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 3H-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 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.

Journal Reference:
Gelineau-van Waes, J., Starr, L., Maddox, J., Aleman, F., Voss, K. A., Wilberding, J. and Riley, R. T. (2005), Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model. Birth Defects Research Part A: Clinical and Molecular Teratology, 73: 487–497. doi: 10.1002/bdra.20148



Study Looks At Suspected Link Between Corn Mycotoxin And Birth Defects


A Creighton University School of Medicine researcher has been awarded a $2.7 million grant by the National Institutes of Health (NIH) to investigate a possible link between the ingestion of tortillas and corn-based food products contaminated with a fungal toxin and increased risk for birth defects.

The three-year award is a collaborative effort among investigators at Creighton, the U.S. Department of Agriculture-Agricultural Research Service (USDA-ARS) in Athens, Georgia; Duke University Medical Center in Durham, N.C., and Centro de Investigaciones en Nutricion y Salud (CIENSA) in Guatemala.

Janee Gelineau-van Waes, D.V.M., Ph.D., principal investigator and associate professor in Creighton's Department of Pharmacology, will use the grant to continue her research studying a potential connection between exposure to fumonisin during early pregnancy and an increased risk for having a baby with a neural tube defect (NTD).

NTDs are one of the most common congenital malformations (one per 1,000 births) and include defects such as anencephaly and spina bifida. NTDs occur when the embryonic neural tube, which forms the brain and spinal cord, fails to close properly during the first few weeks of pregnancy.

Fumonisin is a mycotoxin produced by a common fungal contaminant of corn worldwide.

In animals, the toxin disrupts sphingolipid metabolism, causing diseases such as leukoencephalomalacia in horses, pulmonary edema in pigs and cancer in laboratory rodents. In humans, ingestion of fumonisin-contaminated corn is associated with increased risk for esophageal cancer and having a baby with a NTD.

An unusually high incidence of NTDs (six to 10 cases per 1,000 births) has been observed in regions of Guatemala, China, and South Africa where corn is a dietary staple and fumonisin contamination is frequent.

Gelineau-van Waes and USDA scientists have shown that early gestational exposure to the toxin disrupts sphingolipid metabolism and induces NTDs in mice.

In the new study, preliminary data obtained from mice will be used to validate biomarkers of exposure in blood and urine samples collected from women in Guatemala. The human samples, collected by CIENSA scientists, will be analyzed by the USDA-ARS Mycotoxin Research Unit.

Creighton researchers will use mouse models to investigate underlying signaling mechanisms that result in failure of neural tube closure after fumonisin exposure, and collaborative studies with Duke University will focus on identifying genetic mutations that increase susceptibility.

Gelineau-van Waes' research program is supported by the Nebraska Tobacco Settlement Biomedical Research Program (LB-692). Her current NIH grant was awarded under the American Recovery and Reinvestment Act of 2009, in response to the NIH Director's Opportunity for Research on Global Health.

Background on fumonisin:

-- Fumonisin contamination of corn is periodically a problem in the U.S. In 1990, a cluster of babies born with NTDs was reported among Hispanic women living along the south Texas border. The incident occurred a year after very high levels of fumonisin were reported in the corn crop used to make tortillas, prompting scientists at the Texas Department of Health to suspect a possible connection.

-- In 2001, the U.S. Food and Drug Administration (FDA) established industry guidelines containing recommended maximum levels for fumonisin in corn used to prepare human and animal foods. However, the FDA guidelines do not contain enforceable regulatory limits.

-- In 2002, the World Health Organization (WHO) released provisional maximum tolerable daily intake (PMTDI) for fumonisins and suggested that further research was needed to examine the potential for this compound to cause birth defects.

-- In areas where corn is consumed in large quantities, such as Mexico and Guatemala, a significant percentage of the population exceeds (by more than 20 times) the WHO daily intake limit for fumonisin. In the U.S., a recent analysis of corn tortilla and masa flour samples from various retail sources in southern California indicates that fumonisin contamination of corn-based foods is common, and, depending on the amount an individual consumes, it is possible to exceed the WHO recommended daily limit.

Source: Creighton University