Abstract
Contamination of cereals with the trichothecene deoxynivalenol (DON) is a global problem in agriculture. DON-related cytotoxicity results from inhibition of translation preceded by a ribotoxic stress response, which is characterized by phosphorylation of the mitogen-activated protein kinases and activation of downstream transcription factors. In this study, we measured the expression of AP-1 associated transcription factor mRNA levels in six human cell lines (Hep-G2, A549, U937, A204, Jurkat, and CaCo-2) by using real-time RT-PCR. Previous work suggested that transcription factors mRNA and protein levels are affected by DON in Hep-G2 cells. In this study, we found significant cell-specific differences in mRNA levels for the transcription factors JUN, JUND, FOS, FOSL2, ATF3, and EGR1. After exposure to 1 µmol/l DON for 3 h, the induction of the transcription factor JUN was highest in the Jurkat (342-fold) and Hep-G2 (84-fold) cell lines. JUND expression was mainly affected in the immunocompetent cell-lines U937 (11-fold) and Jurkat (12-fold), whereas significant FOSL2 induction (5-fold) was only found in Jurkat cells. DON-induced expression of FOS was mainly observed in Hep-G2 (96-fold) and U937 cells (59-fold). In contrast, response of A549 cells to DON was characterized by a distinct induction of ATF3 (44-fold) and EGR1 (92-fold). Time- and concentration-dependent induction of the transcription factors by DON was studied in detail for Hep-G2, A549, A204, and U937 cells. Considering the chronic dietary exposure of humans, broader investigations on DON influence on cell signaling pathways are required to understand the impact of this mycotoxin on human health.
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Abbreviations
- DON:
-
Deoxynivalenol
References
Allen-Jennings AE, Hartman MG, Kociba GJ, Hai TW (2002) The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression. J Biol Chem 277:20020–20025
Bouaziz C, Sharaf El Dein O, El Golli E, Abid-Essefi S, Brenner C, Lemaire C, Bacha H (2008) Different apoptotic pathways induced by zearalenone, T-2 toxin and ochratoxin A in human hepatoma cells. Toxicology 254:19–28
Canady RA, Coker RD, Egan SK, Krska R, Kuiper-Goodman T,Olsen M, et al (2001) Deoxynivalenol. In: Safety evaluationof certain mycotoxins in food. Geneva:World HealthOrganization, pp 420–529
Clear RM, Patrick SK (2000) Fusarium head blight pathogens isolated from fusarium-damaged kernels of wheat in western Canada, 1993 to 1998. Can J Plant Pathol 22:51–60
Curtui V, Brockmeyer A, Dietrich R, Kappenstein O, Klaffke H, Lepschy J, Märtlbauer E, Schneider E, Seidler C, Thielert G, Usleber E, Weber R, Wolff J (2005) Deoxynivalenol in food. Mycotoxin Res 21:83–88
Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ (1999) Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J 339:135–141
Foletta VC (1996) Transcription factor AP-1, and the role of Fra-2. Immunol Cell Biol 74:121–133
Gareis M et al (2003) Collection of occurrence data of Fusarium toxins in food and assessment of dietary intake by the population of EU member states. Final Report of SCOOP task 3.2.10, European Commission, Brussels
Goodenough S, Davidson M, Chen WB, Beckmann A, Pujic Z, Otsuki M, Matsumoto I, Wilce P (1997) Immediate early gene expression and delayed cell death in limbic areas of the rat brain after kainic acid treatment and recovery in the cold. Exp Neurol 145:451–461
Gottschalk C, Barthel J, Engelhardt G, Bauer J, Meyer K (2007) Occurrence of type A trichothecenes in conventionally and organically produced oats and oat products. Mol Nutr Food Res 51:1547–1553
