QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marasas, W. F. O. Articles by Merrill, A. H. Search for Related Content PubMed PubMed Citation Articles by Marasas, W. F. O. Articles by Merrill, A. H., Jr.

---

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.

	ABSTRACT

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

 
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

Fumonisins are a family of mycotoxins that were first isolated in South Africa in 1988 from cultures of Fusarium verticillioides (formerly Fusarium moniliforme) strain MRC 826 (1), followed soon thereafter by elucidation of the structures of the prevalent isoforms fumonisin B₁ (FB₁)³ and B₂ (FB₂) (2). Leukoencephalomalacia in horses and pulmonary edema syndrome in pigs (3) were shown to result from administration of FB₁ (4,5), and field outbreaks were associated with fumonisin contamination (6) when analytical methods were developed (7). Fumonisins were also implicated in esophageal cancer when they were found in home-grown maize in a high-incidence area of the Transkei region of South Africa (8). FB₁ has been demonstrated to cause liver and kidney cancer in rats and mice (9,10), with differences in species and sex (10), and the International Agency for Research on Cancer evaluated FB₁ as a Group 2B carcinogen, i.e., possibly carcinogenic to humans (11). In 2002 the Joint FAO/WHO Expert Committee on Food Additives allocated a group provisional maximum tolerable daily intake of 2 µg/kg body weight to FB₁, FB_2, and FB₃, alone or in combination (12).

In addition to the known toxicity and carcinogenicity of fumonisins, evidence has begun to surface that these mycotoxins can also be teratogenic, at least in part through interference with the utilization of folic acid, a dietary supplement used to reduce the incidence of neural tube defects (NTD).⁴ The current knowledge about fumonisins as possible risk factors for birth defects was recently collated at the "Workshop on the Role of Fumonisins in Neural Tube Defects" in Atlanta, Georgia, on January 21, 2003, and this information is summarized in this review.

	Disruption of sphingolipid metabolism

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

 
The mechanism(s) of action of fumonisins appears to involve disruption of sphingolipid biosynthesis by the inhibition of ceramide synthase (13–15), modification of cellular proliferation through changes in cell cycle regulators (16–19), and increased expression of cytokines such as TNF (19–21). Fumonisins inhibit ceramide synthase because they have structural features that resemble the cosubstrates (sphingoid bases and fatty acyl-CoA’s) (14,22), and inhibition has been characterized in vitro as well as in numerous cell lines, animals, plants, and fungi (14,15). Sphinganine accumulates rapidly in vivo and provides a biomarker for fumonisin exposure that has been validated in cells in culture, tissues, serum, and urine (23–25). Depending on the system studied, other metabolites are also elevated (sphingosine, sphinganine 1-phosphate, and N-acetyl-sphinganine and -sphingosine) (26) and significant depletion of complex sphingolipids (ceramide, sphingomyelin, and glycosphingolipids) can occur (13–15).

Because sphingolipids are involved in diverse aspects of cell regulation, disruption of sphingolipid metabolism may underlie many of the aforementioned mechanisms for the toxicity and carcinogenicity of fumonisins. Free sphingoid bases are growth inhibitory and cytotoxic (27) for cells in culture and blockage of sphinganine accumulation reduces the toxicity of FB₁ (28). Sphinganine accumulation in vivo is closely related to liver and kidney toxicity (14,29–32), with increases in free sphinganine usually occurring at or below the fumonisin dosages that cause liver or kidney lesions in rats (32), rabbits (33), mice (34), horses (23), pigs (24), and many other species (15,35) as well as nonneoplastic and neoplastic kidney lesions in Fischer-344/N Nctr BR rats (10). The appearance of free sphinganine in urine is most likely a result of a loss of cell anchorage and detachment into the kidney tubule lumen (36) because most free sphinganine is recovered in dead cells (31). The elevation in urinary sphinganine is reversible and subsides soon after the complete removal of fumonisins (although a supposedly subtoxic dose will maintain elevated sphinganine in rats and mice following exposure to a higher dose) (14,37,38). Extrapolation of these findings to humans is difficult, but disruption of sphingolipid metabolism has been associated with liver and kidney toxicity in nonhuman primates exposed to fumonisins (39). A recent study in China found that the free sphinganine to free sphingosine ratio was significantly greater in urine of males from households where the estimated daily FB₁ intake was >110 µg/kg body weight per day (40).

	Inhibition of folate transport

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

 
In the early 1990s, following investigation of an NTD cluster that occurred among Mexican-American women in Cameron County, Texas, Kate Hendricks from the Texas Department of Health began questioning researchers about the possibility that exposure to fumonisin-contaminated food (tortillas) during gestation may have contributed to these birth defects [reviewed in (41)]. NTD are common congenital malformations that occur when the embryonic neural tube, which ultimately forms the brain and spinal cord, fails to properly close during the first few weeks of development. NTD are among the most common of all human birth defects, yet their etiologic basis and embryology remain poorly understood. Empirical risk figures, along with numerous clinical studies, indicate that NTD are of a multifactorial origin, having both genetic and environmental components (41–47). Epidemiological studies indicate that periconceptional vitamin supplements containing folic acid can significantly reduce (50–70%) a woman’s risk for an NTD affected pregnancy (48,49), and data from clinical trials support the hypothesis that this apparent reduction in risk may be specifically attributable to folic acid (50,51), although the mechanisms underlying the protective effects of folic acid are not fully understood.

