To improve our knowledge of the role of microRNAs (miRs) in responses of the porcine digestive system to two Fusarium mycotoxins, zearalenone (ZEN) and deoxynivalenol (DON), we examined the expression of 7 miRs (miR-9, miR-15a, miR-21, miR-34a, miR-122, miR-125b, and miR-192), previously found to be deregulated in diseased liver and colon cells. In this study, immature gilts were exposed to NOEL doses of ZEN (40 μg/kg/d), DON (12 μg/kg/d), ZEN+DON (40+12 μg/kg/d), and placebo (negative control group) for 7, 14, 21, 28, 35, and 42 days. Before the treatment, expression levels of the selected miRs were measured in the liver, the duodenum, the jejunum, and the ascending and the descending colon of the gilts. Hierarchical clustering of the tissues by their miR expression profiles was consistent with what would be expected based on the anatomical locations and the physiological functions of the organs, suggesting that functions of the miRs are related to the specificities of the tissues in which they are expressed. A subset of 2 pairs of miRs (miR-21+miR-192 and miR-15a+miR-34a), which were assigned to two distinct clusters based on their tissue abundance, was then evaluated in the liver and the ascending and the descending colon during the treatment. The most meaningful results were obtained from the ascending colon, where a significant effect of the treatment was observed, suggesting that during the exposure to mycotoxins, the pathways involved in cell proliferation and survival were disordered. Changes in miR expression in the liver and the descending colon of the treated gilts were smaller, and were associated more with treatment duration than the exposure to ZEN, DON, or ZEN+DON. Further research should focus on identification of genes whose expression is regulated by these aberrantly expressed miRs. This should facilitate understanding of the miRNA-regulated biological effects of mycotoxins.
Ahamed S, Foster JS, Bukovsky A, Wimalasena J (2001) Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7 cells. Mol Carcinog 30: 88-98.
Ambros V (2004) The functions of animal microRNAs. Nature 431: 350-355.
Ason B, Darnell DK, Wittbrodt B, Berezikov E, Kloosterman WP, Wittbrodt J, Antin PB, Plasterk RH (2006) Differences in vertebrate microRNA expression. Proc Natl Acad Sci USA 103: 14385-14389.
Asslaber D, Piñón JD, Seyfried I, Desch P, Stöcher M, Tinhofer I, Egle A, Merkel O, Greil R (2010) micro-RNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia. Blood 115: 4191-4197.
Bala S, Marcos M, Szabo G (2009) Emerging role of micro-RNAs in liver diseases. World J Gastroenterol 15: 5633-5640.
Betel D, Wilson M, Gabow A, Marks DS, Sander C (2008) The microRNA.org resource: targets and expression. Nucleic Acids Res 36: 149-153.
Brzuzan P, Woźny M, Wolińska L, Piasecka A (2012) Expression profiling in vivo demonstrates rapid changes in liver microRNA levels of whitefish (Coregonus lavaretus) following microcystin-LR exposure. Aquat Toxicol 122-123: 188-196.
Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65: 6029-6033.
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102: 13944-13949.
Fink-Gremmels J (1999) Mycotoxins: their implications for human and animal health. Vet Q 21: 115-120.
Fujita S, Ito T, Mizutani T, Minoguchi S, Yamamichi N, Sakurai K, Iba H (2008) miR-21 gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism. J Mol Biol 378: 492-504.
Garzon R, Marcucci G, Croce CM (2010) Targeting micro-RNAs in cancer: rationale strategies and challenges. Nat Rev Drug Discov 9: 774-789.
Georges SA, Biery MC, Kim SY, Schelter JM, Guo J, Chang AN, Jackson AL, Carleton MO, Linsley PS, Cleary MA, Chau BN (2008) Coordinated regulation of cell cycle transcripts by p53-inducible microRNAs, miR-192 and miR-215. Cancer Res 68: 10105-10112.
Girard M, Jacquemin E, Munnich A, Lyonnet S, Henrion-Caude A (2008) miR-122, a paradigm for the role of microRNAs in the liver. J Hepatol 48: 648-656.
Glorian V, Maillot G, Poles S, Iacovoni JS, Favre G, Vagner S (2011) HuR-dependent loading of miRNA RISC to the mRNA encodnig the Ras-related small GTP-ase RhoB controls its translation during UV-induced apoptosis. Cell Death Differ 18: 1692-1701.
Hassen W, Ayed-Boussema I, Oscoz AA, Lopez AC, Bacha H (2007) The role of oxidative stress in zearalenone-mediated toxicity in Hep G2 cells: Oxidative DNA damage, gluthatione depletion and stress proteins induction. Toxicology 232: 294-302.
Hudder A, Novak RF (2008) miRNAs: Effectors of environmental influences on gene expression and disease. Toxicol Sci 103: 228-240.
