Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2001 May;109(Suppl 2):301–308. doi: 10.1289/ehp.01109s2301

Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis.

R T Riley 1, E Enongene 1, K A Voss 1, W P Norred 1, F I Meredith 1, R P Sharma 1, J Spitsbergen 1, D E Williams 1, D B Carlson 1, A H Merrill Jr 1
PMCID: PMC1240679  PMID: 11359699

Abstract

There is a great deal of evidence that altered sphingolipid metabolism is associated with fumonisin-induced animal diseases including increased apoptotic and oncotic necrosis, and carcinogenesis in rodent liver and kidney. The biochemical consequences of fumonisin disruption of sphingolipid metabolism most likely to alter cell regulation are increased free sphingoid bases and their 1-phosphates, alterations in complex sphingolipids, and decreased ceramide (CER) biosynthesis. Because free sphingoid bases and CER can induce cell death, the fumonisin inhibition of CER synthase can inhibit cell death induced by CER but promote free sphingoid base-induced cell death. Theoretically, at any time the balance between the intracellular concentration of effectors that protect cells from apoptosis (decreased CER, increased sphingosine 1-phosphate) and those that induce apoptosis (increased CER, free sphingoid bases, altered fatty acids) will determine the cellular response. Because the balance between the rates of apoptosis and proliferation is important in tumorigenesis, cells sensitive to the proliferative effect of decreased CER and increased sphingosine 1-phosphate may be selected to survive and proliferate when free sphingoid base concentration is not growth inhibitory. Conversely, when the increase in free sphingoid bases exceeds a cell's ability to convert sphinganine/sphingosine to dihydroceramide/CER or their sphingoid base 1-phosphate, then free sphingoid bases will accumulate. In this case cells that are sensitive to sphingoid base-induced growth arrest will die and insensitive cells will survive. If the cells selected to die are normal phenotypes and the cells selected to survive are abnormal, then cancer risk will increase.

Full Text

The Full Text of this article is available as a PDF (350.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abado-Becognee K., Mobio T. A., Ennamany R., Fleurat-Lessard F., Shier W. T., Badria F., Creppy E. E. Cytotoxicity of fumonisin B1: implication of lipid peroxidation and inhibition of protein and DNA syntheses. Arch Toxicol. 1998 Mar;72(4):233–236. doi: 10.1007/s002040050494. [DOI] [PubMed] [Google Scholar]
  2. Abel S., Gelderblom W. C. Oxidative damage and fumonisin B1-induced toxicity in primary rat hepatocytes and rat liver in vivo. Toxicology. 1998 Nov 16;131(2-3):121–131. doi: 10.1016/s0300-483x(98)00123-1. [DOI] [PubMed] [Google Scholar]
  3. Arab S., Murakami M., Dirks P., Boyd B., Hubbard S. L., Lingwood C. A., Rutka J. T. Verotoxins inhibit the growth of and induce apoptosis in human astrocytoma cells. J Neurooncol. 1998 Nov;40(2):137–150. doi: 10.1023/a:1006010019064. [DOI] [PubMed] [Google Scholar]
  4. Arora A. S., Jones B. J., Patel T. C., Bronk S. F., Gores G. J. Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat. Hepatology. 1997 Apr;25(4):958–963. doi: 10.1002/hep.510250428. [DOI] [PubMed] [Google Scholar]
  5. Badiani K., Byers D. M., Cook H. W., Ridgway N. D. Effect of fumonisin B1 on phosphatidylethanolamine biosynthesis in Chinese hamster ovary cells. Biochim Biophys Acta. 1996 Dec 13;1304(3):190–196. doi: 10.1016/s0005-2760(96)00119-1. [DOI] [PubMed] [Google Scholar]
  6. Balsinde J., Balboa M. A., Dennis E. A. Inflammatory activation of arachidonic acid signaling in murine P388D1 macrophages via sphingomyelin synthesis. J Biol Chem. 1997 Aug 15;272(33):20373–20377. doi: 10.1074/jbc.272.33.20373. [DOI] [PubMed] [Google Scholar]