A potential link among fumonisins, folate deficiency, and increased risk for NTD seemed plausible based on the research findings of Stevens and Tang and colleagues (52,53), who demonstrated that receptor-mediated folate uptake was reduced by up to 50% in Caco-2 cells pretreated with fumonisin. The placental, high-affinity folate transporter [folate binding protein 1, Folbp1(murine); folate receptor (human)] is a glycosylphosphatidylinositol (GPI)-anchored protein (54) associated with membrane microdomains (rafts) enriched in cholesterol and sphingolipids (55), which was previously shown to be critical for early embryonic development (56). Fumonisin affects the transporter by altering both its endocytic trafficking (53) and the amount of the receptor that is available for transport (Smith, E. R. and Stevens, V. L., unpublished data). These findings provided a conceptual framework (Fig. 1) whereby exposure to FB₁ might be a risk factor for NTD by disrupting folate utilization via depletion of cellular sphingolipids needed for normal receptor function.

View larger version (29K): [in this window] [in a new window]   FIGURE 1 Disruption of sphingolipid metabolism and folate transport by fumonisins. The scheme shows the step where fumonisins inhibit sphingolipid biosynthesis (the acylation of sphinganine by ceramide synthase in the endoplasmic reticulum), thereby reducing the formation of sphingomyelin, which is a major component of the plasma membrane and is required for the proper function of GPI-anchored proteins, such as the folate transporter.

	Induction of developmental abnormalities in mouse models for neural tube defects

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

Such an interaction was uncovered by studies (62) with early somite neurulating mouse embryos prepared for whole embryo culture on d 9 of gestation, which showed that FB₁ affects overall growth and causes cranial neural tube defects (Fig. 2A, top) in a dose-dependent manner, and supplementing the medium with folate ameliorated these effects (Fig. 2B, bottom). The protection by folate is unlikely to be due to interference with the uptake of FB₁ because sphinganine was elevated in all FB₁-exposed embryos, irrespective of folate concentration. Therefore, fumonisins are able to inhibit embryonic sphingolipid metabolism and this appears to interfere with folate utilization to produce embryotoxicity and neural tube defects.

View larger version (108K): [in this window] [in a new window]   FIGURE 2 Effects of fumonisin B1 (FB1) in mouse embryonic development. A: Embryos after 24 h in culture medium containing none (right) or 50 µmol/L FB1 (left); B: Embryos after 24 h in medium containing 50 µmol/L FB1 (top) or 50 µmol/L FB1 plus 1 µmol/L folinic acid (bottom) (panel B is reproduced from Fig. 3 of Ref. 62). C: Fetus from pregnant LMBc dam injected i.p. with 20 mg/kg body weight FB1 on gestational d 7.5 and 8.5 and killed on d 17.5 (top) versus normal fetus at this gestational age (bottom).

	Incidence of neural tube defects in countries with consumption of fumonisin-contaminated maize

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

 
If fumonisin consumption is a risk factor for NTD in humans, this association might be most evident among populations that consume the highest amounts of maize, such as those of Central and South America and portions of southern Africa and Asia. For example, adults in Guatemala regularly consume several hundred grams of maize daily in the form of tortillas. In 1995 a survey of tortilla consumption and fumonisin amounts was conducted in households in Santa Maria de Jesus (Sacatepequez) and Patzicia (Chimaltenango), which are typical rural Kaqchikel-speaking Mayan communities of Guatemala, located in the Central Highlands (72). Tortillas and nixtamal, the base-treated corn flour that is used to prepare masa for tortillas, was obtained from 50 households in each town and analyzed for the major fumonisin species, FB₁ and AP₁. The latter is produced when the tricarballylic acids of FB₁ are base hydrolyzed and also inhibits ceramide synthase (73), although AP₁ is less toxic than FB₁ (32,74,75). The average fumonisin content (FB₁ + AP₁) of tortillas from Santa Maria de Jesus was 27 µg/g dry weight versus 8 µg/g from Patzicia.⁵ A high percentage (66%) of the tortillas from Santa Maria de Jesus (and over one third from Patzicia) contained 10 µg FB₁ + AP₁/g dry weight. Follow-up studies found that fumonisin contamination is highly variable: for the years 2000 to 2002, only 6 to 8% of the maize samples had >3.7 µg of total fumonisins/g dry weight (Torres, O. R. and Riley, R. T., unpublished data). Fumonisins were also reported in Mexican tortillas (76).

Little is known about the incidence of NTD in rural areas of Guatemala; however, a recent retrospective study of the prevalence of children born with NTD (77) reviewed clinical files of live newborns in national and regional hospitals of different departments of Guatemala (Geographical and Administrative Divisions of the country) with the following inclusion criterion: living newborns of either gender presenting with neural tube defects during the year 2000. Some regions have strikingly high frequencies (compared to that for the general U.S. population of 3/10,000 live births), such as 106 NTD/10,000 live births in Quetzaltenango, which has a mostly indigenous population that consumes high amounts of maize as their staple food (Fig. 3). The most frequent defect was myelomeningocele.

View larger version (21K): [in this window] [in a new window]   FIGURE 3 Incidence of neural tube defects (NTD per 10,000 live births) in different regions of Guatemala, South Africa, and China. Mean incidence and range in incidence of various locations within the regions or countries are shown; the bar for Limpopo represents one data point. Incidence rates for the United States are similar to those for urban areas in South Africa (41).

