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Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance

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Abstract

The trichothecene mycotoxin deoxynivalenol (DON) is produced in wheat, barley and corn following infestation by the fungus Fusarium in the field and during storage. Colloquially known as “vomitoxin” because of its emetic effects in pigs, DON has been associated with human gastroenteritis. Since DON is commonly detected in cereal foods, there are significant questions regarding the risks of acute poisoning and chronic effects posed to persons ingesting this trichothecene. A further challenge is how to best manage perceived risks without rendering critical food staples unavailable to an ever-expanding world population. In experimental animal models, acute DON poisoning causes emesis, whereas chronic low-dose exposure elicits anorexia, growth retardation, immunotoxicity as well as impaired reproduction and development resulting from maternal toxicity. Pathophysiologic effects associated with DON include altered neuroendocrine signaling, proinflammatory gene induction, disruption of the growth hormone axis, and altered gut integrity. At the cellular level, DON induces ribotoxic stress thereby disrupting macromolecule synthesis, cell signaling, differentiation, proliferation, and death. There is a need to better understand the mechanistic linkages between these early dose-dependent molecular effects and relevant pathological sequelae. Epidemiological studies are needed to determine if relationships exist between consumption of high DON levels and incidence of both gastroenteritis and potential chronic diseases. From the perspective of human health translation, a particularly exciting development is the availability of biomarkers of exposure (e.g. DON glucuronide) and effect (e.g. IGF1) now make it possible to study the relationship between DON consumption and growth retardation in susceptible human populations such as children and vegetarians. Ultimately, a fusion of basic and translational research is needed to validate or refine existing risk assessments and regulatory standards for this common mycotoxin.

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References

  • Abbas HK, Mirocha CJ, Tuite J (1986) Natural occurrence of deoxynivalenol, 15-acetyl-deoxynivalenol, and zearalenone in refusal factor corn stored since 1972. Appl Environ Microbiol 51:841–843

    CAS  PubMed  Google Scholar 

  • Accensi F, Pinton P, Callu P, Abella-Bourges N, Guelfi JF, Grosjean F, Oswald IP (2006) Ingestion of low doses of deoxynivalenol does not affect hematological, biochemical, or immune responses of piglets. J Anim Sci 84:1935–1942

    Article  CAS  PubMed  Google Scholar 

  • Amuzie CJ, Pestka JJ (2010) Suppression of insulin-like growth factor acid-labile subunit expression–a novel mechanism for deoxynivalenol-induced growth retardation. Toxicol Sci 113:412–421

    Article  CAS  PubMed  Google Scholar 

  • Amuzie CJ, Shinozuka J, Pestka JJ (2009) Induction of suppressors of cytokine signaling by the trichothecene deoxynivalenol in the mouse. Toxicol Sci 111:277–287

    Article  CAS  PubMed  Google Scholar 

  • Arnold DL, McGuire PF, Nera EA, Karpinski KF, Bickis MG, Zawidzka ZZ, Fernie S, Vesonder RF (1986) The toxicity of orally administered deoxynivalenol (vomitoxin) in rats and mice. Food Chem Toxicol 24:935–941

    Article  CAS  PubMed  Google Scholar 

  • Azcona OJ, Ouyang Y, Murtha J, Chu FS, Pestka JJ (1995) Induction of cytokine mRNAs in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol): relationship to toxin distribution and protein synthesis inhibition. Toxicol Appl Pharmacol 133:109–120

    Article  Google Scholar 

  • Bae HK, Pestka JJ (2008) Deoxynivalenol induces p38 interaction with the ribosome in monocytes and macrophages. Toxicol Sci 105:59–66

    Article  CAS  PubMed  Google Scholar 

  • Bae HK, Gray JS, Li M, Vines L, Kim J, Pestka JJ (2010) Hematopoietic cell kinase associates with the 40S ribosomal subunit and mediates the ribotoxic stress response to deoxynivalenol in mononuclear phagocytes. Toxicol Sci 115:444–452

    Article  CAS  PubMed  Google Scholar 

  • Bensassi F, El Golli-Bennour E, Abid-Essefi S, Bouaziz C, Hajlaoui MR, Bacha H (2009) Pathway of deoxynivalenol-induced apoptosis in human colon carcinoma cells. Toxicology 264:104–109

    Article  CAS  PubMed  Google Scholar 

  • Bergsjo B, Matre T, Nafstad I (1992) Effects of diets with graded levels of deoxynivalenol on performance in growing pigs. Zentralbl Veterinarmed[A] 39:752–758

    CAS  Google Scholar 

  • Bergsjo B, Langseth W, Nafstad I, Jansen JH, Larsen HJ (1993) The effects of naturally deoxynivalenol-contaminated oats on the clinical condition, blood parameters, performance and carcass composition of growing pigs. Vet Res Commun 17:283–294

    Article  CAS  PubMed  Google Scholar 

  • Berthiller F, Dall’Asta C, Schuhmacher R, Lemmens M, Adam G, Krska R (2005) Masked mycotoxins: determination of a deoxynivalenol glucoside in artificially and naturally contaminated wheat by liquid chromatography-tandem mass spectrometry. J Agric Food Chem 53:3421–3425

    Article  CAS  PubMed  Google Scholar 

  • Bhat RV, Beedu SR, Ramakrishna Y, Munshi KL (1989) Outbreak of trichothecene mycotoxicosis associated with consumption of mould-damaged wheat production in Kashmir Valley, India. Lancet 333:35–37

    Article  Google Scholar 

  • Borison HL (1989) Area postrema: chemoreceptor circumventricular organ of the medulla oblongata. Prog Neurobiol 32:351–390