Jochum W, Passegue E, Wagner EF (2001) AP-1 in mouse development and tumorigenesis. Oncogene 20:2401–2412
Königs M, Schwerdt G, Gekle M, Humpf HU (2008) Effects of the mycotoxin deoxynivalenol on human primary hepatocytes. Mol Nutr Food Res 52:830–839
Lu D, Chen J, Hai T (2007) The regulation of ATF3 gene expression by mitogen-activated protein kinases. Biochem J 401:559–567
Mayer S, Curtui V, Usleber E, Gareis M (2007) Airborne mycotoxins in dust from grain elevators. Mycotoxin Res 23:94–100
Mayer S, Engelhart S, Kolk A, Blome H (2008) The significance of mycotoxins in the framework of assessing workplace related risks. Mycotoxin Res 24:151–164
Meyer-ter-Vehn T, Covacci A, Kist M, Pahl HL (2000) Helicobacter pylori activates mitogen-activated protein kinase cascades and induces expression of the proto-oncogenes c-fos and c-jun. J Biol Chem 275:16064–16072
Moon Y, Yang H, Lee SH (2007) Modulation of early growth response gene I and interieukin-8 expression by ribotoxin deoxynivalenol (vomitoxin) via ERK1/2 in human epithelial intestine 407 cells. Biochem Biophys Res Commun 362:256–262
Nakagomi S, Suzuki Y, Namikawa K, Kiryu-Seo S, Kiyama H (2003) Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation. J Neurosci 23:5187–5196
Nielsen C, Lippke H, Didier A, Dietrich R, Martlbauer E (2009a) Potential of deoxynivalenol to induce transcription factors in human hepatoma cells. Mol Nutr Food Res 53:479–491
Nielsen C, Casteel M, Didier A, Dietrich R, Märtlbauer E (2009b) Trichothecene-induced cytotoxity on human cell lines. Mycotoxin Res 25:77–84
Pestka JJ (2008) Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Addit Contam 25:1128–1140
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
Shaulian E, Karin M (2001) AP-1 in cell proliferation and survival. Oncogene 20:2390–2400
Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nature Cell Biol 4:E131–E136
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
Tamura K, Hua BY, Adachi S, Guney I, Kawauchi J, Morioka M, Tamamori-Adachi M, Tanaka Y, Nakabeppu Y, Sunamori M, Sedivy JM, Kitajima S (2005) Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation. EMBO J 24:2590–2601
Turner PC, Rothwell JA, White KLM, Gong Y, Cade JE, Wild CP (2008) Urinary deoxynivalenol is correlated with cereal intake in individuals from the United Kingdom. Environ Health Perspect 116:21–25
Ueno Y (1984) Toxicological features of T-2 toxin and related trichothecenes. Fundam Appl Toxicol 4:S124–S132
Weitzman JB, Fiette L, Matsuo K, Yaniv M (2000) JunD protects cells from p53-dependent senescence and apoptosis. Mol Cell 6:1109–1119
Yang GH, Jarvis BB, Chung YJ, Pestka JJ (2000) Apoptosis induction by the satratoxins and other trichothecene mycotoxins: Relationship to ERK, p38 MARK, and SAP/JNK activation. Toxicol Appl Pharmacol 164:149–160
Zenz R, Wagner EF (2006) Jun signalling in the epidermis: From developmental defects to psoriasis and skin tumors. Int J Biochem Cell Biol 38:1043–1049
Acknowledgement
This work was supported by grants from the Deutsche Forschungsgemeinschaft (GK-1029) and from the “Brigitte and Wolfram Gedek-Stiftung für Mykotoxinforschung”. We thank Brunhilde Minich and Christine Ehlich for excellent technical assistance.
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Casteel, M., Nielsen, C., Didier, A. et al. Induction of MAPK-dependent transcription factors by deoxynivalenol in human cell lines. Mycotox Res 26, 9–14 (2010). https://doi.org/10.1007/s12550-009-0035-x
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DOI: https://doi.org/10.1007/s12550-009-0035-x