	Neural tube defects along the Texas-Mexico border

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

 
Elevated NTD rates have been noted along the Texas-Mexico border (ranging from 27/10,000 live births in 1990–1991 to 15/10,000 live births in a usual year) (41). It is not clear why the NTD rate along the border is 3 to 5 times that observed elsewhere in the United States (41). A number of possibilities have been evaluated in a recent study (Missmer, S. A., Suarez, L., Felkner, M., Wang, E., Merrill, A. H., Rothman, K. J., and Hendricks, K. A., unpublished data) from March 1995 through May 2000, in which 184 Mexican-American women with NTD-affected pregnancies and 225 women with healthy live births were identified from residents delivering or terminating pregnancies in hospitals or birthing centers in any of the 14 Texas-Mexico border counties. Case and control women were interviewed in person about medical, occupational, environmental, and dietary exposures during the periconceptional period and maternal blood samples were collected. In addition, locally made tortillas were collected throughout the region.

After adjusting for body mass index, date of conception, and serum vitamin B-12, intermediate intake of homemade tortillas during the first trimester (301 to 400 tortillas, compared to low, 100) was associated with increased odds of an NTD-affected pregnancy (odds ratio, OR = 2.4; 95% CI = 1.1–5.3) and the association was higher (OR = 2.9, CI = 1.4–5.9) for consumption of any homemade tortillas compared to store purchased tortillas. Although the odds ratio was slightly increased (OR = 1.6, 95% CI = 0.5–5.1) for women with a biomarker for fumonisin exposure (the serum sphinganine:sphingosine ratio, Sa:So), 0.31–0.35 compared to those with Sa:So < 0.10, the confidence interval included 1. Paradoxically, the highest Sa:So ratios (>0.35) were not associated with increased NTD (OR = 0.3, 95% CI = 0.1–1.2). A similar bell-shape relation was observed for self-reported absolute number of tortillas eaten during the first trimester of pregnancy and for absolute micrograms per kilogram of woman’s weight per day of fumonisin exposure as estimated from the local tortilla samples. The observed bell-shape relation may reflect an increased prevalence of NTD at intermediate levels of exposure and an increase in fetal death at higher levels of exposure. Further analyses in humans are necessary to determine temporal associations and possible teratogenic thresholds.

The higher association with homemade tortillas is intriguing. The majority of FB₁ (up to 80%) is removed during nixtamalization and the commercial manufacture of fried tortilla chips (87,88), but less is known about the fate of fumonisins in homemade tortillas. A study of some of the smaller facilities in Cameron County, Texas, found that the methods used were similar to those in commercial production (88) but varied in process details, such as the use of lower calcium hydroxide in some recipes (De La Campa, R., Miller, J. D. and Hendricks, K., unpublished data).

	Summary

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

 
In summary, we suggest that fumonisin consumption is a risk factor for human neural tube defects (and related birth defects such as craniofacial abnormalities), especially when there are other risk factors such as genetic susceptibility or limited availability of dietary folate. This hypothesis is based on current knowledge regarding the mechanism(s) of action of fumonisins as inhibitors of sphingolipid biosynthesis (and thereby of folate transport), recent reports that fumonisins induce developmental abnormalities in mouse embryos in culture and LMBc mice in utero, and the incidence of NTD in regions of the world where substantial consumption of maize and fumonisins has been documented or plausibly suggested. It would be prudent to monitor this possibility.

	ACKNOWLEDGMENTS

 
The authors are grateful to the numerous colleagues who have helped with the work described in this review and to Kate Merrill for help in preparing the manuscript.

	FOOTNOTES

 
¹ Supported in part by the March of Dimes, the Nebraska Research Initiative, the South African Medical Research Council (PROMEC), the U.S. Department of Agriculture, the U.S. National Institutes of Health (GM46368), and the Centers for Disease Control (U85/CCU608761–05 and U50/CCU613232). Support for the workshop on "Fumonisins in Neural Tube Defects" held at Georgia Tech on January 28, 2003, was from the endowment for the Smithgall Institute Chair in Molecular Cell Biology and the U.S. Centers for Disease Control and Prevention.

³ Abbreviations used: AP₁, aminopentol or hydrolyzed fumonisin B₁; FB₁, fumonisin B₁; FB₂, fumonisin B₂; FB₃, fumonisin B₃; NTD, neural tube defects; OR, odds ratio.

⁴ NTD are common congenital malformations that occur when the embryonic neural tube, which ultimately forms the brain and spinal cord, fails to close properly during the first few weeks of development. Anencephaly results from failed closure of the anterior neural tube, with absence of the bones of the cranial vault and absent or rudimentary cerebral and cerebellar hemispheres and brainstem; spina bifida refers to incomplete development and fusion of one or more vertebral arches with associated involvement of the posterior neural tube. NTD are among the most common of all human birth defects, yet their etiologic basis and embryology remain poorly understood. Maternal dietary folate deficiency is a risk factor for neural tube defects (46); however, there is also a strong genetic susceptibility component, and other environmental factors have been suspected to exist.

⁵ For comparison, if a 55 kg woman consumes 200 g of tortillas at 27 µg of fumonisins/g, this is equivalent to ca 100 µg of fumonisins/kg body weight.

Manuscript received 17 December 2003. Initial review completed 28 December 2003. Revision accepted 28 December 2003.