  7. Boldin S., Futerman A. H. Glucosylceramide synthesis is required for basic fibroblast growth factor and laminin to stimulate axonal growth. J Neurochem. 1997 Feb;68(2):882–885. doi: 10.1046/j.1471-4159.1997.68020882.x. [DOI] [PubMed] [Google Scholar]
  8. Bose R., Verheij M., Haimovitz-Friedman A., Scotto K., Fuks Z., Kolesnick R. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell. 1995 Aug 11;82(3):405–414. doi: 10.1016/0092-8674(95)90429-8. [DOI] [PubMed] [Google Scholar]
  9. Cabot M. C., Han T. Y., Giuliano A. E. The multidrug resistance modulator SDZ PSC 833 is a potent activator of cellular ceramide formation. FEBS Lett. 1998 Jul 17;431(2):185–188. doi: 10.1016/s0014-5793(98)00744-3. [DOI] [PubMed] [Google Scholar]
  10. Ciacci-Zanella J. R., Jones C. Fumonisin B1, a mycotoxin contaminant of cereal grains, and inducer of apoptosis via the tumour necrosis factor pathway and caspase activation. Food Chem Toxicol. 1999 Jul;37(7):703–712. doi: 10.1016/s0278-6915(99)00034-4. [DOI] [PubMed] [Google Scholar]
  11. Ciacci-Zanella J. R., Merrill A. H., Jr, Wang E., Jones C. Characterization of cell-cycle arrest by fumonisin B1 in CV-1 cells. Food Chem Toxicol. 1998 Sep-Oct;36(9-10):791–804. doi: 10.1016/s0278-6915(98)00034-9. [DOI] [PubMed] [Google Scholar]
  12. Cohen S. M. Role of cell proliferation in regenerative and neoplastic disease. Toxicol Lett. 1995 Dec;82-83:15–21. doi: 10.1016/0378-4274(95)03542-7. [DOI] [PubMed] [Google Scholar]
  13. DiPietrantonio A. M., Hsieh T. C., Olson S. C., Wu J. M. Regulation of G1/S transition and induction of apoptosis in HL-60 leukemia cells by fenretinide (4HPR). Int J Cancer. 1998 Sep 25;78(1):53–61. doi: 10.1002/(sici)1097-0215(19980925)78:1<53::aid-ijc10>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  14. Dugyala R. R., Sharma R. P., Tsunoda M., Riley R. T. Tumor necrosis factor-alpha as a contributor in fumonisin B1 toxicity. J Pharmacol Exp Ther. 1998 Apr;285(1):317–324. [PubMed] [Google Scholar]
  15. Enongene E. N., Sharma R. P., Bhandari N., Voss K. A., Riley R. T. Disruption of sphingolipid metabolism in small intestines, liver and kidney of mice dosed subcutaneously with fumonisin B(1). Food Chem Toxicol. 2000 Sep;38(9):793–799. doi: 10.1016/s0278-6915(00)00065-x. [DOI] [PubMed] [Google Scholar]
  16. Fukuda H., Shima H., Vesonder R. F., Tokuda H., Nishino H., Katoh S., Tamura S., Sugimura T., Nagao M. Inhibition of protein serine/threonine phosphatases by fumonisin B1, a mycotoxin. Biochem Biophys Res Commun. 1996 Mar 7;220(1):160–165. doi: 10.1006/bbrc.1996.0374. [DOI] [PubMed] [Google Scholar]
  17. Futerman A. H. Inhibition of sphingolipid synthesis: effects on glycosphingolipid-GPI-anchored protein microdomains. Trends Cell Biol. 1995 Oct;5(10):377–380. doi: 10.1016/s0962-8924(00)89078-9. [DOI] [PubMed] [Google Scholar]
  18. Garzotto M., White-Jones M., Jiang Y., Ehleiter D., Liao W. C., Haimovitz-Friedman A., Fuks Z., Kolesnick R. 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Res. 1998 May 15;58(10):2260–2264. [PubMed] [Google Scholar]
  19. Gelderblom W. C., Smuts C. M., Abel S., Snyman S. D., Cawood M. E., van der Westhuizen L., Swanevelder S. Effect of fumonisin B1 on protein and lipid synthesis in primary rat hepatocytes. Food Chem Toxicol. 1996 Apr;34(4):361–369. doi: 10.1016/0278-6915(96)00107-x. [DOI] [PubMed] [Google Scholar]
  20. Gelderblom W. C., Smuts C. M., Abel S., Snyman S. D., Van der Westhuizen L., Huber W. W., Swanevelder S. Effect of fumonisin B1 on the levels and fatty acid composition of selected lipids in rat liver in vivo. Food Chem Toxicol. 1997 Jul;35(7):647–656. doi: 10.1016/s0278-6915(97)00036-7. [DOI] [PubMed] [Google Scholar]
  21. Gelderblom W. C., Snyman S. D., Lebepe-Mazur S., van der Westhuizen L., Kriek N. P., Marasas W. F. The cancer-promoting potential of fumonisin B1 in rat liver using diethylnitrosamine as a cancer initiator. Cancer Lett. 1996 Dec 3;109(1-2):101–108. doi: 10.1016/s0304-3835(96)04431-x. [DOI] [PubMed] [Google Scholar]