    Article  CAS  PubMed  Google Scholar 

  • Canady RA, Coker RD, Rgan SK, Krska R, Kuiper-Goodman T, Olsen M, Pestka JJ, Resnik S, Schlatter J (2001) Deoxynivalenol. Safety evaluation of certain mycotoxins in food. Fifty-sixth report of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series 47. International Programme on Chemical Safety–World Health Organization–Geneva, pp 420–555

  • Castillo MA, Montes R, Navarro A, Segarra R, Cuesta G, Hernandez E (2008) Occurrence of deoxynivalenol and nivalenol in Spanish corn-based food products. J Food Compos Anal 21:423–427

    Article  CAS  Google Scholar 

  • Cecarini V, Gee J, Fioretti E, Amici M, Angeletti M, Eleuteri AM, Keller JN (2007) Protein oxidation and cellular homeostasis: emphasis on metabolism. Biochim Biophys Acta 1773:93–104

    Article  CAS  PubMed  Google Scholar 

  • Cherla RP, Lee SY, Mees PL, Tesh VL (2006) Shiga toxin 1-induced cytokine production is mediated by MAP kinase pathways and translation initiation factor eIF4E in the macrophage-like THP-1 cell line. J Leukoc Biol 79:397–407

    Article  CAS  PubMed  Google Scholar 

  • Choi HJ, Yang H, Park SH, Moon Y (2009) HuR/ELAVL1 RNA binding protein modulates interleukin-8 induction by muco-active ribotoxin deoxynivalenol. Toxicol Appl Pharmacol 240:46–54

    Article  CAS  PubMed  Google Scholar 

  • Chung YJ, Zhou HR, Pestka JJ (2003) Transcriptional and posttranscriptional roles for p38 mitogen-activated protein kinase in upregulation of TNF-alpha expression by deoxynivalenol (vomitoxin). Toxicol Appl Pharmacol 193:188–201

    Article  CAS  PubMed  Google Scholar 

  • Clark DE, Wellman PJ, Harvey RB, Lerma MS (1987) Effects of vomitoxin (deoxynivalenol) on conditioned saccharin aversion and food consumption in adult rats. Pharmacol Biochem Behav 27:247–252

    Article  CAS  PubMed  Google Scholar 

  • Collins TFX, Sprando RL, Black TN, Olejnik N, Eppley RM, Hines FA, Rorie J, Ruggles DI (2006) Effects of deoxynivalenol (DON, vomitoxin) on in utero development in rats. Food Chem Toxicol 44:747–757

    Article  CAS  PubMed  Google Scholar 

  • Croker BA, Kiu H, Nicholson SE (2008) SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19:414–422

    Article  CAS  PubMed  Google Scholar 

  • Debouck C, Haubruge E, Bollaerts P, van Bignoot D, Brostaux Y, Werry A, Rooze M (2001) Skeletal deformities induced by the intraperitoneal administration of deoxynivalenol (vomitoxin) in mice. Int Orthop 25:194–198

    Article  CAS  PubMed  Google Scholar 

  • Der SD, Yang YL, Weissmann C, Williams BR (1997) A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci USA 94:3279–3283

    Article  CAS  PubMed  Google Scholar 

  • English BK, Ihle JN, Myracle A, Yi T (1993) Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages. J Exp Med 178:1017–1022

    Article  CAS  PubMed  Google Scholar 

  • English BK, Orlicek SL, Mei Z, Meals EA (1997) Bacterial LPS and IFN-gamma trigger the tyrosine phosphorylation of vav in macrophages: evidence for involvement of the hck tyrosine kinase. J Leukoc Biol 62:859–864

    CAS  PubMed  Google Scholar 

  • Eriksen GS, Alexander J (1998) Fusarium toxins in cereals-a risk assessment. Nordic Council of Ministers, Copenhagen

    Google Scholar 

  • Ernst M, Inglese M, Scholz GM, Harder KW, Clay FJ, Bozinovski S, Waring P, Darwiche R, Kay T, Sly P, Collins R, Turner D, Hibbs ML, Anderson GP, Dunn AR (2002) Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. J Exp Med 196:589–604

    Article  CAS  PubMed  Google Scholar 

  • Fioramonti J, Dupuy C, Dupuy J, Bueno L (1993) The mycotoxin, deoxynivalenol, delays gastric emptying through serotonin-3 receptors in rodents. J Pharmacol Exp Ther 266:1255–1260

    CAS  PubMed  Google Scholar 

  • Forsell JH, Witt MF, Tai JH, Jensen R, Pestka JJ (1986) Effects of 8-week exposure of the B6C3F1 mouse to dietary deoxynivalenol (vomitoxin) and zearalenone. Food Chem Toxicol 24:213–219

    Article  CAS  PubMed  Google Scholar 

  • Forsell JH, Jensen R, Tai JH, Witt M, Lin WS, Pestka JJ (1987) Comparison of acute toxicities of deoxynivalenol (vomitoxin) and 15-acetyldeoxynivalenol in the B6C3F1 mouse. Food Chem Toxicol 25:155–162

    Article  CAS  PubMed  Google Scholar 

  • Forsyth DM, Yoshizawa T, Morooka N, Tuite J (1977) Emetic and refusal activity of deoxynivalenol to swine. Appl Environ Microbiol 34:547–552

    CAS  PubMed  Google Scholar 

  • Friend DW, Trenholm HL, Elliot JI, Thompson BK, Hartin KE (1982) Effect of feeding vomitoxin-contaminated wheat to pigs. CanJ Anim Sci 62:1211–1222

    Article  CAS  Google Scholar 

  • Froquet R, Sibiril Y, Parent-Massin D (2001) Trichothecene toxicity on human megakaryocyte progenitors (CFU-MK). Human Exper Toxicol 20:84–89