	LITERATURE CITED

TOP ABSTRACT Disruption of sphingolipid... Inhibition of folate transport Induction of developmental... Incidence of neural tube... Neural tube defects along... Summary LITERATURE CITED

 

1. Gelderblom, W.C.A., Jaskiewicz, K., Marasas, W.F.O., Thiel, P. G., Horak, M. J., Vleggaar, R. & Kriek, N.P.J. (1988) Fumonisins—novel mycotoxins with cancer promoting activity produced by Fusarium moniliforme. Appl. Environ. Microbiol. 54:1806-1811.[Abstract/Free Full Text]

2. Bezuidenhout, S. C., Gelderblom, W.C.A., Gorst-Allman, C. P., Horak, R. M., Marasas, W.F.O., Spiteller, G. & Vleggaar, R. (1988) Structure elucidation of the fumonisins, mycotoxins from Fusarium moniliforme. J. Chem. Soc. Chem. Commun. 1988:743-745.

3. Ross, P. F., Nelson, P. E., Richard, J. L., Osweiler, G. D., Rice, L. G., Plattner, R. D. & Wilson, T. M. (1990) Production of fumonisins by Fusarium moniliforme and Fusarium proliferatum isolates associated with equine leukoencephalomalacia and pulmonary edema syndrome in swine. Appl. Environ. Microbiol. 56:3225-3226.[Abstract/Free Full Text]

4. Kellerman, T. S., Marasas, W.F.O., Thiel, P. G., Gelderblom, W.C.A., Cawood, M. & Coetzer, J.A.W. (1990) Leukoencephalomalacia in two horses induced by oral dosing of fumonisin B₁. Onderstepoort. J. Vet. Res. 57:269-275.[Medline]

5. Harrison, L. R., Colvin, B. M., Green, J. T., Newman, L. E. & Cole, J. R. (1990) Pulmonary edema and hydrothorax in swine produced by fumonisin B₁, a toxic metabolite of Fusarium moniliforme. J. Vet. Diagn. Invest. 2:217-221.[Abstract/Free Full Text]

6. Plattner, R. D., Norred, W. P., Bacon, C. W., Voss, K. A., Peterson, R., Shackelford, D. D. & Weisleder, D. (1990) A method of detection of fumonisin in corn samples associated with field cases of equine leukoencephalomalacia. Mycologia 82:698-702.

7. Shephard, G. S., Sydenham, E. W., Thiel, P. G. & Gelderblom, W.C.A. (1990) Quantitative determination of fumonisins B₁ and B₂ by high-performance liquid chromatography with fluorescence detection. J. Liq. Chromatogr. 13:2077-2087.

8. Sydenham, E. W., Thiel, P. G., Marasas, W.F.O., Shephard, G. S., Van Schalkwyk, D. J. & Koch, K. R. (1990) Natural occurrence of some Fusarium mycotoxins in corn from low and high esophageal cancer prevalence areas of the Transkei, southern Africa. J. Agric. Food Chem. 38:1900-1903.

9. Gelderblom, W.C.A., Kriek, N.P.J., Marasas, W.F.O. & Thiel, P. G. (1991) Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B₁, in rats. Carcinogenesis 12:1247-1251.[Abstract/Free Full Text]

10. National Toxicology Program Technical Report (2002) Toxicology and Carcinogenesis Studies of Fumonisin B1 in F344/N rats and B6C3F1 mice 2002:99-3955 NIH Washington, DC. Publication no.

11. International Agency for Research on Cancer Fumonisin B₁ () IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Traditional Medicines, Some Mycotoxins, Naphthalene and Styrene. IARC 82:301-366.

12. World Health Organization (2002) Evaluation of Certain Mycotoxins in Food. Fifty-sixth Report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Technical Report 906:16-27.

13. Wang, E., Norred, W. P., Bacon, C. W., Riley, R. T. & Merrill, A. H., Jr. (1991) Inhibition of sphingolipid biosynthesis by fumonisins: implications for diseases associated with Fusarium moniliforme. J. Biol. Chem. 266:14486-14490.[Abstract/Free Full Text]

14. Merrill, A. H., Jr., Sullards, M. C., Wang, E., Voss, K. A. & Riley, R. T. (2001) Sphingolipid metabolism:roles in signal transduction and disruption by fumonisins. Environ. Health Perspect. 109:283-289.

15. Riley, R. T., Enongene, E., Voss, K. A., Norred, W. P., Meredith, F. I., Sharma, R. P., Spitsbergen, J., Williams, D. E., Carlson, D. B. & Merrill, A. H., Jr. (2001) Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environ. Health Perspect. 109:301-308.

16. Ramljak, D., Calvert, R. J., Wiesenfeld, P. W., Diwan, B. A., Catipovic, B., Marasas, W. F., Victor, T. C., Anderson, L. M. & Gelderblom, W. C. (2000) A potential mechanism for fumonisin B₁-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3beta activity. Carcinogenesis 21:1537-1546.[Abstract/Free Full Text]

17. Gelderblom, W. C., Galendo, D., Abel, S., Swanevelder, S., Marasas, W. F. & Wild, C. P. (2001) Cancer initiation by fumonisin B₁ in rat liver—role of cell proliferation. Cancer Lett. 169:127-137.[Medline]

18. Jones, C., Ciacci-Zanella, J. R., Zhang, Y., Henderson, G. & Dickman, M. (2001) Analysis of fumonisin B₁-induced apoptosis. Environ. Health Perspect. 109(Suppl. 2):315-320.