  22. Gillard B. K., Harrell R. G., Marcus D. M. Pathways of glycosphingolipid biosynthesis in SW13 cells in the presence and absence of vimentin intermediate filaments. Glycobiology. 1996 Jan;6(1):33–42. doi: 10.1093/glycob/6.1.33. [DOI] [PubMed] [Google Scholar]
  23. Goldsworthy T. L., Conolly R. B., Fransson-Steen R. Apoptosis and cancer risk assessment. Mutat Res. 1996 Sep;365(1-3):71–90. doi: 10.1016/s0165-1110(96)90013-5. [DOI] [PubMed] [Google Scholar]
  24. Gumprecht L. A., Beasley V. R., Weigel R. M., Parker H. M., Tumbleson M. E., Bacon C. W., Meredith F. I., Haschek W. M. Development of fumonisin-induced hepatotoxicity and pulmonary edema in orally dosed swine: morphological and biochemical alterations. Toxicol Pathol. 1998 Nov-Dec;26(6):777–788. doi: 10.1177/019262339802600610. [DOI] [PubMed] [Google Scholar]
  25. Gumprecht L. A., Marcucci A., Weigel R. M., Vesonder R. F., Riley R. T., Showker J. L., Beasley V. R., Haschek W. M. Effects of intravenous fumonisin B1 in rabbits: nephrotoxicity and sphingolipid alterations. Nat Toxins. 1995;3(5):395–403. doi: 10.1002/nt.2620030512. [DOI] [PubMed] [Google Scholar]
  26. Hanada K., Izawa K., Nishijima M., Akamatsu Y. Sphingolipid deficiency induces hypersensitivity of CD14, a glycosyl phosphatidylinositol-anchored protein, to phosphatidylinositol-specific phospholipase C. J Biol Chem. 1993 Jul 5;268(19):13820–13823. [PubMed] [Google Scholar]
  27. Hanada K., Nishijima M., Kiso M., Hasegawa A., Fujita S., Ogawa T., Akamatsu Y. Sphingolipids are essential for the growth of Chinese hamster ovary cells. Restoration of the growth of a mutant defective in sphingoid base biosynthesis by exogenous sphingolipids. J Biol Chem. 1992 Nov 25;267(33):23527–23533. [PubMed] [Google Scholar]
  28. Hannun Y. A., Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000 Feb;10(2):73–80. doi: 10.1016/s0962-8924(99)01694-3. [DOI] [PubMed] [Google Scholar]
  29. Harel R., Futerman A. H. Inhibition of sphingolipid synthesis affects axonal outgrowth in cultured hippocampal neurons. J Biol Chem. 1993 Jul 5;268(19):14476–14481. [PubMed] [Google Scholar]
  30. Hidari KIPJ, Ichikawa S., Fujita T., Sakiyama H., Hirabayashi Y. Complete removal of sphingolipids from the plasma membrane disrupts cell to substratum adhesion of mouse melanoma cells. J Biol Chem. 1996 Jun 14;271(24):14636–14641. doi: 10.1074/jbc.271.24.14636. [DOI] [PubMed] [Google Scholar]
  31. Huang C., Dickman M., Henderson G., Jones C. Repression of protein kinase C and stimulation of cyclic AMP response elements by fumonisin, a fungal encoded toxin which is a carcinogen. Cancer Res. 1995 Apr 15;55(8):1655–1659. [PubMed] [Google Scholar]
  32. Humpf H. U., Schmelz E. M., Meredith F. I., Vesper H., Vales T. R., Wang E., Menaldino D. S., Liotta D. C., Merrill A. H., Jr Acylation of naturally occurring and synthetic 1-deoxysphinganines by ceramide synthase. Formation of N-palmitoyl-aminopentol produces a toxic metabolite of hydrolyzed fumonisin, AP1, and a new category of ceramide synthase inhibitor. J Biol Chem. 1998 Jul 24;273(30):19060–19064. doi: 10.1074/jbc.273.30.19060. [DOI] [PubMed] [Google Scholar]
  33. Isogai C., Murate T., Tamiya-Koizumi K., Yoshida S., Ito T., Nagai H., Kinoshita T., Kagami Y., Hotta T., Hamaguchi M. Analysis of bax protein in sphingosine-induced apoptosis in the human leukemic cell line TF1 and its bcl-2 transfectants. Exp Hematol. 1998 Nov;26(12):1118–1125. [PubMed] [Google Scholar]
