FUMONISINS DISRUPT SHPINGOLIPID 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

Authors: MARASAS, WALTER F. - MRC/TYGERBERG,S.AFRICA; Riley, Ronald; HENDRICKS, KATHERINE - TX DEPT HLTH/AUSTIN,TX; STEVENS, VICTORIA - RES/AM CANCER SOC/ATLANTA; SADLER, THOMAS - CELL BIOL/UNC,CHAPEL HILL; GELINEAU-VAN WAES, JANEE - NEB MED CEN, OMAHA, NE; MISSMER, STACEY - PUB HLTH/HARVARD,BOSTON; CABRERA VALVERDE, JULIO - GENETICS/SAN JUAN DE DIOS; TORRES, OLGA - INCAP, GUATEMALA, GT; GELDERBLOM, WENTZEL C. - MRC,TYGERBERG,S. AFRICA; ALLEGOOD, JEREMY - GA INST TECH., ATLANTA; MARTINEZ DE FIGUEROA, ANA CAROLINA - INCAP, GUATEMALA, GT; MADDOX, JOYCE - NEB MED CEN, OMAHA, NE; MILLER, J. DAVID - CARLETON U., OTT/CANADA; STARR, LOIS - NEB MED CEN,OMAHA, NE; SULLARDS, M. CAMERON - GA INST TECH., ATLANTA; ROMAN TRIGO, ANA VICTORIA - INCAP, GUATEMALA, GT; Voss, Kenneth; WANG, ELAINE - GA INST TECH., ATLANTA; MERRILL, JR., ALFRED - GA INST TECH., ATLANTA

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/2003
Publication Date: 3/1/2004
Citation: Marasas, W.O., Riley, R.T., Hendricks, K.A., Stevens, V.L., Sadler, T.W., Gelineau-Van Waes, J., Missmer, S.A., Cabrera Valverde, J., Torres, O.L., Gelderblom, W.A., Allegood, J., Martinez De Figueroa, A., Maddox, J., Miller, J., Starr, L., Sullards, M., Roman Trigo, A., Voss, K.A., Wang, E., Merrill, Jr., A.H. 2004. Fumonisins disrupt shpingolipid 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. Journal of Nutrition 134:711-716.

Interpretive Summary: Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides, a common mold contaminant of maize. Fumonisins block an enzyme that controls the formation of a group of fats that are needed for the proper function of some proteins, including the folate-binding protein (human folate receptor alpha). Folic acid is a vitamin that is important for embryo development. Deficiencies in folate have been associated with human birth defects known as neural tube defects and defects in the proper development of the head and face (craniofacial defects). Because fumonisins interfere with folic acid metabolism, they can cause neural tube and craniofacial defects in mouse embryos in culture and many of these effects are prevented by giving extra folic acid. Recent studies in one type of mouse have found that fumonisin exposure during pregnancy increases the frequency of neural tube and craniofacial defects and administration of folate or a special fat called a ganglioside is preventive. High incidences of neural tube defects 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 neural tube defects in border counties of Texas has found a significant association between neural tube defects and homemade tortilla consumption, and elevations in a chemical marker that is associated with fumonisin exposure. Therefore it is proposed that fumonisins are potential risk factors for neural tube and craniofacial defects because of their apparent interference with folate utilization, and birth defect prevention programs should consider this additional risk factor.

Technical Abstract: Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly F. 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 alpha). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture and many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice have 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 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 has found a significant association between NTD and homemade tortilla consumption, and elevations in a biomarker for fumonisin exposure. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial abnormalities and other birth defects because of their apparent interference with folate utilization, and birth defect prevention programs should consider this additional risk factor.