|Voss, Kenneth - Ken|
|Gelineau-van Waes, J|
Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 1/15/2003
Publication Date: 3/1/2003
Citation: STARR, L., RILEY, R.T., VOSS, K.A., MADDOX, J., BENNETT, G., GELINEAU-VAN WAES, J. 2003. FUMONISIN B1-INDUCED NEURAL TUBE DEFECTS: DISRUPTION OF MEMBRANE SPHINGOLIPIDS AND FOLATE TRANSPORT. TOXICOLOGIST. v.77. p.10. Interpretive Summary: Abstract only
Technical Abstract: Fumonisin B1 (FB1), a mycotoxin produced by F. verticilliodes, is a common contaminant of corn involved in the etiology of various diseases in different species. FB1 disrupts sphingolipid biosynthesis by inhibiting the enzyme ceramide synthase, and has recently been implicated as a potential teratogen. Using a murine model, the current studies investigated maternal FB1 exposure, sphingolipid depletion, and subsequent disruption of folate transport systems in the induction of neural tube defects (NTDs). FB1 exposure during early gestation caused an increase in apoptosis in the dorsal neuroepithelium and subsequent NTDs (exencephaly) in inbred LMBc mice. The timing of maternal FB1 exposure was critical, and the number of affected pups/litter increased in a dose-dependent manner. The ability of FB1 to cross the placenta was demonstrated by injecting pregnant dams with 14C-labeled FB1 and measuring radioactive uptake in embryos and maternal tissues. In addition, sphinganine levels were shown by HPLC analysis to be significantly elevated in both embryos and placentas following FB1 exposure. Maternal folinic acid supplementation by daily oral gavage reduced the incidence of FB1-induced NTDs by approximately 50%. However, co-administration of ganglioside GM1 during FB1 exposure was able to almost completely rescue the phenotype (95%). The impact of FB1 on folate transport was investigated in vivo by measuring 3H-folate uptake in control and FB1 embryos. 3H-folate uptake was significantly inhibited by FB1 exposure, but partially reversed by GM1 co-administration. Immunohistochemical staining for both the folate receptor and GM1 was decreased following FB1 exposure. Since GM1 is co-localized with the GPI-anchored folate receptor in "lipid rafts", it is proposed that GM1 is an important component of the membrane microdomain necessary for proper folate receptor function, and adequate uptake of folate during development to protect against NTDs.