    Article  CAS  Google Scholar 

  • Goh KC, deVeer MJ, Williamss BR (2000) The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin. EMBO J 19:4292–4297

    Article  CAS  PubMed  Google Scholar 

  • Gray JS, Pestka JJ (2007) Transcriptional regulation of deoxynivalenol-induced IL-8 expression in human monocytes. Toxicol Sci 99:502–511

    Article  CAS  PubMed  Google Scholar 

  • Gray JS, Bae HK, Li JC, Lau AS, Pestka JJ (2008) Double-stranded RNA-activated protein kinase mediates induction of interleukin-8 expression by deoxynivalenol, Shiga toxin 1, and ricin in monocytes. Toxicol Sci 105:322–330

    Article  CAS  PubMed  Google Scholar 

  • Groopman JD, Kensler TW (2005) Role of metabolism and viruses in aflatoxin-induced liver cancer. Toxicol Appl Pharmacol 206:131–137

    Article  CAS  PubMed  Google Scholar 

  • Grove JF (1988) Non-macrocyclic trichothecenes. Nat Prod Rep 5:187–209

    Article  CAS  PubMed  Google Scholar 

  • Grove JF (1993) Macrocyclic trichothecenes. Nat Prod Rep 10:429–448

    Article  CAS  Google Scholar 

  • Grove JF (2000) Non-macrocyclic trichothecenes. Part 2. Prog Chem Org Nat Prod 69:1–70

    Google Scholar 

  • He K, Pestka JJ (2010) Deoxynivalenol-induced modulation of microRNA expression in RAW 264.7 macrophages-A potential novel mechanism for translational inhibition. The Toxicologist (Toxicol Sci) 114(Suppl):310

    Google Scholar 

  • Hopton RP, Turner E, Burley VJ, Turner PC, Fisher J (2010) Urine metabolite analysis as a function of deoxynivalenol exposure: an NMR-based metabolomics investigation. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 27:255–261

    CAS  PubMed  Google Scholar 

  • Hughes DM, Gahl MJ, Graham CH, Grieb SL (1999) Overt signs of toxicity to dogs and cats of dietary deoxynivalenol. J Anim Sci 77:693–700

    CAS  PubMed  Google Scholar 

  • Hunder G, Schumann K, Strugala G, Gropp J, Fichtl B, Forth W (1991) Influence of subchronic exposure to low dietary deoxynivalenol, a trichothecene mycotoxin, on intestinal absorption of nutrients in mice. Food Chem Toxicol 29:809–814

    Article  CAS  PubMed  Google Scholar 

  • Hunt JN (1980) A possible relation between the regulation of gastric emptying and food intake. Am J Physiol 239:G1–G4

    CAS  PubMed  Google Scholar 

  • Islam Z, Pestka JJ (2003) Role of IL-1 beta in endotoxin potentiation of deoxynivalenol-induced corticosterone response and leukocyte apoptosis in mice. Toxicol Sci 74:93–102

    Article  CAS  PubMed  Google Scholar 

  • Islam Z, Pestka JJ (2006) LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse. Toxicol Appl Pharmacol 211:53–63

    Article  CAS  PubMed  Google Scholar 

  • Islam Z, Nagase M, Ota A, Ueda S, Yoshizawa T, Sakato N (1998a) Structure-function relationship of T-2 toxin and its metabolites in inducing thymic apoptosis in vivo in mice. Biosci Biotechnol Biochem 62:1492–1497

    Article  CAS  PubMed  Google Scholar 

  • Islam Z, Nagase M, Yoshizawa T, Yamauchi KE, Sakato N (1998b) T-2 toxin induces thymic apoptosis in vivo in mice. Toxicol Appl Pharmacol 148:205–214

    Article  CAS  PubMed  Google Scholar 

  • Islam Z, Moon YS, Zhou HR, King LE, Fraker PJ, Pestka JJ (2002) Endotoxin potentiation of trichothecene-induced lymphocyte apoptosis is mediated by up-regulation of glucocorticoids. Toxicol Appl Pharmacol 180:43–55

    Article  CAS  PubMed  Google Scholar 

  • Islam Z, King LE, Fraker PJ, Pestka JJ (2003) Differential induction of glucocorticoid-dependent apoptosis in murine lymphoid subpopulations in vivo following coexposure to lipopolysaccharide and vomitoxin (deoxynivalenol). Toxicol Appl Pharmacol 187:69–79

    Article  CAS  PubMed  Google Scholar 

  • Islam Z, Gray JS, Pestka JJ (2006) p38 Mitogen-activated protein kinase mediates IL-8 induction by the ribotoxin deoxynivalenol in human monocytes. Toxicol Appl Pharmacol 213:235–244

    Article  CAS  PubMed  Google Scholar 

  • Iverson F, Armstrong C, Nera E, Truelove J, Fernie S, Scott P, Stapley R, Hayward S, Gunner S (1995) Chronic feeding study of deoxynivalenol in B6C3F1 male and female mice. Teratog Carcinog Mutagen 15:283–306

    Article  CAS  PubMed  Google Scholar 

  • Jia Q, Zhou HR, Bennink M, Pestka JJ (2004) Docosahexaenoic acid attenuates mycotoxin-induced immunoglobulin a nephropathy, interleukin-6 transcription, and mitogen-activated protein kinase phosphorylation in mice. J Nutr 134:3343–3349

    CAS  PubMed  Google Scholar 

  • Jia Q, Zhou HR, Shi Y, Pestka JJ (2006) Docosahexaenoic acid consumption inhibits deoxynivalenol-induced CREB/ATF1 activation and IL-6 gene transcription in mouse macrophages. J Nutr 136:366–372