19. Bhandari, N. & Sharma, R. P. (2002) Modulation of selected cell signaling genes in mouse liver by fumonisin B₁. Chem. Biol. Interact. 139:317-331.[Medline]

20. Dugyala, R. R., Sharma, R. P., Tsunoda, M. & Riley, R. T. (1998) Tumor necrosis factor-alpha as a contributor in fumonisin B₁ toxicity. J. Pharmacol. Exp. Ther. 285:317-324.[Abstract/Free Full Text]

21. Voss, K. A., Howard, P. C., Riley, R. T., Sharma, R. P., Bucci, T. J. & Lorentzen, R. J. (2002) Carcinogenicity and mechanism of action of fumonisin B₁: a mycotoxin produced by Fusarium moniliforme (= F. verticillioides). Cancer Detect. Prev. 26:1-9.[Medline]

22. Merrill, A. H., Jr. (2002) De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J. Biol. Chem. 277:25843-25846.[Free Full Text]

23. Wang, E., Ross, P. F., Wilson, T. M., Riley, R. T. & Merrill, A. H., Jr. (1992) Increases in serum sphingosine and sphinganine and decreases in complex sphingolipids in ponies given feed containing fumonisins, mycotoxins produced by Fusarium moniliforme. J. Nutr. 122:1706-1716.

24. Riley, R. T., An, N. H., Showker, J. L., Yoo, H. S., Norred, W. P., Chamberlain, W. J., Wang, E., Merrill, A. H., Jr., Motelin, G., Beasley, V. R. & Haschek, W. M. (1993) Alteration of tissue and serum sphinganine to sphingosine ratio: an early biomarker of exposure to fumonisin-containing feeds in pigs. Toxicol. Appl. Pharmacol. 118:105-112.[Medline]

25. Norred, W. P., Plattner, R. D., Meredith, F. I. & and Riley, R. T. (1997) Mycotoxin-induced elevation of free sphingoid bases in precision-cut rat liver slices: Specificity of the response and structure-activity relationships. Toxicol. Appl. Pharmacol. 147:63-70.[Medline]

26. Sullards, M. C. & Merrill, A. H., Jr. (Jan 30;2001) Analysis of sphingosine 1-phosphate, ceramides, and other bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Sci. STKE. 67:PL1.

27. Stevens, V. L., Nimkar, S., Jamison, W. C., Liotta, D. C. & Merrill, A. H., Jr. (1990) Characteristics of the growth inhibition and cytotoxicity of long-chain (sphingoid) bases for Chinese hamster ovary (CHO) cells: evidence for an involvement of protein kinase C. Biochim. Biophys. Acta 1051:37-45.[Medline]

28. Schmelz, E. M., Dombrink-Kurtzman, M. A., Kozutsumi, Y. & Merrill, A. H., Jr. (1998) Induction of apoptosis by fumonisin B₁ in HT-29 cells is mediated by the accumulation of endogenous free sphingoid bases. Toxicol. Appl. Pharmacol. 148:252-260.[Medline]

29. Yoo, H. S., Norred, W. P., Wang, E., Merrill, A. H., Jr. & Riley, R. T. (1992) Fumonisin inhibition of de novo sphingolipid biosynthesis and cytotoxicity are correlated in LLC-PK1 cells. Toxicol. Appl. Pharmacol. 114:9-15.[Medline]

30. Norred, W. P., Wang, E., Yoo, H., Riley, R. T. & Merrill, A. H., Jr. (1992) In vitro toxicology of fumonisins and the mechanistic implications. Mycopathologia 117:73-78.[Medline]

31. Riley, R. T., Hinton, D. M., Chamberlain, W. J., Bacon, C. W., Wang, E., Merrill, A. H., Jr. & Voss, K. A. (1994) Dietary fumonisin B₁ induces disruption of sphingolipid metabolism in Sprague-Dawley rats: a new mechanism of nephrotoxicity. J. Nutr. 124:594-603.

32. EHC 219 (2000) Environmental health criteria 219: fumonisin B₁. Marasas, W.H.O. Miller, J. D. Riley, R. T. Visconti, A. eds. International Programme on Chemical Safety 2000:1-150 United Nations Environmental Programme, The International Labour Organization, and the World Health Organization Geneva, Switzerland. .

33. LaBorde, J. B., Terry, K. K., Howard, P. C., Chen, J. J., Collins, F. X., Shackelford, M. E. & Hansen, D. K. (1997) Lack of embryotoxicity of fumonisin B₁ in New Zealand white rabbits. Fundam. Appl. Toxicol. 40:120-128.[Medline]

34. Tsunoda, M., Sharma, R. P. & Riley, R. T. (1998) Early fumonisin B₁ toxicity in relation to disrupted sphingolipid metabolism in male BALB/c mice. J. Biochem. Mol. Toxicol. 12:281-289.[Medline]

35. Bolger, M., Coker, R. D., Dinovi, M., Gaylor, D., Gelderblom, W.C.A., Paster, N., Riley, R. T., Shephard, G. & Speijers, J. A. (2001) Fumonisins. In: Safety Evaluation of Certain Mycotoxins in Food. World Health Organization Food Additives Series 47:103-279.

