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Critical Review

Fumonisins Disrupt Sphingolipid Metabolism, Folate Transport, and Neural Tube Development in Embryo Culture and In Vivo: A Potential Risk Factor for Human Neural Tube Defects among Populations Consuming Fumonisin-Contaminated Maize¹

Walter F. O. Marasas^*,2, Ronald T. Riley, Katherine A. Hendricks^**, Victoria L. Stevens, Thomas W. Sadler, Janee Gelineau-van Waes, Stacey A. Missmer^#, Julio Cabrera, Olga Torres^***, Wentzel C. A. Gelderblom^*, Jeremy Allegood^,****, Carolina Martínez^***, Joyce Maddox, J. David Miller, Lois Starr, M. Cameron Sullards^,****, Ana Victoria Roman^***, Kenneth A. Voss, Elaine Wang^**** and Alfred H. Merrill, Jr.^****,2

^* Medical Research Council, PROMEC Unit, Tygerberg 7505, South Africa; Toxicology and Mycotoxin Research Unit, U.S. Department of Agriculture-ARS, Athens, GA 30605; ^** Division of Infectious Disease Epidemiology and Surveillance, Texas Department of Health, Austin, TX 78756; Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA 30329; Twin Bridges, MT 59754; Center for Human Molecular Genetics, Department of Cell Biology & Anatomy; Munroe-Meyer Institute, Nebraska Medical Center, Omaha, NE 68198; ^# Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115; Genetics Clinic, Department of Pediatrics, Hospital General San Juan de Dios, Guatemala City, Guatemala; ^*** Instituto de Nutricion de Centroamerica y Panama (INCAP/OPS), Guatemala City, Guatemala; School of Chemistry and Biochemistry and ^**** School of Biology, Georgia Institute of Technology, Atlanta, GA 30332; and Department of Chemistry, Carleton University, Ottawa, Ontario K1S 5B6, Canada

²To whom correspondence should be addressed. E-mail: wally.marasas@mrc.ac.za or al.merrill{at}biology.gatech.edu.

Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metabolism (sphinganine and other sphingoid bases and derivatives) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor ). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant association between NTD and consumption of tortillas during the first trimester. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.

KEY WORDS: • fumonisins • neural tube defects • craniofacial abnormalities • sphingolipids • folate

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