    CAS  PubMed  Google Scholar 

  • Joffe AZ (1978) Fusarium poae and F. sporotichiodes as principal causal agents of alimentary toxic aleukia. In: Wyllie TD, Morehouse LG (eds) Mycotoxic fungi, mycotoxins, mycotoxicoses: an encylcopedic handbook. Dekker, New York, pp 21–86

    Google Scholar 

  • Khera KS, Whalen C, Angers G, Kuiper Goodman T (1982a) The embryotoxicity of vomitoxin in mice. Teratology 25:A54–A54

    Google Scholar 

  • Khera KS, Whalen C, Angers G, Vesonder RF, Kuiper-Goodman T (1982b) Embryotoxicity of 4-deoxynivalenol (vomitoxin) in mice. Bull Environ Contam Toxicol 29:487–491

    Article  CAS  PubMed  Google Scholar 

  • Khera KS, Arnold DL, Whalen C, Angers G, Scott PM (1984) Vomitoxin (4-deoxynivalenol): effects on reproduction of mice and rats. Toxicol Appl Pharmacol 74:345–356

    Article  CAS  PubMed  Google Scholar 

  • Khera KS, Whalen C, Angers G (1986) A teratology study on vomitoxin (4-deoxynivalenol) in rabbits. Food Chem Toxicol 24:421–424

    Article  CAS  PubMed  Google Scholar 

  • Kincaid MM, Cooper AA (2007) Misfolded proteins traffic from the endoplasmic reticulum (ER) due to ER export signals. Mol Biol Cell 18:455–463

    Article  CAS  PubMed  Google Scholar 

  • Kinser S, Jia Q, Li M, Laughter A, Cornwell P, Corton JC, Pestka J (2004) Gene expression profiling in spleens of deoxynivalenol-exposed mice: immediate early genes as primary targets. J Toxicol Environ Health A 67:1423–1441

    Article  CAS  PubMed  Google Scholar 

  • Kinser S, Li M, Jia Q, Pestka JJ (2005) Truncated deoxynivalenol-induced splenic immediate early gene response in mice consuming (n-3) polyunsaturated fatty acids. J Nutr Biochem 16:88–95

    Article  CAS  PubMed  Google Scholar 

  • Kolf-Clauw M, Castellote J, Joly B, Bourges-Abella N, Raymond-Letron I, Pinton P, Oswald IP (2009) Development of a pig jejunal explant culture for studying the gastrointestinal toxicity of the mycotoxin deoxynivalenol: histopathological analysis. Toxicol In Vitro 23:1580–1584

    Article  CAS  PubMed  Google Scholar 

  • Korcheva V, Wong J, Lindauer M, Jacoby DB, Iordanov MS, Magun B (2007) Role of apoptotic signaling pathways in regulation of inflammatory responses to ricin in primary murine macrophages. Mol Immunol 44:2761–2771

    Article  CAS  PubMed  Google Scholar 

  • Krantis AC, Durst T (2006) Novel multi-ring organic compounds for regulating gut motility, food intake and weight gain. World Intellectual Property Organization. WO/2006/006082. http://www.wipo.int/pctdb/en/wo.jsp?WO=2006006082

  • Kuiper-Goodman T (1994) Prevention of mycotoxicoses through risk management and risk assessment. In: Miller JD, Trenholm HL (eds) Mycotoxins in grain. Eagan Press, St.Paul, pp 439–469

    Google Scholar 

  • Larsen JC, Hunt J, Perrin I, Ruckenbauer P (2004) Workshop on trichothecenes with a focus on DON: summary report. Toxicol Lett 153:1–22

    Article  CAS  PubMed  Google Scholar 

  • Lautraite S, ParentMassin D, Rio B, Hoellinger H (1997) In vitro toxicity induced by deoxynivalenol (DON) on human and rat granulomonocytic progenitors. Cell Biol Toxicol 13:175–183

    Article  CAS  PubMed  Google Scholar 

  • Le Drean G, Auffret M, Batina P, Arnold F, Sibiril Y, Arzur D, Parent-Massin D (2005) Myelotoxicity of trichothecenes and apoptosis: an in vitro study on human cord blood CD34(+) hematopoietic progenitor. Toxicol In Vitro 19:1015–1024

    Article  CAS  PubMed  Google Scholar 

  • Leblanc JC, Tard A, Volatier JL, Verger P (2005) Estimated dietary exposure to principal food mycotoxins from the first French Total Diet Study. Food Addit Contam 22:652–672

    Article  CAS  PubMed  Google Scholar 

  • Leyva-Illades D, Cherla RP, Galindo CL, Chopra AK, Tesh VL (2010) Global transcriptional response of macrophage-like THP-1 cells to Shiga toxin type 1. Infect Immun (in press)

  • Li Y (2007) Sensory signal transduction in the vagal primary afferent neurons. Curr Med Chem 14:2554–2563

    Article  CAS  PubMed  Google Scholar 

  • Li MX, Pestka JJ (2008) Comparative induction of 28S ribosomal RNA cleavage by ricin and the trichothecenes deoxynivalenol and T-2 toxin in the macrophage. Toxicol Sci 105:67–78

    Article  CAS  PubMed  Google Scholar 

  • Li SG, Ouyang YL, Dong WM, Pestka JJ (1997) Superinduction of IL-2 gene expression by vomitoxin (deoxynivalenol) involves increased mRNA stability. Toxicol Appl Pharmacol 147:331–342

    Article  CAS  PubMed  Google Scholar 

  • Li S, Ouyang Y, Yang GH, Pestka JJ (2000) Modulation of transcription factor AP-1 activity in murine EL-4 thymoma cells by vomitoxin (deoxynivalenol). Toxicol Appl Pharmacol 163:17–25

