Deoxynivalenol (DON) is a mycotoxin primarily produced by Fusarium fungi, occurring predominantly in cereal grains. Following the request of the European Commission, the CONTAM Panel assessed the risk to animal and human health related to DON, 3-acetyl-DON (3-Ac-DON), 15-acetyl-DON (15-Ac-DON) and DON-3-glucoside in food and feed. A total of 27,537, 13,892, 7,270 and 2,266 analytical data for DON, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside, respectively, in food, feed and unprocessed grains collected from 2007 to 2014 were used. For human exposure, grains and grain-based products were main sources, whereas in farm and companion animals, cereal grains, cereal by-products and forage maize contributed most. DON is rapidly absorbed, distributed, and excreted. Since 3-Ac-DON and 15-Ac-DON are largely deacetylated and DON-3-glucoside cleaved in the intestines the same toxic effects as DON can be expected. The TDI of 1 μg/kg bw per day, that was established for DON based on reduced body weight gain in mice, was therefore used as a group-TDI for the sum of DON, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside. In order to assess acute human health risk, epidemiological data from mycotoxicoses were assessed and a group-ARfD of 8 μg/kg bw per eating occasion was calculated. Estimates of acute dietary exposures were below this dose and did not raise a health concern in humans. The estimated mean chronic dietary exposure was above the group-TDI in infants, toddlers and other children, and at high exposure also in adolescents and adults, indicating a potential health concern. Based on estimated mean dietary concentrations in ruminants, poultry, rabbits, dogs and cats, most farmed fish species and horses, adverse effects are not expected. At the high dietary concentrations, there is a potential risk for chronic adverse effects in pigs and fish and for acute adverse effects in cats and farmed mink.

Risks to human and animal health related to the presence of deoxynivalenol and its acetylated and modified forms in food and feed

Mycotoxins are the most frequently occurring natural contaminants in human and animal diet. Among them, deoxynivalenol (DON), produced by Fusarium, is one of the most prevalent and thus represents an important health risk. Recent detection methods revealed new mycotoxins and new molecules derivated from the “native” mycotoxins. The main derivates of DON are the acetylated forms produced by the fungi (3- and 15-acetyl-DON), the biologically “modified” forms produced by the plant (deoxynivalenol-3-β-d-glucopyranoside), or after bacteria transformation (de-epoxy DON, 3-epi-DON and 3-keto-DON) as well as the chemically “modified” forms (norDON A-C and DON-sulfonates). High proportions of acetylated and modified forms of DON co-occur with DON, increasing the exposure and the health risk. DON and its acetylated and modified forms are rapidly absorbed following ingestion. At the molecular level, DON binds to the ribosome, induces a ribotoxic stress leading to the activation of MAP kinases, cellular cell-cycle arrest and apoptosis. The toxic effects of DON include emesis and anorexia, alteration of intestinal and immune functions, reduced absorption of the nutrients as well as increased susceptibility to infection and chronic diseases. In contrast to DON, very little information exists concerning the acetylated and modified forms; some can be converted back to DON, their ability to bind to the ribosome and to induce cellular effects varies according to the toxin. Except for the acetylated forms, their toxicity and impact on human and animal health are poorly documented.

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Toxicology of deoxynivalenol and its acetylated and modified forms

There is an increasing awareness of the deleterious effects attributed to mycotoxins during their fate within the gut, particularly for deoxynivalenol (DON), zearalenone (ZEN), ochratoxin A (OTA), fumonisin B1 (FB1), aflatoxin B1 (AFB1), and patulin (PAT). Evidence indicates that disruption of the epithelial barrier is well established. However, intestinal barrier function on its luminal side involves two other partners, mucus and microbiota, which have rarely been considered in the context of mycotoxin exposure. The current review aimed at providing a summary of DON, ZEN, OTA, FB1, AFB1, and PAT effects on intestinal barrier function, with special focus on mucus and microbiota. DON, ZEN, OTA, FB1, AFB1, and PAT are known to markedly affect epithelial cell integrity and functions. Regarding mucus, DON is the most documentated mycotoxin. In vivo, toxicological impact of DON generally has only been assessed through goblet cell number. Evaluation of the mycotoxins/mucus interplay considering other indicators such as composition, thickness, and penetrability of mucus, mucin O-glycosylation thus warrants further attention. With respect to microbiota, few short-term studies to date have been reported indicating deleterious effects. However, long-term exposure to mycotoxins may also produce significant changes in microbiota composition and metabolic activity, which requires further experimentation. In conclusion, mucus and microbiota are key targets for dietary mycotoxins although assessment of induced effects is preliminary. A significant research effort is now underway to determine the adverse consequences of mycotoxins on mucus and microbiota considered as individual but also as tightly connected gut players.

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Impact of mycotoxins on the intestine: are mucus and microbiota new targets?

Worldwide mycotoxins contamination has a significant impact on animal and human health, and leads to economic losses accounted for billions of dollars annually. Since the application of pre- and post- harvest strategies, including chemical or physical removal, are not sufficiently effective, biological transformation is considered the most promising yet challenging approach to reduce mycotoxins accumulation. Although several microorganisms were reported to degrade mycotoxins, only a few enzymes have been identified, purified and characterized for this activity. This review focuses on the biotransformation of mycotoxins performed with purified enzymes isolated from bacteria, fungi and plants, whose activity was validated in in vitro and in vivo assays, including patented ones and commercial preparations. Furthermore, we will present some applications for detoxifying enzymes in food, feed, biogas and biofuel industries, describing their limitation and potentialities.

https://www.mdpi.com/2072-6651/9/4/111/pdf

Mycotoxin Biotransformation by Native and Commercial Enzymes: Present and Future Perspectives

The uplift processes of the Qilian Shan (northern Tibetan Plateau) play a central role in our understanding of the dynamics of outward and upward growth of Tibet due to sustained convergence of the Indian and Asian plates. We employ apatite fission track chronology and geological mapping to reveal the time and pattern of the deformation along the Qilian Shan. Our results indicate that the emergence of the Tuolai Shan in the central Qilian Shan occurred at 17–14 Ma, that northern Qilian Shan thrusting began at 10–8 Ma, and that the Laojunmiao anticline formed ca. 3.6 Ma. Together with previous results that show that uplift of the southern Qilian Shan began in the Oligocene, we suggest that the Qilian Shan has undergone progressively northward expansion in the Cenozoic due to significant crustal shortening driven by Qilian Shan thrust fault systems.

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Progressive northward growth of the northern Qilian Shan-Hexi Corridor (northeastern Tibet) during the Cenozoic

Bacteria are able to de-epoxidize or epimerize deoxynivalenol (DON), a mycotoxin, to deepoxy-deoxynivalenol (deepoxy-DON or DOM-1) or 3-epi-deoxynivalenol (3-epi-DON), respectively. Using different approaches, the intestinal toxicity of 3 molecules was compared and the molecular basis for the reduced toxicity investigated. In human intestinal epithelial cells, deepoxy-DON and 3-epi-DON were not cytotoxic, did not change the oxygen consumption or impair the barrier function. In intestinal explants, exposure for 4 hours to 10 μM DON induced intestinal lesions not seen in explants treated with deepoxy-DON and 3-epi-DON. A pan-genomic transcriptomic analysis was performed on intestinal explants. 747 probes, representing 323 genes, were differentially expressed, between DON-treated and control explants. By contrast, no differentially expressed genes were observed between control, deepoxy-DON and 3-epi-DON treated explants. Both DON and its biotransformation products were able to fit into the pockets of the A-site of the ribosome peptidyl transferase center. DON forms three hydrogen bonds with the A site and activates MAPKinases (mitogen-activated protein kinases). By contrast deepoxy-DON and 3-epi-DON only form two hydrogen bonds and do not activate MAPKinases. Our data demonstrate that bacterial de-epoxidation or epimerization of DON altered their interaction with the ribosome, leading to an absence of MAPKinase activation and a reduced toxicity.

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Microbial biotransformation of DON: molecular basis for reduced toxicity

The enzymatic detoxification of deoxynivalenol (DON) is a promising mitigation strategy for addressing this mycotoxin contamination of cereal grains. A recently described bacterium, Devosia mutans 17-2-E-8, capable of transforming DON into its non-toxic stereoisomer 3-epi-DON, holds promise for the development of such applications. Earlier observations suggested that DON epimerization proceeds via a two-step catalysis with 3-keto-DON as an intermediate. The results of this study indicate that NADPH is required for DON epimerization by cell-free protein extracts of D. mutans, while high concentrations of glucose and sucrose have a suppressive effect. Chemically synthesized 3-keto-DON incubated with D. mutans protein fractions enriched by ammonium sulfate precipitation at 35–55% saturation selectively reduced 3-keto-DON to 3-epi-DON, but fell short of supporting the complete epimerization of DON. In addition, seven Devosia species investigated for DON epimerization were all able to reduce 3-keto-DON to 3-epi-DON, but only a few were capable of epimerizing DON. The above observations collectively confirm that the enzymes responsible for the oxidation of DON to 3-keto-DON are physically separate from those involved in 3-keto-DON reduction to 3-epi-DON. The enzymatic nature of DON epimerization suggests that the process could be used to develop genetically engineered crops or microorganisms, ultimately reducing foodborne exposure of consumers and farm animals to DON.

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Jian Wei He

Papers

Microbial biotransformation of DON: molecular basis for reduced toxicity

The enzymatic epimerization of deoxynivalenol by Devosia mutans proceeds through the formation of 3-keto-DON intermediate.