Mycotoxins and metabolites, toxicity and implications

Transcription

1 Berlin, June 21- Mycotoxins and metabolites, toxicity and implications Daniela Marin 1, Ionelia Taranu 1, Gina Manda 2 1 National Institute for Research and Development for Biology and Animal Nutrition, Laboratory of Animal Biology, Calea Bucuresti, no. 1, Balotesti, Romania 2 National Institute of Pathology Victor Babes, Splaiul Independentei No , Bucharest , Romania 2nd FoodSeg Symposium, Bucharest, june

2 MYCOTOXINS Berlin, June 21- Secondary metabolites from micromycetes belonging to Aspergillus, Penicillium, Fusarium, Alternaria and Claviceps genera They can contaminate food and feed, especially cereals, forages, grain, fruits and manufactured products 25 % of world productions of cereal grains is contaminated One mycotoxin could be produced by different genera of fungi and a fungus could produce more than one mycotoxin Most mycotoxins are stable at heat and remain in food long time, being detected even in the absence of the producing fungi Aflatoxin B1 Mycotoxins have a different chemical structure Zearalenone Deoxynivalenol Fumonisin B1

3 Contamination by mouldsstrains (mycotoxinogenesis) PLANT MYCOTOXINS IN THE FOOD CHAIN Berlin, June 21- Animal health ANIMAL (breeding) FOOD PRODUCT (of animal origin) HUMANS (Public health)

4 TOXIC EFFECTS OF MYCOTOXINS Berlin, June 21- Specific target organs, but could induce other effects as well.. MYCOTOXINS Aflatoxins, Sterigmatocystin, Fumonisins Ochratoxin, Citrinin Citreoviridin, Rye ergot Citreoviridin, Acid penicillic Terric acid Aflatoxins, Ochratoxin, Trichothecenes, Fumonisins Trichothecenes Zearalenone Aflatoxines, Ochratoxin Aflatoxines, Ochratoxin, Fumonisines EFFECTS Hepatoxic Nephrotoxic Neurotoxic Cardiotoxic Diabetogen Immunotoxic Tremorigen Estrogenic Teratogenenic Cancerigenic

5 Biological fate of mycotoxines Berlin, June 21- absorption MYCOTOXINS BLOOD (Adducts) distribution absorption LUNG Intestin LIVER PATHOLOGICAL EFFECTS bioactivation METABOLITES Faeces excretion Urine Bile Milk

6 Aflatoxins Berlin, June 21- Produced by many species of Aspergillus, especially Aspergillus flavus and Aspergillus parasiticus Contaminats of cereals, cotton seed, peanuts, rice, sorghum, sunflower seeds, tree nuts, spices. Aflatoxin B 1 Aflatoxine B2 Aflatoxine G1 Aflatoxine G2 Blu fluorescence UV Jellow fluorescence High-level aflatoxin exposure produces an acute hepatic necrosis, resulting later in cirrhosis or carcinoma of the liver. Acute hepatic failure is made manifest by hemorrhage, edema, alteration in digestion, changes to the absorption and/or metabolism of nutrients, and mental changes and/or coma

7 Metabolic biotransformation of AFB 1 Berlin, June 21- Toxicity Aflatoxine B 1 Epoxyde hydrolase? CYP450(s) Lipoxygenase(s) PHS Aflatoxin B 1 8,9 epoxide Exo-, endo- stereoisomers Toxicity AFM 1, AFP 1, AFQ 1 Toxicity DNA adducts UDP-GT, ST Glucuronide and Sulfate Conjugates DNA Reparation GST Dihydrodyol Adducts with proteines Mutations GSH Conjugates Cell death TOXICITY CANCER

8 Ochratoxins Berlin, June 21- Produced by some Aspergillusspecies (mainly A. ochraceus, but also by 33% of A. nigerindustrial strains) and some Penicillium species OTA occur in commodities such as cereals, coffee, dried fruit and red wine Ochratoxin A Exposure to ochratoxins through diet can cause acute toxicity in mammalian kidneys, and may be carcinogenic. Possible involvement in Balcan Endemic Nephropathy

9 Berlin, June 21- Toxicity Metabolic biotransformation of OTA Carboxypeptidase Chimotrypsin Hydrolisis Dechlorination Toxicity Toxicity