36. Hard, G. C., Howard, P. C., Kovatch, R. M. & Bucci, T. J. (2001) Rat kidney pathology induced by chronic exposure to fumonisin B₁ includes rare variants of renal tubule tumor. Toxicol. Pathol. 29:379-386.[Medline]

37. Enongene, E. N., Sharma, R. P., Bhandari, N., Meredith, F. I., Voss, K. A. & Riley, R. T. (2002) Persistence and reversibility of the elevation in free sphingoid bases induced by fumonisin inhibition of ceramide synthase. Toxicol. Sci. 67:173-181.[Abstract/Free Full Text]

38. Wang, E., Riley, R. T., Meredith, F. I. & Merrill, A. H., Jr. (1999) Time course, dose-dependence, and reversibility of increases in urinary sphinganine and sphingosine in animals fed defined diets containing fumonisin B₁: characteristics of urinary biomarkers for exposure to fumonisins. J. Nutr. 129:214-220.[Abstract/Free Full Text]

39. Van der Westhuizen, L., Shephard, G. S. & van Schalkwyk, D. J. (2001) The effect of a single gavage dose of fumonisin B₁ on the sphinganine and sphingosine levels in vervet monkeys. Toxicon 39:273-281.[Medline]

40. Qui, M., Liu, X. & Wang, Y. (2001) Determination of sphinganine, sphingosine, and Sa/So ratio in urine of humans exposed to dietary fumonisin B₁. Food Addit. Contam. 18:263-269.[Medline]

41. Hendricks, K. (1999) Fumonisins and neural tube defects in South Texas. Epidemiology 10:198-200.[Medline]

42. Campbell, L. R., Dayton, D. H. & Sohal, G. S. (1986) Neural tube defects: a review of human and animal studies on the etiology and neural tube defects. Teratology 34:171-187.[Medline]

43. MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet II:131-137.

44. Gelineau-van Waes, J. & Finnell, R. H. (2001) Genetics of neural tube defects. Semin. Pediatr. Neurol. 8:160-164.[Medline]

45. Finnell, R. H., Gelineau-van Waes, J., Bennett, G. D., Barber, R. C., Wlodarczyk, B., Shaw, G. M., Lammer, E. J., Piedrahita, J. A. & Eberwine, J. H. (2000) Genetic basis of susceptibility to environmentally-induced neural tube defects. Ann. N. Y. Acad. Sci. 919:261-277.[Abstract/Free Full Text]

46. Finnell, R. H., Gelineau-van Waes, J., Eudy, J. & Rosenquist, T. H. (2002) Molecular basis of environmentally-induced birth defects. Ann. Rev. Pharmacol. Toxicol. 42:181-208.[Medline]

47. Juriloff, D. M. & Harris, M. J. (2000) Mouse models for neural tube closure defects. Hum. Mol. Genet. 9:993-1000.[Abstract/Free Full Text]

48. Czeizel, A. E. & Dudas, I. (1992) Prevention of the first occurrence of neural-tube defects by periconceptual vitamin supplementation. N. Engl. J. Med. 327:1832-1835.[Abstract]

49. Shaw, G. M., Schaffer, D., Velie, E., Morland, K. M. & Harris, J. A. (1995) Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 6:219-226.[Medline]

50. Werler, M. M., Sharpio, S. & Mitchell, A. A. (1993) Periconceptual folic acid exposure and risk of occurrent neural tube defects. J. Am. Med. Assoc. 269:1257-1261.[Abstract]

51. Green, N. S. (2002) Folic acid supplementation and prevention of birth defects. J. Nutr. 132:2356S-2360S.[Abstract/Free Full Text]

52. Stevens, V. L. & Tang, J. (1997) Fumonisin B₁-induced sphingolipid depletion inhibits vitamin uptake via the glycosylphosphatidylinositol-anchored folate receptor. J. Biol. Chem. 272:18020-18025.[Abstract/Free Full Text]

53. Chatterjee, S., Smith, E. R., Hanada, K., Stevens, V. L. & Mayor, S. (2001) GPI anchoring leads to sphingolipid-dependent retention of endocytosed proteins in the recycling endosomal compartment. EMBO J. 20:1583-1592.[Medline]

54. Luhrs, C. A. & Slomiany, B. L. (1989) A human membrane-associated folate binding protein is anchored by a glycosyl-phosphatidylinositol tail. J. Biol. Chem. 264:21446-21449.[Abstract/Free Full Text]

55. Brown, D. A. & London, E. (1998) Functions of lipid rafts in biological membranes. Annu. Rev. Cell Dev. Biol. 14:111-136.[Medline]

56. Piedrahita, J. A., Oetama, B., Bennett, G. D., van Waes, J., Kamen, B. A., Richardson, J., Lacey, S. W., Anderson, R. G. & Finnell, R. H. (1999) Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nat. Genet. 23:228-232.[Medline]

57. Collins, T.F.X., Sprando, R. L., Black, T. N., Shackelford, M. E., LaBorde, J. B., Hansen, D. K., Eppley, R. M., Trucksess, M. W., Howard, P. C., Bryant, M. A., Ruggles, D. I., Olejnik, N. & Rorie, J. I. (1998) Effects of fumonisin B₁ in pregnant rats. Part 2. Food Chem. Toxicol. 36:673-685.[Medline]

58. Reddy, R. V., Johnson, G., Rottinghaus, G. E., Casteel, S. W. & Reddy, C. S. (1996) Developmental effects of fumonisin B₁ in CD1 mice. Mycopathologia 134:161-166.[Medline]

59. Zacharias, C., van Echten-Deckert, G., Wang, E., Merrill, A. H., Jr. & Sandhoff, K. (1996) The effect of fumonisin B₁ on developing chick embryos: correlation between de novo sphingolipid biosynthesis and gross morphological changes. Glycoconj. J. 13:167-175.[Medline]

60. Flynn, T. J., Pritchard, D., Bradlaw, J., Eppley, R. & Page, S. (1996) In vivo embryotoxicity of fumonisin B₁ evaluated with cultured postimplantation staged rat embryos. In Vitro Toxicol. 9:271-279.