  34. Kang Y. J., Alexander J. M. Alterations of the glutathione redox cycle status in fumonisin B1-treated pig kidney cells. J Biochem Toxicol. 1996;11(3):121–126. doi: 10.1002/(SICI)1522-7146(1996)11:3<121::AID-JBT3>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  35. Kolesnick R. N., Krönke M. Regulation of ceramide production and apoptosis. Annu Rev Physiol. 1998;60:643–665. doi: 10.1146/annurev.physiol.60.1.643. [DOI] [PubMed] [Google Scholar]
  36. LaBorde J. B., Terry K. K., Howard P. C., Chen J. J., Collins T. F., Shackelford M. E., Hansen D. K. Lack of embryotoxicity of fumonisin B1 in New Zealand white rabbits. Fundam Appl Toxicol. 1997 Nov;40(1):120–128. doi: 10.1006/faat.1997.2380. [DOI] [PubMed] [Google Scholar]
  37. Lavie Y., Cao H., Bursten S. L., Giuliano A. E., Cabot M. C. Accumulation of glucosylceramides in multidrug-resistant cancer cells. J Biol Chem. 1996 Aug 9;271(32):19530–19536. doi: 10.1074/jbc.271.32.19530. [DOI] [PubMed] [Google Scholar]
  38. Lee J. Y., Leonhardt L. G., Obeid L. M. Cell-cycle-dependent changes in ceramide levels preceding retinoblastoma protein dephosphorylation in G2/M. Biochem J. 1998 Sep 1;334(Pt 2):457–461. doi: 10.1042/bj3340457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lemmer E. R., de la Motte Hall P., Omori N., Omori M., Shephard E. G., Gelderblom W. C., Cruse J. P., Barnard R. A., Marasas W. F., Kirsch R. E. Histopathology and gene expression changes in rat liver during feeding of fumonisin B1, a carcinogenic mycotoxin produced by Fusarium moniliforme. Carcinogenesis. 1999 May;20(5):817–824. doi: 10.1093/carcin/20.5.817. [DOI] [PubMed] [Google Scholar]
  40. Li W., Riley R. T., Voss K. A., Norred W. P. Role of proliferation in the toxicity of fumonisin B1: enhanced hepatotoxic response in the partially hepatectomized rat. J Toxicol Environ Health A. 2000 Aug 11;60(7):441–457. doi: 10.1080/00984100050079511. [DOI] [PubMed] [Google Scholar]
  41. Liao W. C., Haimovitz-Friedman A., Persaud R. S., McLoughlin M., Ehleiter D., Zhang N., Gatei M., Lavin M., Kolesnick R., Fuks Z. Ataxia telangiectasia-mutated gene product inhibits DNA damage-induced apoptosis via ceramide synthase. J Biol Chem. 1999 Jun 18;274(25):17908–17917. doi: 10.1074/jbc.274.25.17908. [DOI] [PubMed] [Google Scholar]
  42. Lim C. W., Parker H. M., Vesonder R. F., Haschek W. M. Intravenous fumonisin B1 induces cell proliferation and apoptosis in the rat. Nat Toxins. 1996;4(1):34–41. doi: 10.1002/19960401nt5. [DOI] [PubMed] [Google Scholar]
  43. Meivar-Levy I., Sabanay H., Bershadsky A. D., Futerman A. H. The role of sphingolipids in the maintenance of fibroblast morphology. The inhibition of protrusional activity, cell spreading, and cytokinesis induced by fumonisin B1 can be reversed by ganglioside GM3. J Biol Chem. 1997 Jan 17;272(3):1558–1564. doi: 10.1074/jbc.272.3.1558. [DOI] [PubMed] [Google Scholar]
  44. Memon R. A., Holleran W. M., Moser A. H., Seki T., Uchida Y., Fuller J., Shigenaga J. K., Grunfeld C., Feingold K. R. Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin. Arterioscler Thromb Vasc Biol. 1998 Aug;18(8):1257–1265. doi: 10.1161/01.atv.18.8.1257. [DOI] [PubMed] [Google Scholar]
  45. Meredith F. I., Riley R. T., Bacon C. W., Williams D. E., Carlson D. B. Extraction, quantification, and biological availability of fumonisin B1 incorporated into the Oregon test diet and fed to rainbow trout. J Food Prot. 1998 Aug;61(8):1034–1038. doi: 10.4315/0362-028x-61.8.1034. [DOI] [PubMed] [Google Scholar]
  46. Merrill A. H., Jr Characterization of serine palmitoyltransferase activity in Chinese hamster ovary cells. Biochim Biophys Acta. 1983 Dec 20;754(3):284–291. doi: 10.1016/0005-2760(83)90144-3. [DOI] [PubMed] [Google Scholar]
  47. Merrill A. H., Jr, Schmelz E. M., Dillehay D. L., Spiegel S., Shayman J. A., Schroeder J. J., Riley R. T., Voss K. A., Wang E. Sphingolipids--the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharmacol. 1997 Jan;142(1):208–225. doi: 10.1006/taap.1996.8029. [DOI] [PubMed] [Google Scholar]
