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Title: Placental and neural tube defects after maternal fumonisin or FRY720 exposure

Author
item GELINEAU-VAN WAES, J - U.NEBRASKA MED CEN, OMAHA
item MADDOX, J - U.NEBRASKA MED CEN, OMAHA
item WILBERDING, J - U.NEBRASKA MED CEN, OMAHA
item Voss, Kenneth
item Riley, Ronald

Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 12/15/2008
Publication Date: 3/15/2009
Citation: Gelineau-Van Waes, J., Maddox, J., Wilberding, J., Voss, K.A., Riley, R.T. 2009. Placental and neural tube defects after maternal fumonisin or FRY720 exposure. Toxicological Sciences 108:132.

Interpretive Summary: Abstract - no summary required

Technical Abstract: Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of maize. Increased neural tube defect (NTD) risk is observed in human populations that rely heavily on maize as a dietary staple. FB1 inhibition of ceramide synthase results in elevated sphingoid bases. FTY720 is a sphingoid base analog currently in Phase III human clinical trials. Phosphorylated FTY720 acts as an immunosuppressant by modulating S1P receptor-mediated pathways involved in lymphocyte chemotaxis. FB1 (20mg/kg/day ip, E7.5-8.5) or FTY720 (10mg/kg/day po, E6.5-8.5) were administered to pregnant SWV and LM/Bc mice. Maternal plasma and whole blood were collected on E10.5, embryonic phenotype was recorded, and placental/embryonic tissues were collected for histology, or LC-ESI-MS analysis of sphingoid base 1-phosphates. Trophoblast cells were labeled with cytokeratin, and uterine natural killer (uNK) cells were identified with DBA lectin. Strain and/or treatment-specific differences in sphingolipid gene expression were analyzed by qRT-PCR. Maternal FB1 or FTY720 resulted in elevation of bioactive sphinganine-1-P or FTY720-1-P in maternal blood and placental tissue, and increased NTDs and/or resorptions. Sphingosine kinase gene expression was significantly elevated in placental tissue from treated dams. Placentas from exencephalic embryos had a shallow ectoplacental cone, fewer uNK at the implant site, proliferative and invasive giant trophoblast cells, and a disorganized vascular labyrinth. Maternal FB1 or FTY720 exposure results in accumulation of bioactive sphingoid base-1-P in maternal and fetal tissue, altered migration of uNK cells, abnormal formation of the placenta, and increased risk for NTDs. Sa-1-P and FTY720-1-P act as agonists or functional antagonists on G protein-coupled S1P receptors. Elevated levels of Sa-1-P or FTY720-1-P may therefore alter S1P-receptor-mediated signaling pathways involved in uNK migration, placental formation, and neural tube closure.