61. Flynn, T. J., Stack, M. E., Troy, A. L. & Chirtel, S. J. (1997) Assessment of the embryotoxic potential of the total hydrolysis product of fumonisin B1 using cultured organogenesis-staged rat embryos. Food Chem. Toxicol. 35:1135-1141.[Medline]

62. Sadler, T. W., Merrill, A. H., Jr., Stevens, V. L., Sullards, M. C., Wang, E. & Wang, P. (2002) Prevention of fumonisin B₁-induced neural tube defects by folic acid. Teratology 66:169-176.[Medline]

63. Gelineau-van Waes, J., Maddox, J., Grabowski, L., Heller, S. & Bennett, G. (2002) Role of folate in fumonisin B₁-induced neural tube defects. Mycopathologia 155:36.

64. Gelineau-van Waes, J., Starr, L., Maddox, J., Heller, S. & Bennett, G. (2002) Fumonisin B₁-induced neural tube defects: disruption of membrane sphingolipids and folate transport. Teratology 65:302.

65. Maddox, J., Bennett, G., Starr, L., Aleman, F. & Gelineau-van Waes, J. (2002) Role of folate in fumonisin-induced neural tube defects. Toxicologist 66:113.

66. Juriloff, D. M., Harris, M. J. & Miller, J. R. (1983) The lidgap defect in mice: update and hypotheses. Can. J. Genet. Cytol. 25:246-254.[Medline]

67. Harris, M. J., Juriloff, D. M. & Biddle, F. G. (1984) Cortisone cure of the lidgap defect in fetal mice: a dose-response and time-response study. Teratology 29:287-295.[Medline]

68. Schnitzer, J. E., McIntosh, D. P., Dvorak, A. M., Liu, J. & Oh, P. (1995) Separation of caveolae from associated microdomains of GPI-anchored proteins. Science 269:1435-1439.[Abstract/Free Full Text]

69. Ilangumaran, S., Briol, A. & Hoessli, D. C. (1997) Distinct interactions among GPI-anchored, transmembrane and membrane associated intracellular proteins, and sphingolipids in lymphocyte and endothelial cell plasma membranes. Biochim. Biophys. Acta 1328:227-236.[Medline]

70. Harder, T. & Simons, K. (1999) Clusters of glycolipid and glycosylphosphatidylinositol-anchored proteins in lymphoid cells: accumulation of actin regulated by local tyrosine phosphorylation. Eur. J. Immunol. 29:556-562.[Medline]

71. Kenworthy, A. K., Petranova, N. & Edidin, M. (2000) High resolution FRET microscopy of cholera toxin B-subunit and GPI-anchored proteins in cell plasma membranes. Mol. Cell Biol. 11:1645-1655.

72. Meredith, F. I., Torres, O. R., Saenz de Tejada, S., Riley, R. T. & Merrill, A. H., Jr. (1999) Fumonisin B₁ and hydrolyzed fumonisin B₁ levels in nixtamalized maize (Zea mays L.) and tortillas from two different geographical locations in Guatemala. J. Food Prot. 62:1218-1222.[Medline]

73. Norred, W. P., Plattner, R. D., Dombrink-Kurtzman, M. A., Meredith, F. I. & Riley, R. T. (1997) Mycotoxin-induced elevation of free sphingoid bases in precision-cut rat liver slices: specificity of the response and structure-activity relationships. Toxicol. Appl. Pharmacol. 143:63-70.

74. Howard, P. C., Couch, L. H., Patton, R. E., Eppley, R. M., Doerge, D. R., Churchwell, M. I., Matilde Marques, M. & Okerberg, C. V. (2002) Comparison of the toxicity of several fumonisin derivatives in a 28-day feeding study with female B6C3F₁ mice. Toxicol. Appl. Pharmacol. 185:153-165.[Medline]

75. Hendrich, S., Miller, K. A., Wilson, T. M. & Murphy, P. A. (1993) Toxicity of Fusarium proliferatum-fermented nixtamalized corn-based diets fed to rats: effect of nutritional status. J. Agric. Food Chem. 41:1649-1654.

76. Dombrink-Kurtzman, M. A. & Dvorak, T. J. (1999) Fumonisin content in masa and tortillas from Mexico. J. Agric. Food Chem. 47:622-627.[Medline]

77. Cifuentes, G. () Perfil epidemiologico de las anomalias del tubo neural en Guatemala, durante el año 2000. Graduation thesis, Universidad San Carlos de Guatemala School of Medicine. .

78. Ncayiyana, D. J. (1986) Neural tube defects among rural blacks in a Transkei district. S. A. Med. J. 69:618-620.

79. Venter, P. A., Christianson, A. L., Hutamo, C. M., Makhura, M. P. & Gericke, G. S. (1995) Congenital anomalies in rural black South African neonates-a silent epidemic?. S. Afr. Med. J. 83:15-20.