Jakimiuk E, Gajęcka M, Jana B, Brzuzan P, Zielonka Ł, Skorska-Wyszyńska E, Gajęcki M (2009) Factors determining sensitivity of prepubertal gilts to hormonal influence of zearalenone. Pol J Vet Sci 12: 149-158.
Kouadio JH, Mobioa TA, Baudrimont I, Moukha S, Dano SD, Creppy EE (2005) Comparative study of cytotoxicity and oxidative stress induced by deoxynivalenol, zearalenone or fumonisin B1 in human intestinal cell line Caco-2. Toxicology 213: 56-65.
Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M, Lin C, Socci ND, Hermida L, Fulci V, Chiaretti S, Foà R, Schliwka J, Fuchs U, Novosel A, Muller RU, Schermer B, Bissels U, Inman J, Phan Q, Chien M, Weir DB, Choksi R, De Vita G, Frezzetti D, Trompeter HI, Hornung V, Teng G, Hartmann G, Palkovits M, Di Lauro R, Wernet P, Macino G, Rogler CE, Nagle JW, Ju J, Papavasiliou FN, Benzing T, Lichter P, Tam W, Brownstein MJ, Bosio A, Borkhardt A, Russo JJ, Sander C, Zavolan M, Tuschl T (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129: 1401-1414.
Liang Y, Ridzon D, Wong L, Chen C (2007) Characterization of microRNA expression profiles in normal human tissues. BMC Genomics 8: 166.
Mei Y, Bian C, Li J, Du Z, Zhou H, Yang Z, Zhao RC (2013) miR-21 modulates the ERK-MAPK signaling pathway by regulating SPRY2 expression during human mesenchymal stem cell differentiation. J Cell Biochem 114: 1374-1384.
Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431: 343-349.
Ofir M, Hacohen D, Ginsberg D (2011) MiR-15 and miR-16 are direct transcriptional targets of E2F1 that limit E2F-induced proliferation by targeting cyclin E. Mol Cancer Res 9: 440-447.
Olsen CM, Meussen-Elholm ET, Hongslo JK, Stenersen J, Tollefsen KE (2005) Estrogenic effects of environmental chemicals: an interspecies comparison. Comp Biochem Physiol C Toxicol Pharmacol 141: 267-274.
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.
Pinton P, Nougayrède 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.
Pinton P, Guzylack-Piriou L, Kolf-Clauw M, Oswald IP (2012) The effect on the intestine of some fungal toxins: the trichothecenes. Curr Immunol Rev 8: 193-208.
Podolska A, Anthon C, Bak M, Tommerup N, Skovgaard K, Heegaard PM, Gorodkin J, Cirera S, Fredholm M (2012) Profiling microRNAs in lung tissue from pigs infected with Actinobacillus pleuropneumoniae. BMC Genomics 13: 459.
Rotkrua P, Akiyama Y, Hashimoto Y, Otsubo T, Yuasa Y (2011) MiR-9 downregulates CDX2 expression in gastric cancer cells. Int J Cancer 129: 2611-2620.
Roy S, Sen CK (2011) MiRNA in innate immune responses: novel players in wound inflammation. Physiol Genomics 43: 557-565.
Spachmo B, Arukwe A (2012) Endocrine and developmental effects in Atlantic salmon (Salmo salar) exposed to perfluorooctane sulfonic or perfluorooctane carboxylic acids. Aquat Toxicol 108: 112-124.
Surdziel E, Cabanski M, Dallmann I, Lyszkiewicz M, Krueger A, Ganser A, Scherr M, Eder M (2011) Enforced expression of miR-125b affects myelopoiesis by targeting multiple signaling pathways. Blood 117: 4338-4348.
Takemura H, Shim JY, Sayama K, Tsubura A, Zhu BT, Shimoi K (2007) Characterization of the estrogenic activities of zearalenone and zeranol in vivo and in vitro. J Steroid Biochem Mol Biol 103: 170-177.
Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H (2007) Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6: 1586-1593.
Tiemann U, Tomek W, Schneider F, Vanselow J (2003) Effects of the mycotoxins alpha- and beta-zearalenol on regulation of progesterone synthesis in cultured granulosa cells from porcine ovaries. Reprod Toxicol 17: 673-681.
Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, Huang Y, Chen HC, Lee CH, Tsai TF, Hsu MT, Wu JC, Huang HD, Shiao MS, Hsiao M, Tsou AP (2012) Micro-RNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 122(8): 2884-2897.
Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH (2008) MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology 135: 1624-1635.
Ye L, Su X, Wu Z, Zheng X, Wang J, Zi C, Zhu G, Wu S, Bao W (2012) Analysis of Differential miRNA Expression in the Duodenum of Escherichia coli F18-Sensitive and -Resistant Weaned Piglets. PLoS ONE 7: e43741.
Zhou HR, Jia Q, Pestka JJ (2005) Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Toxicol Sci 85: 916-926.
Zinedine A, Soriano JM, Moltó JC, Mañes J (2007) Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: an oestrogenic mycotoxin. Food Chem Toxicol 45: 1-18.