  48. Merrill A. H., Jr, Wang E., Gilchrist D. G., Riley R. T. Fumonisins and other inhibitors of de novo sphingolipid biosynthesis. Adv Lipid Res. 1993;26:215–234. [PubMed] [Google Scholar]
  49. Merrill A. H., Jr, Wang E., Vales T. R., Smith E. R., Schroeder J. J., Menaldino D. S., Alexander C., Crane H. M., Xia J., Liotta D. C. Fumonisin toxicity and sphingolipid biosynthesis. Adv Exp Med Biol. 1996;392:297–306. doi: 10.1007/978-1-4899-1379-1_25. [DOI] [PubMed] [Google Scholar]
  50. Merrill A. H., Jr, van Echten G., Wang E., Sandhoff K. Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ. J Biol Chem. 1993 Dec 25;268(36):27299–27306. [PubMed] [Google Scholar]
  51. Michel C., van Echten-Deckert G., Rother J., Sandhoff K., Wang E., Merrill A. H., Jr Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem. 1997 Sep 5;272(36):22432–22437. doi: 10.1074/jbc.272.36.22432. [DOI] [PubMed] [Google Scholar]
  52. Nakamura S., Kozutsumi Y., Sun Y., Miyake Y., Fujita T., Kawasaki T. Dual roles of sphingolipids in signaling of the escape from and onset of apoptosis in a mouse cytotoxic T-cell line, CTLL-2. J Biol Chem. 1996 Jan 19;271(3):1255–1257. doi: 10.1074/jbc.271.3.1255. [DOI] [PubMed] [Google Scholar]
  53. Norred W. P., Plattner R. D., Dombrink-Kurtzman M. A., Meredith F. I., Riley R. T. Mycotoxin-induced elevation of free sphingoid bases in precision-cut rat liver slices: specificity of the response and structure-activity relationships. Toxicol Appl Pharmacol. 1997 Nov;147(1):63–70. doi: 10.1006/taap.1997.8272. [DOI] [PubMed] [Google Scholar]
  54. Paumen M. B., Ishida Y., Muramatsu M., Yamamoto M., Honjo T. Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem. 1997 Feb 7;272(6):3324–3329. doi: 10.1074/jbc.272.6.3324. [DOI] [PubMed] [Google Scholar]
  55. Radin N. S. Chemotherapy by slowing glucosphingolipid synthesis. Biochem Pharmacol. 1999 Mar 15;57(6):589–595. doi: 10.1016/s0006-2952(98)00274-3. [DOI] [PubMed] [Google Scholar]
  56. Ramasamy S., Wang E., Hennig B., Merrill A. H., Jr Fumonisin B1 alters sphingolipid metabolism and disrupts the barrier function of endothelial cells in culture. Toxicol Appl Pharmacol. 1995 Aug;133(2):343–348. doi: 10.1006/taap.1995.1159. [DOI] [PubMed] [Google Scholar]
  57. 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. A potential mechanism for fumonisin B(1)-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3beta activity. Carcinogenesis. 2000 Aug;21(8):1537–1546. [PubMed] [Google Scholar]
  58. Riboni L., Prinetti A., Bassi R., Viani P., Tettamanti G. The effects of exogenous sphingosine on Neuro2a cells are strictly related to the overall capacity of cells to metabolize sphingosine. J Biochem. 1998 Nov;124(5):900–904. doi: 10.1093/oxfordjournals.jbchem.a022205. [DOI] [PubMed] [Google Scholar]
  59. 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. Alteration of tissue and serum sphinganine to sphingosine ratio: an early biomarker of exposure to fumonisin-containing feeds in pigs. Toxicol Appl Pharmacol. 1993 Jan;118(1):105–112. doi: 10.1006/taap.1993.1015. [DOI] [PubMed] [Google Scholar]
  60. Riley R. T., Hinton D. M., Chamberlain W. J., Bacon C. W., Wang E., Merrill A. H., Jr, Voss K. A. Dietary fumonisin B1 induces disruption of sphingolipid metabolism in Sprague-Dawley rats: a new mechanism of nephrotoxicity. J Nutr. 1994 Apr;124(4):594–603. doi: 10.1093/jn/124.4.594. [DOI] [PubMed] [Google Scholar]
  61. Riley R. T., Plattner R. D. Fermentation, partial purification, and use of serine palmitoyltransferase inhibitors from Isaria (= Cordyceps) sinclairii. Methods Enzymol. 2000;311:348–361. doi: 10.1016/s0076-6879(00)11095-x. [DOI] [PubMed] [Google Scholar]
  62. Roccamo A. M., Pediconi M. F., Aztiria E., Zanello L., Wolstenholme A., Barrantes F. J. Cells defective in sphingolipids biosynthesis express low amounts of muscle nicotinic acetylcholine receptor. Eur J Neurosci. 1999 May;11(5):1615–1623. doi: 10.1046/j.1460-9568.1999.00574.x. [DOI] [PubMed] [Google Scholar]
