Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model

Janee Gelineau-Van Waes, Lois Starr, Joyce Maddox, Francisco Aleman, Kenneth A. Voss, Justin Wilberding, Ronald T. Riley

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

BACKGROUND: Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, a common contaminant of corn worldwide. FB1 disrupts sphingolipid biosynthesis by inhibiting the enzyme ceramide synthase, resulting in an elevation of free sphingoid bases and depletion of downstream glycosphingolipids. A relationship between maternal ingestion of FB1-contaminated corn during early pregnancy and increased risk for neural tube defects (NTDs) has recently been proposed in human populations around the world where corn is a dietary staple. The current studies provide an in vivo mouse model of FBI teratogenicity. METHODS: Pregnant LM/Bc mice were injected with increasing doses of FBI on GD 7.5 and 8.5, and exposed fetuses were examined for malformations. Sphingolipid profiles and 3H-folate concentrations were measured in maternal and fetal tissues. Immunohistochemical expression of the GP1-anchored folate receptor (Folbp1) and its association with the lipid raft component, ganglioside GM1, were characterized. Rescue experiments were performed with maternal folate supplementation or administration of gangliosides. RESULTS: Maternal FB1 administration (20 mg/kg of body weight) during early gestation resulted in 79% NTDs in exposed fetuses. Sphingolipid profiles were significantly altered in maternal and embryonic tissues following exposure, and 3H-folate levels and immunohistochemical expression of Folbp1 were reduced. Maternal folate supplementation partially rescued the NTD phenotype, whereas GM1 significantly restored folate concentrations and afforded almost complete protection against FB1-induced NTDs. CONCLUSIONS: Maternal FB1 exposure altered sphingolipid metabolism and folate concentrations in LM/Bc mice, resulting in a dose-dependent increase in NTDs that could be prevented when adequate folate levels were maintained.

Original languageEnglish (US)
Pages (from-to)487-497
Number of pages11
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume73
Issue number7
DOIs
StatePublished - Jul 2005

Keywords

  • Folate
  • Fumonisin
  • Ganglioside GM1
  • Lipid raft
  • Neural tube defects
  • Sphingolipids

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Developmental Biology

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