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Title: Accumulation of sphingoid bases, the structural sphingoid base analog FTY720 and their phosphorylated metabolites in blood, plasma and decidua of SWV and LMBC mice treated with Fumonisin B1 or FTY720

Author
item Riley, Ronald
item Voss, Kenneth
item MADDOX, JOYCE - UNEB MED CEN, OMAHA, NE
item WILBERDING, JUSTIN - UNEB MED CEN, OMAHA, NE
item GELINEAU-VAN WAES, JANEE - UNEB MED CEN, OMAHA, NE

Submitted to: Toxicological Sciences
Publication Type: Abstract Only
Publication Acceptance Date: 12/7/2007
Publication Date: 3/16/2008
Citation: Riley, R.T., Voss, K.A., Maddox, J.R., Wilberding, J., Gelineau-Van Waes, J.B. 2008. Accumulation of sphingoid bases, the structural sphingoid base analog FTY720 and their phosphorylated metabolites in blood, plasma and decidua of SWV and LMBC mice treated with Fumonisin B1 or FTY720. Toxicological Sciences. March 16-20, 2008. Seattle, Washington.

Interpretive Summary: Abstract - no summary required.

Technical Abstract: Fumonisins (FB) are mycotoxins in maize and inhibitors of ceramide synthase (CS). FB1 has been shown to cause neural tube defects (NTD) in mice with the LMBc strain being more sensitive than the SWV or other strains. FTY720 (FTY) is a sphingoid base analog derivative of myriocin, another fungal metabolite. FTY is currently in human clinical trials as a prototype immunosuppressant drug, and our results show that it also causes NTD in mice. Phosphorylated sphingoid bases and phosphorylated FTY (FTY 1-P) are ligands for the lysophospholipid receptors known as S1P receptors (S1P 1-5). We have shown that sphinganine (Sa) and Sa 1-phosphate (Sa 1-P) are significantly elevated in fetal liver of LMBc mice consuming FB in the diet. The role of elevated S1P receptor agonists in NTD development is however unknown. The present study was undertaken to see if Sa 1-P and FTY 1-P were elevated in blood, plasma and other tissues of SWV and LMBc mice treated with FB (ip injection) or FTY (gavage). The results show that in FB treated mice the levels of sphingoid bases and sphingoid base 1-phosphates are significantly elevated in blood, plasma and decidua. In the blood and plasma of FB treated mice the amount of Sa and Sa-1P was significantly greater in the LMBc mice as was the NTD incidence compared to the SWV mice. In the FTY treated animals FTY 1-P was significantly elevated in plasma and decidua in both strains although the levels in LMBc mice were greater than in the SWV as was the incidence of NTD. Similarly, following FB treatment the incidence of NTD after exposure to FTY was greater in the LMBc mice. The results suggest that elevation in S1P receptor agonists may play a mechanistic role in NTD development in mice.