Toxicity of Deoxynivalenol and Its Acetylated Derivatives on the Intestine: Differential Effects on Morphology, Barrier Function, Tight Junction Proteins, and Mitogen-Activated Protein Kinases

* INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France
Toxicological Sciences (Impact Factor: 3.85). 08/2012; 130(1):180-90. DOI: 10.1093/toxsci/kfs239
Source: PubMed


The intestinal epithelium is the first barrier against food contaminants and is highly sensitive to mycotoxins, especially de oxynivalenol (DON). Consumption of DON-contaminated food is associated with outbreaks of gastroenteritis. In cereals and their byproducts, DON is present together with two acetylated derivatives, 3-ADON and 15-ADON. The aim of this study was to compare the intestinal toxicity of DON and A-DONs, using noncytotoxic doses. The toxicity was assessed using in vitro (intestinal epithelial cell line), ex vivo (intestinal explants), and in vivo (animals exposed to mycotoxin-contaminated diets) models. The effects were studied on cell proliferation, barrier function, and intestinal structure. The mechanism of toxicity was investigated by measuring the expression of the tight junction proteins and of phosphorylated ERK1/2, p38, and JNK, which are effectors of signaling pathway involved in cellular programs including embryogenesis, proliferation, differentiation, and apoptosis. On proliferating cells, 3-ADON was less toxic than DON, which was less toxic than 15-ADON. On differentiated cells, 15-ADON impaired the barrier function, whereas DON and 3-ADON did not have a significant effect. Similarly, ex vivo and in vivo, 15-ADON caused more histological lesions than DON or 3-ADON. At the molecular level, the 15-ADON activated the mitogen-activated protein kinases (MAPK) ERK1/2, p38, and JNK in the intestinal cell line, explants, and the jejunum from exposed animals at lower dose than DON and 3-ADON. Our results show that the higher toxicity of 15-DON is due to its ability to activate the MAPK. Given that cereal-based foods are contaminated with DON and acetylated-DON, the higher toxicity of 15-ADON should be taken into account.

