Please cite this article in press as: Gerez JR, et al. Deoxynivalenol alone or in combination with nivalenol and zearalenone induce systemic histological changes in pigs. Exp Toxicol Pathol (2014), http://dx.doi.org/10.1016/j.etp.2014.10.001 ARTICLE IN PRESS G Model ETP-50851; No. of Pages 10 Experimental and Toxicologic Pathology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Experimental and Toxicologic Pathology j ourna l h omepage: www.elsevier.de/etp Deoxynivalenol alone or in combination with nivalenol and zearalenone induce systemic histological changes in pigs Juliana R. Gerez a , Philippe Pinton b,c , Patrick Callu d , Franc ¸ ois Grosjean d , Isabelle P. Oswald b,c , Ana Paula F.L. Bracarense a,∗ a Universidade Estadual de Londrina, Laboratory of Animal Pathology, Londrina, Brazil b INRA, Toxalim UMR 1331, Research Center in Food Toxicology, F31027 Toulouse, France c University of Toulouse, INP, ToxAlim, UMR 1331, F31027 Toulouse, France d Arvalis Institut du Végétal, Pouline, 41100 Villerable, France a r t i c l e i n f o Article history: Received 15 July 2014 Accepted 20 October 2014 Keywords: Multi-contamination Mycotoxins Deoxynivalenol Nivalenol Zearalenone Intestinal morphology a b s t r a c t Deoxynivalenol (DON), nivalenol (NIV) and zearalenone (ZEA) are mycotoxins commonly produced by Fusarium species. The purpose of the present study was to investigate the effects of DON alone and in combination with NIV and ZEA on several parameters including weight gain and histological aspects of pigs submitted to chronic intoxication. Twenty, 5-week-old piglets received for 28 days one of the fol- lowing diets: a control diet, a diet mono- contaminated with DON (1.5 mg/kg), a diet multi-contaminated with DON (2 mg/kg) + NIV (1.3 mg/kg) + ZEA (1.5 mg/kg) or a diet contaminated with DON (3 mg/kg) + NIV (1.3 mg/kg) + ZEA (1.5 mg/kg). Animals fed the multi-contaminated diets presented a significant decrease in weight gain over the total period. The chronic ingestion of the contaminated diets induced a signifi- cant increase on histological changes on the intestine, liver and lymphoid organs. In addition, a significant increase on lymphocyte apoptosis was observed in lymph nodes and spleen in the animals receiving the contaminated diets. These data provide a better understanding of the possible effects of Fusarium tox- ins, alone or in combinations on the morphology of the intestine and lymphoid organs, which would contribute to the risk assessment of these toxins. © 2014 Elsevier GmbH. All rights reserved. 1. Introduction Mycotoxins are secondary metabolites produced by a wide vari- ety of fungal species that cause nutritional losses and represent a significant hazard to the food chain. According to the Food and Agri- culture Organization (FAO) of the United Nations, it is estimated that approximately 25% of the cereals produced in the world are contaminated by mycotoxins (Rice and Ross, 1994). Zearalenone (ZEA), fumonisin B1 (FB1) and trichothecenes, in particular, deoxynivalenol (DON) and nivalenol (NIV) are amongst the most toxicologically important Fusarium toxins that occur fre- quently in combination in cereal grains. In Europe, DON is the major contaminant, often in co-occurrence with ZEA (Streit et al., 2012). However, to date, very little is known about the potential interac- tive toxic effects among fusariotoxins (Grenier and Oswald, 2011; Wan et al., 2013a). ∗ Corresponding author. Tel.: +55 43 33714485; fax: +55 43 33714485. E-mail addresses: anapaula@uel.br, ana.bracarense@pq.cnpq.br (A.P.F.L. Bracarense). It is well-known that trichothecenes induce various toxic effects in animals such as suppression of body growth and immune func- tion, diarrhea, and general loss of condition. Trichothecenes exhibit inhibitory influence on protein synthesis by binding to ribosomes, and inhibition of DNA and RNA synthesis has also been reported (Hascheck et al., 2002). Therefore, organs/tissues showing high rate of cell turnover are regarded as particularly susceptible to tri- chothecenes, such as the lymphoid and hematopoietic tissues, and the gastrointestinal tract (Hascheck et al., 2002; Rocha et al., 2005). In addition, trichothecenes have been shown to affect immuno- logical functions by deregulating production of cytokines and immunoglobulins and by inducing apoptosis (Bondy and Pestka, 2000; Pestka et al., 2004). DON causes toxic and immunotoxic effects in a variety of cell systems and animal species (Hascheck et al., 2002; Pestka and Smolinski, 2005). Swine are more sensitive to DON than other species, in part because of differences in the metabolism of DON. Chronic low dietary concentrations (0.28; 0.56; 0.84 mg/kg of feed) induced no changes on animal performance, biochem- ical and hematological variables and immunological parameters (Accensi et al., 2006), while acute higher doses induce vomiting, http://dx.doi.org/10.1016/j.etp.2014.10.001 0940-2993/© 2014 Elsevier GmbH. All rights reserved.