    Article  CAS  PubMed  Google Scholar 

  • Luo X (1994) Food poisoning caused by Fusarium toxins. Proceedings of the Second Asian Conference on Food Safety. ILSI Thailand, pp 129–136

  • Maresca M, Mahfoud R, Garmy N, Fantini J (2002) The mycotoxin deoxynivalenol affects nutrient absorption in human intestinal epithelial cells. J Nutr 132:2723–2731

    CAS  PubMed  Google Scholar 

  • Maresca M, Yahi N, Younes-Sakr L, Boyron M, Caporiccio B, Fantini J (2008) Both direct and indirect effects account for the pro-inflammatory activity of enteropathogenic mycotoxins on the human intestinal epithelium: stimulation of interleukin-8 secretion, potentiation of interleukin-1 beta effect and increase in the transepithelial passage of commensal bacteria. Toxicol Appl Pharmacol 228:84–92

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin JE, Bin-Umer MA, Tortora A, Mendez N, McCormick S, Tumer NE (2009) A genome-wide screen in Saccharomyces cerevisiae reveals a critical role for the mitochondria in the toxicity of a trichothecene mycotoxin. Proc Natl Acad Sci USA 106:21883–21888

    Article  CAS  PubMed  Google Scholar 

  • McMullen M, Jones R, Gallenberg D (1997) Scab of wheat and barley: a re-emerging disease of devasting impact. Plant Dis 81:1340–1348

    Article  Google Scholar 

  • Meky FA, Turner PC, Ashcroft AE, Miller JD, Qiao YL, Roth MJ, Wild CP (2003) Development of a urinary biomarker of human exposure to deoxynivalenol. Food Chem Toxicol 41:265–273

    Article  CAS  PubMed  Google Scholar 

  • Miura K, Nakajima Y, Yamanaka N, Terao K, Shibato T, Ishino S (1998) Induction of apoptosis with fusarenon-X in mouse thymocytes. Toxicology 127:195–206

    Article  CAS  PubMed  Google Scholar 

  • Moon Y, Pestka JJ (2002) Vomitoxin-induced cyclooxygenase-2 gene expression in macrophages mediated by activation of ERK and p38 but not JNK mitogen-activated protein kinases. Toxicol Sci 69:373–382

    Article  CAS  PubMed  Google Scholar 

  • Moon Y, Pestka JJ (2003) Cyclooxygenase-2 mediates interleukin-6 upregulation by vomitoxin (deoxynivalenol) in vitro and in vivo. Toxicol Appl Pharmacol 187:80–88

    Article  CAS  PubMed  Google Scholar 

  • Moon Y, Uzarski R, Pestka JJ (2003) Relationship of trichothecene structure to COX-2 induction in the macrophage: selective action of type B (8-keto) trichothecenes. J Toxicol Environ Health A 66:1967–1983

    Article  CAS  PubMed  Google Scholar 

  • Morrissey RE (1984) Teratological study of Fischer rats fed diet containing added vomitoxin. Food Chem Toxicol 22:453–457

    Article  CAS  PubMed  Google Scholar 

  • Morrissey RE, Vesonder RF (1985) Effect of deoxynivalenol (vomitoxin) on fertility, pregnancy, and postnatal development of Sprague-Dawley rats. Appl Environ Microbiol 49:1062–1066

    CAS  PubMed  Google Scholar 

  • Morrissey RE, Norred WP, Vesonder RF (1985) Subchronic toxicity of vomitoxin in Sprague-Dawley rats. Food Chem Toxicol 23:995–999

    Article  CAS  PubMed  Google Scholar 

  • Nagase M, Alam MM, Tsushima A, Yoshizawa T, Sakato N (2001) Apoptosis induction by T-2 toxin: activation of caspase-9, caspase-3, and DFF-40/CAD through cytosolic release of cytochrome c in HL-60 cells. Biosci Biotechnol Biochem 65:1741–1747

    Article  CAS  PubMed  Google Scholar 

  • Nejdfors P, Ekelund M, Jeppsson B, Westrom BR (2000) Mucosal in vitro permeability in the intestinal tract of the pig, the rat, and man: spe. Scand J Gastroenterol 35:501–507

    Article  CAS  PubMed  Google Scholar 

  • Nielsen C, Lippke H, Didier A, Dietrich R, Martlbauer E (2009) Potential of deoxynivalenol to induce transcription factors in human hepatoma cells. Mol Nutr Food Res 53:479–491

    Article  CAS  PubMed  Google Scholar 

  • Ok HE, Kim HJ, Cho TY, Oh KS, Chun HS (2009) Determination of deoxynivalenol in cereal-based foods and estimation of dietary exposure. J Toxicol Environ Health Part A Current Issues 72:1424–1430

    Article  CAS  Google Scholar 

  • Ossenkopp KP, Hirst M, Rapley WA (1994) Deoxynivalenol (vomitoxin)-induced conditioned taste aversions in rats are mediated by the chemosensitive area postrema. Pharmacol Biochem Behav 47:363–367

    Article  CAS  PubMed  Google Scholar 

  • Ouyang YL, Li S, Pestka JJ (1996) Effects of vomitoxin (deoxynivalenol) on transcription factor NF-kappa B/Rel binding activity in murine EL-4 thymoma and primary CD4 + T cells. Toxicol Appl Pharmacol 140:328–336

    Article  CAS  PubMed  Google Scholar 

  • Paterson RRM, Lima N (2009) How will climate change affect mycotoxins in food? Food Res Int (in press)

  • Pestka JJ (2007) Deoxynivalenol: Toxicity, mechanisms and animal health risks. Anim Feed Sci Technol 137:283–298

