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.

Deoxynivalenol (DON) is a common mycotoxin that contaminates cereals and their by-products. The gastrointestinal tract is the first physical barrier against ingested food contaminants. DON contributes to the loss of barrier function of the intestine through the decreased expression of claudin-4 protein, a tight junction protein. The mechanism by which DON alters the intestinal barrier function remains poorly characterized. Therefore, we investigated the involvement of mitogen-activated protein kinases (MAPK) in the DON-induced loss of barrier function. We first verified that 30 μmol/L of DON activated MAPK in a highly sensitive porcine intestinal epithelial cell line (IPEC-1). Inhibition of p44/42 extracellular signal-regulated kinase (ERK) phosphorylation, with 0.5 μmol/L of the specific MAPK pharmacological inhibitor U0126 for 2 h, restored the barrier function of the differentiated intestinal epithelial cell monolayers. The restoration of barrier function was evaluated by trans-epithelial electrical resistance measurements and tracer flux paracellular permeability experiments. The U0126 also restored the intestinal expression of claudin-4 protein, thereby demonstrating that MAPK activation is involved in claudin-4 protein expression and claudin-4 is involved in the maintenance of the intestinal epithelial cell barrier function. Further experiments indicated that p44/42 ERK is not involved in the transcriptional regulation of claudin-4. In conclusion, we demonstrated that DON-induced activation of the p44/42 ERK signaling pathway inhibits the expression of claudin-4 protein, which leads to impaired intestinal barrier function. Given the high levels of DON in cereal grains, these observations of impaired barrier function have implications for human and animal health.

Mycotoxins are a group of structurally diverse fungal secondary metabolites that elicit a wide spectrum of toxicological effects. Of particular interest is the capacity of some mycotoxins to alter normal immune function when present in food at levels below observable overt toxicity. The sensitivity of the immune system to mycotoxin-induced immunosuppression arises from the vulnerability of the continually proliferating and differentiating cells that participate in immune-mediated activities and regulate the complex communication network between cellular and humoral components. Mycotoxin-induced immunosuppression may be manifested as depressed T- or B-lymphocyte activity, suppressed antibody production and impaired macrophage/neutrophil-effector functions. The immune system is primarily responsible for defence against invading organisms. Suppressed immune function by mycotoxins may eventually decrease resistance to infectious diseases, reactivate chronic infections and/or decrease vaccine and drug efficacy.

Mycotoxins are secondary fungal metabolites produced mainly by Aspergillus, Penicillium, and Fusarium. As evidenced by large-scale surveys, humans and animals are simultaneously exposed to several mycotoxins. Simultaneous exposure could result in synergistic, additive or antagonistic effects. However, most toxicity studies addressed the effects of mycotoxins separately. We present the experimental designs and we discuss the conclusions drawn from in vitro experiments exploring toxicological interactions of mycotoxins. We report more than 80 publications related to mycotoxin interactions. The studies explored combinations involving the regulated groups of mycotoxins, especially aflatoxins, ochratoxins, fumonisins, zearalenone and trichothecenes, but also the "emerging" mycotoxins beauvericin and enniatins. Over 50 publications are based on the arithmetic model of additivity. Few studies used the factorial designs or the theoretical biology-based models of additivity. The latter approaches are gaining increased attention. These analyses allow determination of the type of interaction and, optionally, its magnitude. The type of interaction reported for mycotoxin combinations depended on several factors, in particular cell models and the tested dose ranges. However, synergy among Fusarium toxins was highlighted in several studies. This review indicates that well-addressed in vitro studies remain valuable tools for the screening of interactive potential in mycotoxin mixtures.

A feeding trial was conducted to evaluate the effect of aflatoxin (AF)-contaminated diets on growth and hematological and immunological parameters. Low doses of aflatoxins (140 and 280 ppb) were included in a corn-soybean diet provided for ad libitum consumption to 36 weanling piglets for a period of 4 wk. A "dose-related" decrease in weight gain was observed in treated animals. This effect was significant (P < 0.05) in the 280 ppb-treated group compared to the control group. Ingestion of AF-contaminated feed at either level had no effect on total red blood cell numbers or on their relative number of lymphocytes, monocytes, neutrophils, basophils, and eosinophils in blood. Likewise, AF did not alter globulin, albumins, or total protein concentrations in serum, nor did AF alter the expression of regulatory cytokines produced by either Th1 (IL-2) or Th2 (IL-4) lymphocyte subsets in phytohemagglutinin-stimulated blood samples. By contrast, AF had a biphasic effect on total white blood cell number; the low dose of AF (140 ppb) decreased the total number of white blood cells, whereas the high dose (280 ppb) had the opposite effect. Consumption of AF also increased the concentration of gamma-globulin in the serum. A reduced immune response induced by Mycoplasma agalactiae in the 280-ppb-treated group was also observed. Cytokine mRNA expression in phytohemagglutinin-stimulated blood cells indicated that AF decreased proinflammatory (IL-1beta, TNF-alpha) and increased anti-inflammatory (IL-10) cytokine mRNA expression. These results demonstrate that low doses of AF depress growth and alter many aspects of humoral and cellular immunity in pigs.

Fumonisins, mycotoxins primarily produced by Fusarium verticillioides and Fusarium proliferatum, occur predominantly in cereal grains, especially in maize. The European Commission asked EFSA for a scientific opinion on the risk to animal health related to fumonisins and their modified and hidden forms in feed. Fumonisin B 1 (FB 1 ), FB 2 and FB 3 are the most common forms of fumonisins in feedstuffs and thus were included in the assessment. FB 1 , FB 2 and FB 3 have the same mode of action and were considered as having similar toxicological profile and potencies. For fumonisins, the EFSA Panel on Contaminants in the Food Chain (CONTAM) identified no-observed-adverse-effect levels (NOAELs) for cattle, pig, poultry (chicken, ducks and turkeys), horse, and lowest-observed-adverseeffect levels (LOAELs) for fish (extrapolated from carp) and rabbits. No reference points could be identified for sheep, goats, dogs, cats and mink. The dietary exposure was estimated on 18,140 feed samples on FB 1-3 representing most of the feed commodities with potential presence of fumonisins. Samples were collected between 2003 and 2016 from 19 different European countries, but most of them from four Member States. To take into account the possible occurrence of hidden forms, an additional factor of 1.6, derived from the literature, was applied to the occurrence data. Modified forms of fumonisins, for which no data were identified concerning both the occurrence and the toxicity, were not included in the assessment. Based on mean exposure estimates, the risk of adverse health effects of feeds containing FB 1-3 was considered very low for ruminants, low for poultry, horse, rabbits, fish and of potential concern for pigs. The same conclusions apply to the sum of FB 1-3 and their hidden forms, except for pigs for which the risk of adverse health effect was considered of concern.Acknowledgements: The CONTAM Panel wishes to acknowledge all European countries and other stakeholder organisations that provided feed consumption data and chemical occurrence data on fumonisins, modified forms and hidden forms in feed.This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made.The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. Fumonisins in feed www.efsa.europa.eu/efsajournal 2 EFSA Journal 2018;16(5):5242 Fumonisins in feed www.efsa.europa.eu/efsajournal 3 EFSA Journal 2018;16(5):5242Ruminants are considered less sensitive than horses and pigs. Gross and histopathological lesions, as well as changes in serum enzymes and biochemistry indicate an impairment of liver and possibly kidney function. Taking as endpoints the increase in serum enzymes, cholesterol and bilirubin as well as the decrease in lymphocyte blastogenesis a no-observed-adverse-effect level (NOAEL) of (31 mg FB 1-3 /kg feed) could be set only for cattle....

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