  63. Rotter B. A., Oh Y. N. Mycotoxin fumonisin B1 stimulates nitric oxide production in a murine macrophage cell line. Nat Toxins. 1996;4(6):291–294. doi: 10.1002/(SICI)(1996)4:6<291::AID-NT7>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
  64. Rotter B. A., Thompson B. K., Prelusky D. B., Trenholm H. L., Stewart B., Miller J. D., Savard M. E. Response of growing swine to dietary exposure to pure fumonisin B1 during an eight-week period: growth and clinical parameters. Nat Toxins. 1996;4(1):42–50. doi: 10.1002/19960401nt6. [DOI] [PubMed] [Google Scholar]
  65. Sakata K., Sakata A., Vela-Roch N., Espinosa R., Escalante A., Kong L., Nakabayashi T., Cheng J., Talal N., Dang H. Fas (CD95)-transduced signal preferentially stimulates lupus peripheral T lymphocytes. Eur J Immunol. 1998 Sep;28(9):2648–2660. doi: 10.1002/(SICI)1521-4141(199809)28:09<2648::AID-IMMU2648>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  66. Sandvig K., Garred O., van Helvoort A., van Meer G., van Deurs B. Importance of glycolipid synthesis for butyric acid-induced sensitization to shiga toxin and intracellular sorting of toxin in A431 cells. Mol Biol Cell. 1996 Sep;7(9):1391–1404. doi: 10.1091/mbc.7.9.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Sauviat M. P., Laurent D., Kohler F., Pellegrin F. Fumonisin, a toxin from the fungus Fusarium moniliforme sheld, blocks both the calcium current and the mechanical activity in frog atrial muscle. Toxicon. 1991;29(8):1025–1031. doi: 10.1016/0041-0101(91)90085-6. [DOI] [PubMed] [Google Scholar]
  68. Schmelz E. M., Dombrink-Kurtzman M. A., Roberts P. C., Kozutsumi Y., Kawasaki T., Merrill A. H., Jr Induction of apoptosis by fumonisin B1 in HT29 cells is mediated by the accumulation of endogenous free sphingoid bases. Toxicol Appl Pharmacol. 1998 Feb;148(2):252–260. doi: 10.1006/taap.1997.8356. [DOI] [PubMed] [Google Scholar]
  69. Schroeder J. J., Crane H. M., Xia J., Liotta D. C., Merrill A. H., Jr Disruption of sphingolipid metabolism and stimulation of DNA synthesis by fumonisin B1. A molecular mechanism for carcinogenesis associated with Fusarium moniliforme. J Biol Chem. 1994 Feb 4;269(5):3475–3481. [PubMed] [Google Scholar]
  70. Schwarz A., Rapaport E., Hirschberg K., Futerman A. H. A regulatory role for sphingolipids in neuronal growth. Inhibition of sphingolipid synthesis and degradation have opposite effects on axonal branching. J Biol Chem. 1995 May 5;270(18):10990–10998. doi: 10.1074/jbc.270.18.10990. [DOI] [PubMed] [Google Scholar]
  71. Sharma R. P., Bhandari N., Riley R. T., Voss K. A., Meredith F. I. Tolerance to fumonisin toxicity in a mouse strain lacking the P75 tumor necrosis factor receptor. Toxicology. 2000 Feb 21;143(2):183–194. doi: 10.1016/s0300-483x(99)00168-7. [DOI] [PubMed] [Google Scholar]
  72. Sharma R. P., Bhandari N., Tsunoda M., Riley R. T., Voss K. A. Fumonisin hepatotoxicity is reduced in mice carrying the human tumour necrosis factor alpha transgene. Arch Toxicol. 2000 Jul;74(4-5):238–248. doi: 10.1007/s002040000106. [DOI] [PubMed] [Google Scholar]
  73. Sharma RP, Bhandari N, Tsunoda M, Riley RT, Voss KA, Meredith FI. Fumonisin toxicity in a transgenic mouse model lacking the mdr1a/1b P-glycoprotein genes. Environ Toxicol Pharmacol. 2000 Mar 1;8(3):173–182. doi: 10.1016/s1382-6689(00)00038-7. [DOI] [PubMed] [Google Scholar]
  74. Shimabukuro M., Zhou Y. T., Levi M., Unger R. H. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498–2502. doi: 10.1073/pnas.95.5.2498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Smith E. R., Jones P. L., Boss J. M., Merrill A. H., Jr Changing J774A.1 cells to new medium perturbs multiple signaling pathways, including the modulation of protein kinase C by endogenous sphingoid bases. J Biol Chem. 1997 Feb 28;272(9):5640–5646. doi: 10.1074/jbc.272.9.5640. [DOI] [PubMed] [Google Scholar]
