exencephalic E9.5 LM/Bc mouse embryos in response to FB1 inhibition of CerS1, suggesting reciprocal feedback regulation between CerS1 and Gdf1. Lipidomics (LC/MS) analysis of control vs. FB1-treated (40 µM for 24 hr) LM/Bc, SWV, Gdf1 wildtype and Gdf1 knockout mouse embryonic fibroblast (MEF) cells demonstrates a critical role for Gdf1 genotype in regulating CerS1 expression and the amount of nuclear and cytosolic Sa1P that accumulate in response to FB1. Our studies in MEFs further demonstrate that increased accumulation of nuclear Sa1P in response to FB1 is associated with decreased histone deacetylase (HDAC) activity, and post-translational modifications (acetylation and methylation) in core histones. Cell signaling studies in MEFs demonstrate a critical role for Gdf1 in modulating downstream effectors (Smads) of TGF-Beta/Activin/Nodal signaling, and in regulating cytosolic Sa1P accumulation and activation of S1P receptors in response to FB1. The bicistronic CerS1-Gdf1 gene appears to be a novel regulator of the balance between nuclear and cytosolic lipid mediators that integrate epigenetic modifications, gene regulation, and cell signaling pathways involved in neural tube closure. FB1 inhibition of CerS1 in mice and cells with genetic variation in Gdf1 provides unique insight into the gene-environment interactions and perturbations in epigenetic and cell signaling events that confer enhanced susceptibility to FB1-NTDs.