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    • "Control intestinal explants displayed normal villi lined with columnar enterocytes and goblet cells (Fig. 4a). As already described (Pinton et al. 2012), the main histological changes observed on explants after 4-h incubation with 10 µM DON were multifocal to diffuse villi atrophy, multifocal villi fusion, necrosis of apical enterocytes and cellular debris (Fig. 4b). Conversely, explants exposed to D3G showed normal villi height lined with columnar enterocytes . "
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    ABSTRACT: Natural food contaminants such as mycotoxins are an important problem for human health. Deoxynivalenol (DON) is one of the most common mycotoxins detected in cereals and grains. Its toxicological effects mainly concern the immune system and the gastrointestinal tract. This toxin is a potent ribotoxic stressor leading to MAP kinase activation and inflammatory response. DON frequently co-occurs with its glucosylated form, the masked mycotoxin deoxynivalenol-3-β-D-glucoside (D3G). The toxicity of this later compound remains unknown in mammals. This study aimed to assess the ability of D3G to elicit a ribotoxic stress and to induce intestinal toxicity. The toxicity of D3G and DON (0-10 µM) was studied in vitro, on the human intestinal Caco-2 cell line, and ex vivo, on porcine jejunal explants. First, an in silico analysis revealed that D3G, contrary to DON, was unable to bind to the A-site of the ribosome peptidyl transferase center, the main targets for DON toxicity. Accordingly, D3G did not activate JNK and P38 MAPKs in treated Caco-2 cells and did not alter viability and barrier function on cells, as measured by the trans-epithelial electrical resistance. Treatment of intestinal explants for 4 h with 10 µM DON induced morphological lesions and up-regulated the expression of pro-inflammatory cytokines as measured by qPCR and pan-genomic microarray analysis. By contrast, expression profile of D3G-treated explants was similar to that of controls, and these explants did not show histomorphology alteration. In conclusion, our data demonstrated that glucosylation of DON suppresses its ability to bind to the ribosome and decreases its intestinal toxicity.
    Archives of Toxicology 09/2015; DOI:10.1007/s00204-015-1592-8 · 5.98 Impact Factor
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    • "Consumer health risks may result from hydrolysis of these conjugates into their toxic parent forms during mammalian digestion (De Boevre et al., 2013). The best known substances in this respect are 3-acetyldeoxynivalenol (3-ADON) and 15-acetyldeoxynivalenol (15- ADON), arising from a common precursor of 3,15-diacetyldeoxynivalenol and both are biosynthetic precursors of DON (Pinton et al., 2012). Maize and wheat can be infected by the toxigenic molds leading to the co-occurrence of DON, 3-ADON and 15-ADON, and reportedly , more than 30% of the DON-contaminated samples contained one or two derivatives (Ediage et al., 2011; Juan et al., 2013; Spanjer et al., 2008). "
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    ABSTRACT: Humans are naturally and frequently exposed to a multitude of mycotoxins, but health risk assessments are usually performed on individual mycotoxins, which may underestimate the total risks. In this study, we assessed for the first time the cumulative health risks of concomitant exposure via dietary intake (DI) to multiple mycotoxins, namely deoxynivalenol (DON) and its acetyl derivatives of 3-acetyldeoxynivalenol (3-ADON) and 15-acetyldeoxynivalenol (15-ADON), based on the concentration addition (CA) concept. A cross-sectional study was conducted in seven districts in Shanghai, China with 1269 participants and 330 wheat and maize samples analyzed. After probabilistic analysis using Monte Carlo simulation, the results showed no health risks to the population in Shanghai considering individual mycotoxins. However, if the cumulative health risks were calculated based on the combined consideration of DON with either 3-ADON or 15-ADON or both, the DI values in 95th percentile were up to 1087 ng/kg body weight/day, exceeding the Provisional Maximum Tolerable Daily Intake (PMTDI) of 1000 ng/kg body weight/day and hence representing potential health risks to the population in Shanghai. The integrated study proposed here could be a model strategy for cumulative health risk assessment on the co-occurring hazards in the fields of food safety combined with environmental contaminants.
    Food and Chemical Toxicology 11/2014; 74. DOI:10.1016/j.fct.2014.10.018 · 2.90 Impact Factor
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    • "In 2010 JECFA considered the toxicity of the acetylated derivatives equal to DON, but a recent study suggested that higher toxicity of 15-ADON should be taken into account. Another DON masked form detected in cereals and beers, namely DON-3-glucoside (DON-3- G), also shows a non-negligible contribution to the overall DON contamination (Berthiller et al. 2009; JECFA 2011; De Boevre et al. 2012; Pinton et al. 2012). "
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    ABSTRACT: An immunogen synthesis strategy was designed to develop anti-deoxynivalenol (DON) monoclonal antibodies with low cross-reactivity against structurally similar trichothecenes. A total of eight different DON immunogens were synthesised, differing in the type and position of the linker on the DON molecule. After immunisation, antisera from mice immunised with different DON immunogens were checked for the presence of relevant antibodies. Then, both homologous and heterologous enzyme-linked immunosorbent assays (ELISAs) were performed for hybridoma screening. Finally, three monoclonal antibodies against DON and its analogues were generated. In addition, monoclonal antibody 13H1 could recognise DON and its analogues in the order of HT-2 toxin > 15-acetyldeoxynivalenol (15-ADON) > DON, with IC50 ranging from 1.14 to 2.13 µg ml(-1). Another monoclonal antibody 10H10 manifested relatively close sensitivities to DON, 3-acetyldeoxynivalenol (3-ADON) and 15-ADON, with IC50 values of 22, 15 and 34 ng ml(-1), respectively. Using an indirect ELISA format decreases the 10H10 sensitivity to 15-ADON with 92%. A third monoclonal antibody 2A9 showed to be very specific and sensitive to 3-ADON, with IC50 of 0.38 ng ml(-1). Using both 2A9 and 10H10 monoclonal antibodies allows determining sole DON contamination.
    Food Additives and Contaminants - Part A Chemistry, Analysis, Control, Exposure and Risk Assessment 09/2014; 31(10):1-9. DOI:10.1080/19440049.2014.955887 · 1.80 Impact Factor
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