  76. Smith E. R., Merrill A. H., Jr Differential roles of de novo sphingolipid biosynthesis and turnover in the "burst" of free sphingosine and sphinganine, and their 1-phosphates and N-acyl-derivatives, that occurs upon changing the medium of cells in culture. J Biol Chem. 1995 Aug 11;270(32):18749–18758. doi: 10.1074/jbc.270.32.18749. [DOI] [PubMed] [Google Scholar]
  77. Spiegel S. Sphingosine 1-phosphate: a prototype of a new class of second messengers. J Leukoc Biol. 1999 Mar;65(3):341–344. doi: 10.1002/jlb.65.3.341. [DOI] [PubMed] [Google Scholar]
  78. Stevens V. L., Nimkar S., Jamison W. C., Liotta D. C., Merrill A. H., Jr Characteristics of the growth inhibition and cytotoxicity of long-chain (sphingoid) bases for Chinese hamster ovary cells: evidence for an involvement of protein kinase C. Biochim Biophys Acta. 1990 Jan 23;1051(1):37–45. doi: 10.1016/0167-4889(90)90171-9. [DOI] [PubMed] [Google Scholar]
  79. Stevens V. L., Tang J. Fumonisin B1-induced sphingolipid depletion inhibits vitamin uptake via the glycosylphosphatidylinositol-anchored folate receptor. J Biol Chem. 1997 Jul 18;272(29):18020–18025. doi: 10.1074/jbc.272.29.18020. [DOI] [PubMed] [Google Scholar]
  80. Strum J. C., Swenson K. I., Turner J. E., Bell R. M. Ceramide triggers meiotic cell cycle progression in Xenopus oocytes. A potential mediator of progesterone-induced maturation. J Biol Chem. 1995 Jun 2;270(22):13541–13547. doi: 10.1074/jbc.270.22.13541. [DOI] [PubMed] [Google Scholar]
  81. Suzuki A., Iwasaki M., Kato M., Wagai N. Sequential operation of ceramide synthesis and ICE cascade in CPT-11-initiated apoptotic death signaling. Exp Cell Res. 1997 May 25;233(1):41–47. doi: 10.1006/excr.1997.3498. [DOI] [PubMed] [Google Scholar]
  82. Sweeney E. A., Sakakura C., Shirahama T., Masamune A., Ohta H., Hakomori S., Igarashi Y. Sphingosine and its methylated derivative N,N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines. Int J Cancer. 1996 May 3;66(3):358–366. doi: 10.1002/(SICI)1097-0215(19960503)66:3<358::AID-IJC16>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  83. Tolleson W. H., Couch L. H., Melchior W. B., Jr, Jenkins G. R., Muskhelishvili M., Muskhelishvili L., McGarrity L. J., Domon O., Morris S. M., Howard P. C. Fumonisin B1 induces apoptosis in cultured human keratinocytes through sphinganine accumulation and ceramide depletion. Int J Oncol. 1999 May;14(5):833–843. doi: 10.3892/ijo.14.5.833. [DOI] [PubMed] [Google Scholar]
  84. Tsunoda M., Sharma R. P., Riley R. T. Early fumonisin B1 toxicity in relation to disrupted sphingolipid metabolism in male BALB/c mice. J Biochem Mol Toxicol. 1998;12(5):281–289. doi: 10.1002/(sici)1099-0461(1998)12:5<281::aid-jbt4>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  85. Ueda N., Kaushal G. P., Hong X., Shah S. V. Role of enhanced ceramide generation in DNA damage and cell death in chemical hypoxic injury to LLC-PK1 cells. Kidney Int. 1998 Aug;54(2):399–406. doi: 10.1046/j.1523-1755.1998.00008.x. [DOI] [PubMed] [Google Scholar]
  86. Voss K. A., Chamberlain W. J., Bacon C. W., Herbert R. A., Walters D. B., Norred W. P. Subchronic feeding study of the mycotoxin fumonisin B1 in B6C3F1 mice and Fischer 344 rats. Fundam Appl Toxicol. 1995 Jan;24(1):102–110. doi: 10.1006/faat.1995.1012. [DOI] [PubMed] [Google Scholar]
  87. Voss K. A., Plattner R. D., Riley R. T., Meredith F. I., Norred W. P. In vivo effects of fumonisin B1-producing and fumonisin B1-nonproducing Fusarium moniliforme isolates are similar: fumonisins B2 and B3 cause hepato- and nephrotoxicity in rats. Mycopathologia. 1998;141(1):45–58. doi: 10.1023/a:1006810916344. [DOI] [PubMed] [Google Scholar]