10 Trichotecens Berlin, June 21- Trichothecene-producing genera include Fusarium, Myrothecium, Spicellum, Stachybotrys, Cephalosporium, Trichoderma, and Trichothecium Deoxynivalenol Nivalenol Diacetoxyscirpenol T-2 Toxine HT-2 Toxine Low to moderate dose acute oral exposure to trichothecenes cause vomiting, diarrhea and gastroenteritis, Higher doses cause severe damage to the lymphoid and epithelial cells of the gastrointestinal mucosa resulting in hemorrhage, endotoxemia and shock

11 DON AND ITS METABOLITES Berlin, June 21- Toxicity Toxicity DOM-1 3-acetyl DON Deepoxydation Acetylation Glycosilation 15-acetyl DON DON Oxidation Epimerization 3-oxo-DON 3-epi-DON DON-3-O-glucuronide DON-3-glucoside DON-15-O-glucuronide DON-15-glucoside

12 Zearalenone Berlin, June 21- Zearalenone is a oestrogenic mycotoxin synthesized by a variety of Fusarium fungi, including F. graminearum (Gibberella zeae), F. culmorum, F. cerealis, F. equiseti, F. crookwellense and F. semitectum, which are common soil fungi, in temperate and warm countries, and are regular contaminants of cereal crops worldwide Reproductive system is the major target of ZEN toxicity : Decreased fertility, reduced litter size, changed weight of adrenal, thyroid and pituitary glands and change in serum levels of progesterone and oestradiol Swine are very susceptible to zearalenone intoxication

13 ZEN AND ITS METABOLITES Berlin, June 21- Reductase α-zearalenol α-zearalanol Hydroxilation Reductase Oxidation Zearalenone Hydroxilation Zearalanone Oxidation UDPGT UDPGT UDPGT UDPGT UDPGT Conjugation with glucuronic acid Glucuronides β-zearalenol β-zearalanol Urine enterohepatic circulation Bile α-zol, α-zal, and β-zal have relatively higher estrogenic activity than ZEN binding affinities for ER rank: α-zol > α-zal > β-zal > ZEN > β-zol

14 Effect of ZEN and its metabolites on swine PMN Berlin, June 21- Cytotoxic effects, expresses as IC50 of zearalenone and its derivatives on PMA stimulated swine neutrophiles Effect of ZEN and ZEN derivatives on IL-8 production by swine neutrophils Marin et al., Toxicon, 2010 In accordance with the amplitude of their toxic effects, the toxicity of the four mycotoxins investigated was as follow: ZAN > b-zol > a-zol > ZEN

15 Effect of ZEN and its metabolites on swine PBMC Berlin, June 21- PBMC viability PBMC proliferation for some parameters as viability, proliferation and antibody synthesis, b-zol was the most toxic for inflammatory cytokine synthesis, ZEN and ZAN had similar toxicity, and were the most IgGtoxic among of mycotoxins tested. IgM Marin et al., Toxicology in vitro, 2010

16 Effect of ZEN and its metabolites on IPEC1 cell line Berlin, June 21- Transepithelial electrical resistence Toxins Ω TEER (kohms x cm 2 ) ZEN alpha-zol IPEC-1 cells beta-zol Day of treatment TEER (kohms x cm 2 ) TEER (kohms x cm 2 ) Day of treatment Day of treatment

17 Conclusions Berlin, June 21- Differences in range of toxicity were observed for ZEN and its metabolites depending of the type of cell and of the investigated parameter. The toxicity degree of ZEN and its metabolites observed in different immunocellular toxicity tests was not always correlated with the estrogenic potency of ZEN and its derivatives, for which alpha-zol was the most powerful. Some additional studies of co-contamination are needed in order to understand the interactions between ZEN and its metabolites.

18 TAKE HOME MESSAGES Berlin, June 21- The most frequent way of intoxication is the oral way ; Mycotoxin uptake and subsequent tissue distribution is governed by absorption in the gut ; Mycotoxin metabolism can occur in both the liver and the digestive tract ; Some mycotoxins need activation in order to be toxic; Absorption, distribution, and elimination of mycotoxins among animal species might account for the different species sensitivity to mycotoxins ; Sometimes, the mycotoxins metabolites have low toxicity, but in same cases the toxicity could also increase after the metabolism; The additive or synergic effects of mycotoxins and their metabolites should be taken into account ;

19 Berlin, June 21- THANK YOU FOR YOUR ATTENTION!