Toxicity of deoxynivalenol and its acetylated derivatives on the intestine: Differential effects on morphology, barrier function, tight function proteins, and mitogen-activated protein kinases

* INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France
Toxicological Sciences (Impact Factor: 4.48). 08/2012; 130(1):180-90. DOI: 10.1093/toxsci/kfs239
Source: PubMed

ABSTRACT 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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    • "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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    • "However, on IPEC-1 differentiated cells, 3-ADON showed higher toxicity, coinciding with our results. The effect on this kind of cells was demonstrated by 3-ADON's ability to activate the MAPK (mitogen-activated protein kinases) (Pinton et al., 2012); which might be also happening in our cells. The MTT test, linked to mitochondrial, was used for the indirect measurement of proliferation and viability of HepG2 cells. "
    Toxicology Letters 09/2014; 229. DOI:10.1016/j.toxlet.2014.06.603 · 3.36 Impact Factor
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    ABSTRACT: Mycotoxins are secondary metabolites produced by fungi especially those belonging to the genus Aspergillus, Penicillum and Fusarium. Mycotoxin contamination can occur in all agricultural commodities in the field and/or during storage, if conditions are favourable to fungal growth. Regarding animal feed, five mycotoxins (aflatoxins, deoxynivalenol, zearalenone, fumonisins and ochratoxin A) are covered by EU legislation (regulation or recommendation). Transgressions of these limits are rarely observed in official monitoring programs. However, low level contamination by Fusarium toxins is very common (e.g., deoxynivalenol (DON) is typically found in more than 50% of the samples) and co-contamination is frequently observed. Multi-mycotoxin studies reported 75%-100% of the samples to contain more than one mycotoxin which could impact animal health at already low doses. Co-occurrence of mycotoxins is likely to arise for at least three different reasons (i) most fungi are able to simultaneously produce a number of mycotoxins, (ii) commodities can be contaminated by several fungi, and (iii) completed feed is made from various commodities. In the present paper, we reviewed the data published since 2004 concerning the contamination of animal feed with single or combinations of mycotoxins and highlighted the occurrence of these co-contaminations.
    Toxins 10/2012; 4(10):788-809. DOI:10.3390/toxins4100788 · 2.48 Impact Factor