Maternal fumonisin exposure and risk for neural tube defects

Mechanisms in an in vivo mouse model

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

Research output: Contribution to journalArticle

120 Citations (Scopus)

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 1 2005

Fingerprint

Fumonisins
Maternal Exposure
Neural Tube Defects
Folic Acid
Mothers
Sphingolipids
Zea mays
Fetus
G(M1) Ganglioside
Pregnancy
Glycosphingolipids
Mycotoxins
Gangliosides
Fusarium
fumonisin B1
Fungi
Eating
Body Weight
Phenotype
Lipids

Keywords

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

ASJC Scopus subject areas

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

Cite this

Maternal fumonisin exposure and risk for neural tube defects : Mechanisms in an in vivo mouse model. / Gelineau-Van Waes, Janee; Starr, Lois J; Maddox, Joyce; Aleman, Francisco; Voss, Kenneth A.; Wilberding, Justin; Riley, Ronald T.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 73, No. 7, 01.07.2005, p. 487-497.

Research output: Contribution to journalArticle

Gelineau-Van Waes, Janee ; Starr, Lois J ; Maddox, Joyce ; Aleman, Francisco ; Voss, Kenneth A. ; Wilberding, Justin ; Riley, Ronald T. / Maternal fumonisin exposure and risk for neural tube defects : Mechanisms in an in vivo mouse model. In: Birth Defects Research Part A - Clinical and Molecular Teratology. 2005 ; Vol. 73, No. 7. pp. 487-497.
@article{16a5a70db786416a8d26dbd3bf6e4596,
title = "Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model",
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.",
keywords = "Folate, Fumonisin, Ganglioside GM1, Lipid raft, Neural tube defects, Sphingolipids",
author = "{Gelineau-Van Waes}, Janee and Starr, {Lois J} and Joyce Maddox and Francisco Aleman and Voss, {Kenneth A.} and Justin Wilberding and Riley, {Ronald T.}",
year = "2005",
month = "7",
day = "1",
doi = "10.1002/bdra.20148",
language = "English (US)",
volume = "73",
pages = "487--497",
journal = "Teratology",
issn = "1542-0752",
publisher = "Wiley-Liss Inc.",
number = "7",

}

TY - JOUR

T1 - Maternal fumonisin exposure and risk for neural tube defects

T2 - Mechanisms in an in vivo mouse model

AU - Gelineau-Van Waes, Janee

AU - Starr, Lois J

AU - Maddox, Joyce

AU - Aleman, Francisco

AU - Voss, Kenneth A.

AU - Wilberding, Justin

AU - Riley, Ronald T.

PY - 2005/7/1

Y1 - 2005/7/1

N2 - 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.

AB - 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.

KW - Folate

KW - Fumonisin

KW - Ganglioside GM1

KW - Lipid raft

KW - Neural tube defects

KW - Sphingolipids

UR - http://www.scopus.com/inward/record.url?scp=22944452718&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=22944452718&partnerID=8YFLogxK

U2 - 10.1002/bdra.20148

DO - 10.1002/bdra.20148

M3 - Article

VL - 73

SP - 487

EP - 497

JO - Teratology

JF - Teratology

SN - 1542-0752

IS - 7

ER -