  88. Wang E., Norred W. P., Bacon C. W., Riley R. T., Merrill A. H., Jr Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme. J Biol Chem. 1991 Aug 5;266(22):14486–14490. [PubMed] [Google Scholar]
  89. Wang E., Riley R. T., Meredith F. I., Merrill A. H., Jr Fumonisin B1 consumption by rats causes reversible, dose-dependent increases in urinary sphinganine and sphingosine. J Nutr. 1999 Jan;129(1):214–220. doi: 10.1093/jn/129.1.214. [DOI] [PubMed] [Google Scholar]
  90. Wang E., Ross P. F., Wilson T. M., Riley R. T., Merrill A. H., Jr Increases in serum sphingosine and sphinganine and decreases in complex sphingolipids in ponies given feed containing fumonisins, mycotoxins produced by Fusarium moniliforme. J Nutr. 1992 Aug;122(8):1706–1716. doi: 10.1093/jn/122.8.1706. [DOI] [PubMed] [Google Scholar]
  91. Wattenberg E. V., Badria F. A., Shier W. T. Activation of mitogen-activated protein kinase by the carcinogenic mycotoxin fumonisin B1. Biochem Biophys Res Commun. 1996 Oct 14;227(2):622–627. doi: 10.1006/bbrc.1996.1555. [DOI] [PubMed] [Google Scholar]
  92. Wieder T., Orfanos C. E., Geilen C. C. Induction of ceramide-mediated apoptosis by the anticancer phospholipid analog, hexadecylphosphocholine. J Biol Chem. 1998 May 1;273(18):11025–11031. doi: 10.1074/jbc.273.18.11025. [DOI] [PubMed] [Google Scholar]
  93. Witty J. P., Bridgham J. T., Johnson A. L. Induction of apoptotic cell death in hen granulosa cells by ceramide. Endocrinology. 1996 Dec;137(12):5269–5277. doi: 10.1210/endo.137.12.8940345. [DOI] [PubMed] [Google Scholar]
  94. Xu J., Yeh C. H., Chen S., He L., Sensi S. L., Canzoniero L. M., Choi D. W., Hsu C. Y. Involvement of de novo ceramide biosynthesis in tumor necrosis factor-alpha/cycloheximide-induced cerebral endothelial cell death. J Biol Chem. 1998 Jun 26;273(26):16521–16526. doi: 10.1074/jbc.273.26.16521. [DOI] [PubMed] [Google Scholar]
  95. Yates A. J., Rampersaud A. Sphingolipids as receptor modulators. An overview. Ann N Y Acad Sci. 1998 Jun 19;845:57–71. doi: 10.1111/j.1749-6632.1998.tb09662.x. [DOI] [PubMed] [Google Scholar]
  96. Yeung J. M., Wang H. Y., Prelusky D. B. Fumonisin B1 induces protein kinase C translocation via direct interaction with diacylglycerol binding site. Toxicol Appl Pharmacol. 1996 Nov;141(1):178–184. doi: 10.1006/taap.1996.0274. [DOI] [PubMed] [Google Scholar]
  97. Yin J. J., Smith M. J., Eppley R. M., Page S. W., Sphon J. A. Effects of fumonisin B1 on lipid peroxidation in membranes. Biochim Biophys Acta. 1998 Apr 22;1371(1):134–142. doi: 10.1016/s0005-2736(98)00018-2. [DOI] [PubMed] [Google Scholar]
  98. Yoo H. S., Norred W. P., Showker J., Riley R. T. Elevated sphingoid bases and complex sphingolipid depletion as contributing factors in fumonisin-induced cytotoxicity. Toxicol Appl Pharmacol. 1996 Jun;138(2):211–218. doi: 10.1006/taap.1996.0119. [DOI] [PubMed] [Google Scholar]
  99. Yoo H. S., Norred W. P., Wang E., Merrill A. H., Jr, Riley R. T. Fumonisin inhibition of de novo sphingolipid biosynthesis and cytotoxicity are correlated in LLC-PK1 cells. Toxicol Appl Pharmacol. 1992 May;114(1):9–15. doi: 10.1016/0041-008x(92)90090-f. [DOI] [PubMed] [Google Scholar]
  100. Zacharias C., van Echten-Deckert G., Wang E., Merrill A. H., Jr, Sandhoff K. The effect of fumonisin B1 on developing chick embryos: correlation between de novo sphingolipid biosynthesis and gross morphological changes. Glycoconj J. 1996 Apr;13(2):167–175. doi: 10.1007/BF00731491. [DOI] [PubMed] [Google Scholar]
  101. van der Westhuizen L., Shephard G. S., Snyman S. D., Abel S., Swanevelder S., Gelderblom W. C. Inhibition of sphingolipid biosynthesis in rat primary hepatocyte cultures by fumonisin B1 and other structurally related compounds. Food Chem Toxicol. 1998 Jun;36(6):497–503. doi: 10.1016/s0278-6915(98)00012-x. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES