Lecture 4 Mycotoxins Fall 2021 PDF

Mycotoxins  Mycotoxins are secondary metabolites of fungi, which are capable of producing acute toxic, carcinogenic, mutagenic, teratogenic, immunotoxic and oestrogenic effects on animals at the level of exposure.  Toxic syndromes resulting from the intake of mycotoxins by man and...

Mycotoxins  Mycotoxins are secondary metabolites of fungi, which are capable of producing acute toxic, carcinogenic, mutagenic, teratogenic, immunotoxic and oestrogenic effects on animals at the level of exposure.  Toxic syndromes resulting from the intake of mycotoxins by man and animals are known to as “mycotoxicosis”. What are mycotoxins?!!  Mycotoxins are secondary metabolites of fungi. Factors causing variation in effects of Mycotoxins  Species  Age  Sex  Nutritional status  Other diseases  Other mycotoxins  Extent of exposure Mycotoxins can cause:  Poor performance  Respiratory problems  Reproductive problems  Liver, kidney or other organ damage  Cancer  Death Feeds Most Susceptible to Fungi- producing Mycotoxins  Corn ‫حبوب ذرة‬  Wheat ‫قمح‬  Oats ‫الشوفان‬  Barley ‫الشعير‬  Sorghum ‫الذرة الرفيعة‬  Cottonseed ‫بذرة القطن‬  Peanut meal ‫الفول السوداني‬ Many fungi do not produce Mycotoxins  Many fungi are edible ‫صالح لأل كل‬  Mushrooms are fungi  Moldy ‫ متعفن‬feeds may be degraded without presence of mycotoxin  Mycotoxin contamination of the feed and food is a global problem.  The primary classes of mycotoxins are aflatoxins, zearalenones, trichothecenes, ochratoxins, and ergot alkaloids. Mycotoxin producing fungal genera are....  Aspergillus Fusarium Penicillium Aspergillus Fusarium Penicillium Some mycotoxins are formed in the field, some in storage Storage conditions that favor production of mycotoxins:  Temperature (40 - 90o F ; 4 - 32o C)  Relative Humidity (> 70%)  Moisture (22-23% in grain)  Oxygen (1-2%) Fusarium toxins  Zearalenone: Estrogenic effects  Zearalenone (ZEA)  Zearalenone is a non-steroidal estrogenic mycotoxin.  have been associated with estrogenic syndromes in swine and experimental animals Zearalenone (ZEA) Zearalenone (ZEA)  Occur in high moisture storage of corn , rice and wheat Mechanism ZEA can bind to estrogen receptors in uterus and liver: 1. Causing immunotoxin and genotoxic effects: 1. Leading to decreased fertility , increased embryo lethal resorption, and decrease the serum levels of the estrogen. 2. May cause cancer. Patulin  Patulin is a mycotoxin produced by several penicillium and Aspergillus species.  Most common in ripe apples.  Mechanism Patulin has immunosuppressive effect and inhibits DNA synthesis, mutagenic, carcinogenic and teratogenic effects. Cellular mechanism by binding to sulfhydryl groups in proteins and amino acids in plama membrane.  Reduce glutathione levels and increase the oxidative damage.  Lead to mitochondrial dysfunction.  Can induce intestinal epithelial cell degeneration, inflammation, ulceration, and hemorrhage. Ergot alkaloids  Ergot alkaloids are mycotoxins that contaminate the cereal grains. Ergot alkaloids  Affect the nervous and reproductive systems of exposed individuals through the interactions with monoamine receptors ("serotonin and adrenaline antagonism).  The most important peripheral effect through vasoconstriction of the smooth muscles of the uterus. Deoxynivalenol  Feed refusal factor for pigs.  Emetic (vomiting) Deoxynivalenol - Feed Refusal  Nearly complete refusal at low dosages (~5 ppm) by swine ‫خنزير‬.  Reduced intake and poor performance at very low dosages (~1 ppm or less).  DON doesn’t account for all the feed refusal; other metabolites are involved. Deoxynivalenol contaminates different cereal crops (wheat, maize) used for food and feed production  Aflatoxin (AF) They are unavoidable natural contaminants produced by Aspergillus flavus. They are common fungal contaminants of nuts ‫ المكسرات‬but are also found growing on a variety of feedstuff, including maize, wheat, rice, and cottonseed. AFB1, AFB2, AFG1, and AFG2 occur naturally and are significant contaminants of a wide variety of foods and feeds. Aflatoxins A few of many Aflatoxins AFLATOXIN EFFECTS  Inhibits protein synthesis  Poor gain  Liver damage  Susceptibility to Infection  Residues / carcinogenicity  Reproduction AFs may be converted to more reactive, electrophilic epoxides by phase I metabolism occurring primarily in the liver. This group of mycotoxins also possesses high teratogenic, mutagenic, and immunosuppressive activities. The liver is the main target organ for AF toxicity and carcinogenicity. Aflatoxicosis can progress to potentially lethal acute hepatitis ‫التهاب‬ ‫ الكبد‬with vomiting, abdominal pain, and eventually death. AFs can cross placental barrier, and thus can adversely affect fetal systems, to increase stillbirths and neonatal mortality.‫موت الجنين داخل الرحم و وفيات األطفال حديثي الوالدة‬ The aflatoxins are known causes of acute aflatoxicosis in humans. But chronic forms of aflatoxicosis, especially carcinomas, are more problematic. AFB1 is considered to be the most toxic and carcinogenic compound of this group of mycotoxins. Exposure to AF in the diet is considered an important risk factor for the development of primary hepatocellular carcinoma, particularly in individuals already exposed to hepatitis B.  Ochratoxin A A secondary fungal metabolite is produced by Penicillium and Aspergillus species of fungi during the storage of cereals, cereal products, and other plant- derived products. There are four ochratoxin homologues: A, B, C, and D. Ochratoxin A and C are the most toxic. OTA can enter the human food chain by the foods, i.e., cereals, coffee, spices, beer, cocoa, dried fruits, and pork meats. The main source of dietary OTA intake is the cereals and their derived products, which account for around half of intake. Although mechanism of action of OA remains unclear, it has been suggested that ochratoxins act by disrupting phenylalanine metabolism, interfering with signal transduction pathways in cells, and imposing oxidative stress and apoptosis. It is immunosuppressive, genotoxic, teratogenic, and carcinogenic to human. The most prominent effect of OA being nephrotoxicity. OA can alter both barrier and absorption function of the intestinal epithelium causing intestinal injuries, including inflammation and diarrhea. OA in combination with AF showed a synergistic toxicity. For OA the elimination half-life in human was calculated to be 840 h.  There are four ochratoxin homologues: A,B,C and D Ochratoxin A is the most toxic one. Produced in storage period  T-2 toxin The trichothecene group of mycotoxins accounts for over 100 fungal metabolites, of which T-2 toxin, produced by the Fusarium fungus was the first to be studied. It contaminates mainly corn, wheat, barley, and oat.  The adverse effects of T-2 toxin on health are expressed in a diverse range of symptoms including skin lesions, immunosuppression, hepatotoxicity, nephrotoxicity, neurotoxicity, genotoxicity and even death.  The damage caused by T-2 toxin results primarily from the toxin’s interruption of cell division in bone marrow, and intestinal mucosa, resulting in a serious immunosuppressive effect. T-2 toxin also has a strong inhibitory effect on protein synthesis, which in turn results in the inhibition of DNA and RNA synthesis. It affects the actively dividing cells such as those lining the gastrointestinal tract, skin, lymphoid, and erythroid cells. T-2 toxin can decrease antibody levels, immunoglobulins, and cytokines. Molecular Mechanisms of Mycotoxin Action  BASIC OUTLINES Oxidative stress as a consequence ofMycotoxicoses Mycotoxins and Apoptosis Mycotoxinsand Gene Expression 1- Oxidative stress as a consequence of Mycotoxicoses  There is a balance between antioxidants and pro- oxidants in the body in general and specifically in the cell , is responsible for regulation of various metabolic pathways  This balance can be regulated by dietary antioxidants , including vitamin E , carotenoids , and selenium  On the other hand, nutritional stress factors have a negative impact on this balance, Mycotoxins are among the most important feed-born stress factors  Mycotoxins stimulate lipid peroxidation directly by enhancing free radical production or increased tissue susceptibility to lipid peroxidation is a result of compromised antioxidant system 2- Mycotoxins and Apoptosis  The maintance of tissue homeostasis involves the damaged cells this process is called ( programmed cell death or apoptosis)  The cells activate intrinsic death program such as  1) initiation of death signals at the plasma membrane  2) expression of pro-apoptotic oncoproteins  3) activation of death proteases, end nucleases, ultimately coalesce to a common irreversible execution to cell demise Balance between cell shrinkage, nuclear pyknosis death and survival factors Apoptosis Necrosis - Is characterized by cell - Cell death is induced shrinkage, nuclear by osmotic, physical, pyknosis, chromatin chemical damage, condensation, DNA disruption of external cleavage into fragments and internal membranes and activation of takes place with cysteine proteases called liberation of denatured caspases proteins into the cellular space  Reactive oxygen species play a major role in apoptosis, being involved in the initiation as well as execution of apoptosis  GSH depletion increases the percentage of apoptotic cells  Apoptosis is considered as mechanism of toxicity of various Mycotoxins  Balance in the cell ( redox status ) is responsible for a regulation of apoptosis  Natural antioxidants and Selenoproteins such as GSH- PX, Thioredoxin reductase and Methionine Sulfoxide reductase B could be involved in prevention of mycotoxin - related apoptosis  There are approaches to control mycotoxins in feeds by special management programs including  1) storage at low moisture levels  2) Prevention of grain damage during processing  Protective effects against Lipid peroxidation caused by mycotoxins were attributed to various antioxidant compounds including Vitamin A, Vitamin E, Ascorbic acid, Selenium and antioxidant enzymes Preventing Mycotoxins  Use “clean” procedures.  Prevent contamination  Inhibit mold growth  Drying  Refrigeration  Mold inhibitors Advice- continued  I would:  Feed NO moldy feeds to reproducing animals.  Feed a small test amount to growers but DO NOT encourage consumption.  If no ill effect is observed in test, then dilute the suspect feed and incorporate small amount into normal diet. References  Australian Mycotoxin Newsletter  http://www.aciar.gov.au/aciarptp/myconews.htm  Third Joint FAO/WHO UNEP International Conference on Mycotoxins, Mar 1999  http://www.fao.org/WAICENT/FAOINFO/ECONO MICS/ESN/mycoto/papers/