80. Buccimazza, S. S., Molteno, C. D., Dunne, T. T. & Viljoen, D. L. (1994) Prevelance of neural tube defects in Cape Town. Teratology 50:194-199.[Medline]

81. Delport, S. D., Christianson, A. L., van den Berg, H.J.S., Wolmarans, L. & Gericke, G. S. (1995) Congenital anomalies in black South African liveborn neonates at an urban academic hospital. S. Afr. Med. J. 85:11-15.[Medline]

82. Kromberg, J.G.R. & Jenkins, T. (1982) Common birth defects in South African blacks. S. Afr. Med. J. 62:599-602.[Medline]

83. Lian, Z-H., Yang, H-Y. & Li, Z. (1987) Neural tube defects in Beijing-Tianjin area of China. Urban-rural distribution and some other epidemiological characteristics. J. Epidemiol. Community Health 41:259-262.[Abstract]

84. Moore, C. A., Li, S., Gu, H., Berry, R. J., Mulinare, J. & Erickson, J. D. (1997) Elevated rates of severe neural tube defects in a high-prevalence area in Northern China. Am. J. Med. Genet. 73:113-118.[Medline]

85. Rheeder, J. P., Marasas, W.F.O., Thiel, P. G., Sydenham, E. W., Shephard, G. S. & Van Schalkwyk, D. J. (1992) Fusarium moniliforme and fumonisins in corn in relation to human esophageal cancer in Transkei. Phytopathology 82:353-357.

86. Yoshizawa, T., Yamashita, A. & Luo, Y. (1994) Fumonisin occurrence in corn from high- and low-risk areas for human esophageal cancer in China. Appl. Environ. Microbiol. 60:1626-1629.[Abstract/Free Full Text]

87. Dombrink-Kurtzman, M. A., Dvorak, T. J., Barron, M. E. & Rooney, L. W. (2000) Effect of nixtamalization (alkaline cooking) on fumonisin-contaminated corn for production of masa and tortillas. J. Agric. Food Chem. 48:5781-5786.[Medline]

88. Voss, K. A., Poling, S. M., Meredith, F. I., Bacon, C. W. & Saunders, D. S. (2001) Fate of fumonisins during the production of fried tortilla chips. J. Agric. Food Chem. 49:3120-3126.[Medline]

This article has been cited by other articles:

				Y. Y. Gong, L. Torres-Sanchez, L. Lopez-Carrillo, J. H. Peng, A. E. Sutcliffe, K. L. White, H.-U. Humpf, P. C. Turner, and C. P. Wild Association between Tortilla Consumption and Human Urinary Fumonisin B1 Levels in a Mexican Population Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 688 - 694. [Abstract] [Full Text] [PDF]

				O. A. Torres, E. Palencia, L. L. de Pratdesaba, R. Grajeda, M. Fuentes, M. C. Speer, A. H. Merrill Jr., K. O'Donnell, C. W. Bacon, A. E. Glenn, et al. Estimated Fumonisin Exposure in Guatemala Is Greatest in Consumers of Lowland Maize J. Nutr., December 1, 2007; 137(12): 2723 - 2729. [Abstract] [Full Text] [PDF]

				W.-N. Chang, J.-N. Tsai, B.-H. Chen, H.-S. Huang, and T.-F. Fu Serine Hydroxymethyltransferase Isoforms Are Differentially Inhibited by Leucovorin: Characterization and Comparison of Recombinant Zebrafish Serine Hydroxymethyltransferases Drug Metab. Dispos., November 1, 2007; 35(11): 2127 - 2137. [Abstract] [Full Text] [PDF]

				A. M. Abdel Nour, D. Ringot, J.-L. Gueant, and A. Chango Folate receptor and human reduced folate carrier expression in HepG2 cell line exposed to fumonisin B1 and folate deficiency Carcinogenesis, November 1, 2007; 28(11): 2291 - 2297. [Abstract] [Full Text] [PDF]

				D. W. Brown, R. A. E. Butchko, M. Busman, and R. H. Proctor The Fusarium verticillioides FUM Gene Cluster Encodes a Zn(II)2Cys6 Protein That Affects FUM Gene Expression and Fumonisin Production Eukaryot. Cell, July 1, 2007; 6(7): 1210 - 1218. [Abstract] [Full Text] [PDF]

				K. Krishnamurthy, G. Wang, J. Silva, B. G. Condie, and E. Bieberich Ceramide Regulates Atypical PKC{zeta}/{lambda}-mediated Cell Polarity in Primitive Ectoderm Cells: A NOVEL FUNCTION OF SPHINGOLIPIDS IN MORPHOGENESIS J. Biol. Chem., February 2, 2007; 282(5): 3379 - 3390. [Abstract] [Full Text] [PDF]

				K. A. Voss, J. Liu, S. P. Anderson, C. Dunn, J. D. Miller, J. R. Owen, R. T. Riley, C. W. Bacon, and J. C. Corton Toxic Effects of Fumonisin in Mouse Liver Are Independent of the Peroxisome Proliferator-Activated Receptor {alpha} Toxicol. Sci., January 1, 2006; 89(1): 108 - 119. [Abstract] [Full Text] [PDF]

				K. Mizugishi, T. Yamashita, A. Olivera, G. F. Miller, S. Spiegel, and R. L. Proia Essential Role for Sphingosine Kinases in Neural and Vascular Development Mol. Cell. Biol., December 15, 2005; 25(24): 11113 - 11121. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marasas, W. F. O.