    Article  CAS  Google Scholar 

  • Pestka JJ (2008) Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Addit Contam (in press)

  • Pestka JJ, Amuzie CJ (2008) Tissue distribution and proinflammatory cytokine gene expression following acute oral exposure to deoxynivalenol: comparison of weanling and adult mice. Food Chem Toxicol 46:2826–2831

    Article  CAS  PubMed  Google Scholar 

  • Pestka JJ, Smolinski AT (2005) Deoxynivalenol: toxicology and potential effects on humans. J Toxicol Environ Health B Crit Rev 8:39–69

    CAS  PubMed  Google Scholar 

  • Pestka JJ, Lin WS, Miller ER (1987) Emetic activity of the trichothecene 15-acetyldeoxynivalenol in swine. Food Chem Toxicol 25:855–858

    Article  CAS  PubMed  Google Scholar 

  • Pestka JJ, Yan D, King LE (1994) Flow cytometric analysis of the effects of in vitro exposure to vomitoxin (deoxynivalenol) on apoptosis in murine T-cells, B-cells and IgA(+)-cells. Food Chem Toxicol 32:1125–1136

    Article  CAS  PubMed  Google Scholar 

  • Pestka JJ, Zhou HR, Moon Y, Chung YJ (2004) Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox. Toxicol Lett 153:61–73

    Article  CAS  PubMed  Google Scholar 

  • Pestka JJ, Uzarski RL, Islam Z (2005) Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes. Toxicology 206:207–219

    Article  CAS  PubMed  Google Scholar 

  • Pieters MN, Fiolet DCM, Baars AJ (1998) Deoxynivalenol: derivation of concentration limits in wheat and wheat containing food products. National Institute of Public Health and the Environment, Bilthoven, pp 1–32

    Google Scholar 

  • Pinton P, Nougayrede JP, Del Rio JC, Moreno C, Marin DE, Ferrier L, Bracarense AP, Kolf-Clauw M, Oswald IP (2009) The food contaminant deoxynivalenol, decreases intestinal barrier permeability and reduces claudin expression. Toxicol Appl Pharmacol 237:41–48

    Article  CAS  PubMed  Google Scholar 

  • Poapolathep A, Kumagai S, Suzuki H, Doi K (2004) Development of early apoptosis and changes in T-cell subsets in mouse thymocyte primary cultures treated with nivalenol. Exp Mol Pathol 77:149–152

    Article  CAS  PubMed  Google Scholar 

  • Prelusky DB (1993) The effect of low-level deoxynivalenol on neurotransmitter levels measured in pig cerebral spinal fluid. J Environ Sci Health B 28:731–761

    Article  CAS  PubMed  Google Scholar 

  • Prelusky DB (1994) The effect of deoxynivalenol on serotoninergic neurotransmitter levels in pig blood. J Environ Sci Health B 29:1203–1218

    Article  CAS  PubMed  Google Scholar 

  • Prelusky DB, Trenholm HL (1993) The efficacy of various classes of anti-emetics in preventing deoxynivalenol-induced vomiting in swine. Nat Toxins 1:296–302

    Article  CAS  PubMed  Google Scholar 

  • Prelusky DB, Gerdes RG, Underhill KL, Rotter BA, Jui PY, Trenholm HL (1994) Effects of low-level dietary deoxynivalenol on haematological and clinical parameters of the pig. Nat Toxins 2:97–104

    Article  CAS  PubMed  Google Scholar 

  • Prelusky DB, Rotter BA, Thompson BK, Trenholm HL (1997) Effect of the appetite stimulant cyproheptadine on deoxynivalenol-induced reductions in feed consumption and weight gain in the mouse. J Environ Sci Health B 32:429–448

    Article  CAS  PubMed  Google Scholar 

  • Rasmussen PH, Ghorbani F, Berg T (2003) Deoxynivalenol and other Fusarium toxins in wheat and rye flours on the Danish market. Food Addit Contam 20:396–404

    Article  CAS  PubMed  Google Scholar 

  • Rio B, Lautraite S, Parent-Massin D (1997) In vitro toxicity of trichothecenes on human erythroblastic progenitors. Hum Exp Toxicol 16:673–679

    Article  CAS  PubMed  Google Scholar 

  • Robbana-Barnat S, Loridon-Rosa B, Cohen H, Lafarge-Frayssinet C, Neish GA, Frayssinet C (1987) Protein synthesis inhibition and cardiac lesions associated with deoxynivalenol ingestion in mice. Food Addit Contam 4:49–56

    CAS  PubMed  Google Scholar 

  • Rocha O, Ansari K, Doohan FM (2005) Effects of trichothecene mycotoxins on eukaryotic cells: a review. Food Addit Contam 22:369–378

    Article  CAS  PubMed  Google Scholar 

  • Roth RA, Harkema JR, Pestka JP, Ganey PE (1997) Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents? Toxicol Appl Pharmacol 147:300–311

    Article  CAS  PubMed  Google Scholar 

  • Rotter BA, Thompson BK, Lessard M, Trenholm HL, Tryphonas H (1994a) Influence of low-level exposure to Fusarium mycotoxins on selected immunological and hematological parameters in young swine. Fundam Appl Toxicol 23:117–124

    Article  CAS  PubMed  Google Scholar 

  • Rotter BA, Thompson BK, Rotter RG (1994b) Optimization of the mouse bioassay for deoxynivalenol as an alternative to large animal studies. Bull Environ Contam Toxicol 53:642–647

    Article  CAS  PubMed  Google Scholar 

  • Rotter BA, Prelusky DB, Pestka JJ (1996) Toxicology of deoxynivalenol (vomitoxin). J Toxicol Environ Health 48:1–34

