Maternal fumonisin exposure and risk for neural tube defects: mechanisms in an in vivo mouse model.
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 FB1 teratogenicity.


METHODS
Pregnant LM/Bc mice were injected with increasing doses of FB1 on GD 7.5 and 8.5, and exposed fetuses were examined for malformations. Sphingolipid profiles and (3)H-folate concentrations were measured in maternal and fetal tissues. Immunohistochemical expression of the GPI-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 (3)H-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.
Gelineau-van Waes
Janee
J
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455. jvanwaes@unmc.edu
Starr
Lois
L
Maddox
Joyce
J
Aleman
Francisco
F
Voss
Kenneth A
KA
Wilberding
Justin
J
Riley
Ronald T
RT
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism / Q000627:therapeutic use; D037341:Fumonisins / Q000633:toxicity*; D005677:G(M1) Ganglioside / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D009183:Mycotoxins / Q000633:toxicity; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000517:prevention & control; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D011956:Receptors, Cell Surface / Q000378:metabolism; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D037341:Fumonisins; D009183:Mycotoxins; D011956:Receptors, Cell Surface; D013107:Sphingolipids; D013723:Teratogens; D005677:G(M1) Ganglioside; C056933:fumonisin B1; D005492:Folic Acid; D013110:Sphingosine; C005682:safingol