    Article  CAS  PubMed  Google Scholar 

  • Schollenberger M, Drochner W, Rufle M, Suchy S, Terry-Jara H, Muller HM (2005) Trichothecene toxins in different groups of conventional and organic bread of the German market. J Food Compos Anal 18:69–78

    Article  CAS  Google Scholar 

  • Schothorst RC, van Egmond HP (2004) Report from SCOOP task 3.2.10 “collection of occurrence data of Fusarium toxins in food and assessment of dietary intake by the population of EU member states”–Subtask: trichothecenes. Toxicol Lett 153:133–143

    Article  CAS  PubMed  Google Scholar 

  • Sergent T, Parys M, Garsou S, Pussemier L, Schneider YJ, Larondelle Y (2006) Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. Toxicol Lett 164:167–176

    Article  CAS  PubMed  Google Scholar 

  • Shi YH, Porter K, Parameswaran N, Bae HK, Pestka JJ (2009) Role of GRP78/BiP Degradation and ER Stress in deoxynivalenol-induced interleukin-6 upregulation in the macrophage. Toxicol Sci 110:249–250

    Article  CAS  Google Scholar 

  • Shifrin VI, Anderson P (1999) Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J Biol Chem 274:13985–13992

    Article  CAS  PubMed  Google Scholar 

  • Sprando RL, Collins TFX, Black TN, Olejnik N, Rorie JI, Eppley RM, Ruggles DI (2005) Characterization of the effect of deoxynivalenol on selected male reproductive endpoints. Food Chem Toxicol 43:623–635

    Article  CAS  PubMed  Google Scholar 

  • Sugita-Konishi Y, Pestka JJ (2001) Differential upregulation of TNF-alpha, IL-6, and IL-8 production by deoxynivalenol (vomitoxin) and other 8-ketotrichothecenes in a human macrophage model. J Toxicol Environ Health A 64:619–636

    Article  CAS  PubMed  Google Scholar 

  • Szelenyi I, Herold H, Gothert M (1994) Emesis induced in domestic pigs: a new experimental tool for detection of antiemetic drugs and for evaluation of emetogenic potential of new anticancer agents. J Pharmacol Toxicol Methods 32:109–116

    Article  CAS  PubMed  Google Scholar 

  • Thuvander A, Moller T, Barbieri HE, Jansson A, Salomonsson AC, Olsen M (2001) Dietary intake of some important mycotoxins by the Swedish population. Food Addit Contam 18:696–706

    CAS  PubMed  Google Scholar 

  • Ting JPY, Duncan JA, Lei Y (2010) How the noninflammasome NLRs function in the innate immune system. Science 327:286–290

    Article  CAS  PubMed  Google Scholar 

  • Trenholm HL, Hamilton RM, Friend DW, Thompson BK, Hartin KE (1984) Feeding trials with vomitoxin (deoxynivalenol)-contaminated wheat: effects on swine, poultry, and dairy cattle. J Am Vet Med Assoc 185:527–531

    CAS  PubMed  Google Scholar 

  • Tritscher AM, Page SW (2004) The risk assessment paradigm and its application for trichothecenes. Toxicol Lett 153:155–163

    Article  CAS  PubMed  Google Scholar 

  • Tryphonas H, Iverson F, So Y, Nera EA, McGuire PF, O’Grady L, Clayson DB, Scott PM (1986) Effects of deoxynivalenol (vomitoxin) on the humoral and cellular immunity of mice. Toxicol Lett 30:137–150

    Article  CAS  PubMed  Google Scholar 

  • Tsygankov AY, Shore SK (2004) Src: regulation, role in human carcinogenesis and pharmacological inhibitors. Curr Pharm Des 10:1745–1756

    Article  CAS  PubMed  Google Scholar 

  • Turner PC, Burley VJ, Rothwell JA, White KLM, Cade JE, Wild CP (2008) Dietary wheat reduction decreases the level of urinary deoxynivalenol in UK adults. J Expo Sci Environ Epidemiol 18:392–399

    Article  CAS  PubMed  Google Scholar 

  • Turner PC, Taylor EF, White KLM, Cade JE, Wild CP (2009) A comparison of 24 h urinary deoxynivalenol with recent v. average cereal consumption for UK adults. British J Nutr 102:1276–1284

    Article  CAS  Google Scholar 

  • Ueno Y (1983) General toxicology. In: Ueno Y (ed) Trichothecenes: chemical, biological, and toxicological aspects. Elsevier, New York, pp 135–146

    Google Scholar 

  • Uzarski RL, Pestka JJ (2003) Comparative susceptibility of B cells with different lineages to cytotoxicity and apoptosis induction by translational inhibitors. J Toxicol Environ Health A 66:2105–2118

    Article  CAS  PubMed  Google Scholar 

  • Uzarski RL, Islam Z, Pestka JJ (2003) Potentiation of trichothecene-induced leukocyte cytotoxicity and apoptosis by TNF-alpha and Fas activation. Chem Biol Interact 146:105–119

    Article  CAS  PubMed  Google Scholar 

  • Van der Heyden S, Goossens J, Vandenbroucke V, Vercauteren G, Chiers K, Pasmans F, Haesebrouck F, De Backer P, Croubels S, Ducatelle R (2009) Reduced expression of intestinal P-glycoprotein following ingestion of deoxynivalenol (DON) contaminated feed in pigs. J Comp Pathol 141:5

    Google Scholar 

  • Vesonder RF, Ciegler A, Jensen AH (1973) Isolation of the emetic principle from Fusarium-infected corn. Appl Microbiol 26:1008–1010

    CAS  PubMed  Google Scholar 

  • Voss KA (2010) A new perspective on deoxynivalenol and growth suppression. Toxicol Sci 113:281–283

    Article  CAS  PubMed  Google Scholar 

  • Williams BR (2001) Signal integration via PKR. SciSTKE 2001:RE2

  • Wong SS, Zhou HR, Marin-Martinez ML, Brooks K, Pestka JJ (1998) Modulation of IL-1beta, IL-6 and TNF-alpha secretion and mRNA expression by the trichothecene vomitoxin in the RAW 264.7 murine macrophage cell line. Food Chem Toxicol 36:409–419

    Article  CAS  PubMed  Google Scholar 

  • Wong S, Schwartz RC, Pestka JJ (2001) Superinduction of TNF-alpha and IL-6 in macrophages by vomitoxin (deoxynivalenol) modulated by mRNA stabilization. Toxicology 161:139–149

    Article  CAS  PubMed  Google Scholar 

  • Wong SS, Zhou HR, Pestka JJ (2002) Effects of vomitoxin (deoxynivalenol) on the binding of transcription factors AP-1, NF-kappaB, and NF-IL6 in raw 264.7 macrophage cells. J Toxicol Environ Health A 65:1161–1180

    Article  CAS  PubMed  Google Scholar 

  • Xu J, Yang S, Cai S, Dong J, Li X, Chen Z (2010) Identification of biochemical changes in lactovegetarian urine using 1H NMR spectroscopy and pattern recognition. Anal Bioanal Chem 396:1451–1463

    Article  CAS  PubMed  Google Scholar 

  • Yang GH, Jarvis BB, Chung YJ, Pestka JJ (2000a) Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation. Toxicol Appl Pharmacol 164:149–160

    Article  CAS  PubMed  Google Scholar 

  • Yang GH, Li S, Pestka JJ (2000b) Down-regulation of the endoplasmic reticulum chaperone GRP78/BiP by vomitoxin (Deoxynivalenol). Toxicol Appl Pharmacol 162:207–217

    Article  CAS  PubMed  Google Scholar 

  • Yazar S, Omurtag GZ (2008) Fumonisins, trichothecenes and zearalenone in cereals. Int J Mol Sci 9:2062–2090

    Article  CAS  PubMed  Google Scholar 

  • Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(2):1542–1552

    Article  CAS  PubMed  Google Scholar 

  • Yoshino N, Takizawa M, Akiba H, Okumura H, Tashiro F, Honda M, Ueno Y (1996) Transient elevation of intracellular calcium ion levels as an early event in T-2 toxin-induced apoptosis in human promyelotic cell line HL-60. Nat Toxins 4:234–241

    Article  CAS  PubMed  Google Scholar 

  • Yoshizawa T (1983) Trichothecenes–chemical, biological, and toxicological aspects. In: Ueno Y (ed) Dev, Food Sci. Red-mold diseases and natural occurence in Japan. Kodansha Ltd., Tokyo, pp 195–209

    Google Scholar 

  • Yoshizawa T, Morooka N (1973) Deoxynivalenol and its monoacetate: new mycotoxins from Fusaruium roseum and moldy barley. Agric Biol Chem 37:2933–2934

    CAS  Google Scholar 

  • Young LG, McGirr L, Valli VE, Lumsden JH, Lun A (1983) Vomitoxin in corn fed to young pigs. J Anim Sci 57:655–664

    CAS  PubMed  Google Scholar 

  • Zhou HR, Yan D, Pestka JJ (1997) Differential cytokine mRNA expression in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol): dose response and time course. Toxicol Appl Pharmacol 144:294–305

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Yan D, Pestka JJ (1998) Induction of cytokine gene expression in mice after repeated and subchronic oral exposure to vomitoxin (Deoxynivalenol): differential toxin-induced hyporesponsiveness and recovery. Toxicol Appl Pharmacol 151:347–358

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Harkema JR, Yan D, Pestka JJ (1999) Amplified proinflammatory cytokine expression and toxicity in mice coexposed to lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol). J Toxicol Environ Health 57:115–136

    Article  CAS  Google Scholar 

  • Zhou HR, Harkema JR, Hotchkiss JA, Yan D, Roth RA, Pestka JJ (2000) Lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol) synergistically induce apoptosis in murine lymphoid organs. Toxicol Sci 53:253–263

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Islam Z, Pestka JJ (2003a) Kinetics of lipopolysaccharide-induced transcription factor activation/inactivation and relation to proinflammatory gene expression in the murine spleen. Toxicol Appl Pharmacol 187:147–161

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Islam Z, Pestka JJ (2003b) Rapid, sequential activation of mitogen-activated protein kinases and transcription factors precedes proinflammatory cytokine mRNA expression in spleens of mice exposed to the trichothecene vomitoxin. Toxicol Sci 72:130–142

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Lau AS, Pestka JJ (2003c) Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicol Sci 74:335–344

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Islam Z, Pestka JJ (2005a) Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoxic trichothecene deoxynivalenol. Toxicol Sci 87:113–122

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Jia Q, Pestka JJ (2005b) Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Toxicol Sci 85:916–926

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the USDA, under a cooperative project with U.S. Wheat and Barley Scab Initiative (JJP). Any findings, opinions, conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of USDA. This project was also funded in part by Public Health Service Grant ES 3358 (JJP) from the National Institute for Environmental Health Sciences.

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  1. Department of Microbiology and Molecular Genetics, Michigan State University, 234 G.M. Trout Building, East Lansing, MI, 48824, USA

    James J. Pestka

  2. Department of Food Science and Human Nutrition, Michigan State University, 234 G.M. Trout Building, East Lansing, MI, 48824, USA

    James J. Pestka

  3. Center for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA

    James J. Pestka

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Pestka, J.J. Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance. Arch Toxicol 84, 663–679 (2010). https://doi.org/10.1007/s00204-010-0579-8

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