Aflatoxins Biodetoxification Strategies Based on Probiotic Bacteria

Journal Pre-proof Aflatoxins Biodetoxification Strategies Based on Probiotic Bacteria

Parvaneh Afshar, Mohammad Shokrzadeh, Shahram Naghizadeh Raeisi, Azade Ghorbani-HasanSaraei, Leila Roozbeh Nasiraii PII:

S0041-0101(20)30038-6

DOI:

https://doi.org/10.1016/j.toxicon.2020.02.007

Reference:

TOXCON 6285

To appear in:

Toxicon

Received Date:

29 November 2019

Accepted Date:

10 February 2020

Please cite this article as: Parvaneh Afshar, Mohammad Shokrzadeh, Shahram Naghizadeh Raeisi, Azade Ghorbani-HasanSaraei, Leila Roozbeh Nasiraii, Aflatoxins Biodetoxification Strategies Based on Probiotic Bacteria, Toxicon (2020), https://doi.org/10.1016/j.toxicon. 2020.02.007

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

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Aflatoxins Biodetoxification Strategies Based on Probiotic Bacteria Parvaneh Afshara, Mohammad Shokrzadehb, c*, Shahram Naghizadeh Raeisi d, Azade GhorbaniHasanSaraei d, Leila Roozbeh Nasiraiie* a

Department of Food Science and Technology, Ayatollah Amoli Branch, Islamic Azad

University, Amol. Iran. b

Research and Development Unit & Medical Mycology Unit of Referral Laboratory, Deputy of

Health Management, Mazandaran University of Medical Sciences, Sari, Iran. c

Department of Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical

Sciences, Sari, Iran d

Department of Food Science and Technology, Ayatollah Amoli Branch, Islamic Azad

University, Amole. Iran e

Department of Food Science and Technology, Nour Branch, Islamic Azad University, Nour.

Iran

Running title: aflatoxins biodetoxification *Corresponding Author: Dr.Mohammad Shokrzadeh,PhD Professor, Department of Pharmacology, Faculty of Pharmacy,

Mazandaran

University

of

Medical

[email protected] orcid.org/0000-0002-0071-6530

1

Sciences,

Sari,

Iran

E-mail:

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Dr. Leila Roozbeh Nasiraii, PhD. Assistant Professor, Department of Food Science and Industry, Nour Branch, Islamic Azad university, Nour. Iran. E-mail: [email protected] https://orcid.org/0000-0002-6260-0103 ABSTRACT Aflatoxins are secondary metabolites of fungi that are the most dangerous mycotoxin and food safety challenges. Human exposure to mycotoxins occurs directly throughout the intake of contaminated agricultural products or indirectly throughout the consumption of products prepared with animal origin or obtained from animals that were fed with contaminated material. For detoxification and reducing threats to public health and the economic damage caused by the aflatoxins in animal and plants food products, different techniques (physical, chemical and biological) has been studied. All of these methods, by modifying and destroying the toxin molecular structure, would inhibit its transfer to the digestive system and could reduce the accessibility of toxins to the target tissue and eliminate it. In terms of the overarching challenges presented by the aflatoxins (AFs) contamination in foods and feeds, there is an urgent need to evolve cost-effective and appropriate strategies to combat this hazard. The review addresses have been noted the pathogenicity of AFs and the plausible mechanism of their-induced toxicity. Furthermore, assessed the AFs degradation using probiotic bacteria of their biological substance, and converting it into non-toxic or less toxic products, as a costeffective and environmentally friendly strategy of detoxification method for providing appropriate solutions. Key words: Mycotoxin, Probiotic bacteria, Biodetoxification, Cancer, Aflatoxins

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1. Introduction Human exposure to different natural or synthetic toxic chemical compounds may be correlated with a widespread range of human health problems like reproductive tract and mental health disorders, immune system suppression, organ dysfunction (liver and kidney damage) and some types of cancer promotion. (Shahbazi et al., 2016, Shahbazi et al., 2015) One of the main natural chemical compounds is mycotoxins by-products metabolites of fungi, particularly its Aspergillus, Penicillium and Fusarium species, and a serious concern of food hygiene throughout the world. (Afshar et al., 2013) The mycotoxins probably evolved as a kind of "chemical defense system" in order to protect the mold from insects, microorganisms, nematodes, and grazing animals and human.(Ertas et al., 2011) Although, this material does not play a role of natural metabolism process and growth of fungi, but due to the sustainability of raw, processed or cooked conditions of foods, which could remain in the final food products, these materials are transmitted throughout nutrition to the human body and livestock and are major contributor to food hygiene as a major environmental risk factor. In addition, this could cause very serious damages to health condition, particularly cancer. (Ji et al., 2016, Sarlak et al., 2017, Anfossi et al., 2016, Wu et al., 2015, Alberts et al., 2017) Furthermore, mycotoxins will lead to large economic losses, including the humans and animals deaths, crop products loss, and livestock feed annually. (Zain, 2011) Given the directly or indirectly mycotoxins effect on human’s health and despite numerous studies were done about the preventing, eliminating or inactivating. Aim of the updated review addresses were highlighted on the a; pathogenicity of AFs and the plausible mechanism of theirinduced toxicity b; the AFs degradation methods notably based on biodegradation strategy via probiotic bacteria mechanism as providing appropriate solutions in environmentally friendly approaches 3

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2. Mycotoxins and Important mycotoxins Mycotoxins are low molecular weight and have very different molecular structure; from a single heterocyclic rings ~ 50 Da molecular weight to the complex of 6-8 irregularly heterocyclic rings with more than 500 Da molecular weight. (da Rocha et al., 2014) The mycotoxin production occurs with fungi growth and proliferation under the proper temperature and humidity in crops of agricultural areas before and after the harvest time, or during processing and storing in the warehouse, and has consistent effect on the quality of human foods and animal feeds. (Ji et al., 2016, Sarlak et al., 2017, Anfossi et al., 2016, Wu et al., 2015, Alberts et al., 2017)Human exposure to mycotoxins occurs directly throughout the intake of contaminated agricultural products (cereals, corn, fruits, etc.), or indirectly throughout the products with animal origin consumption (meat, eggs, milk, and other edible products, etc.), which were prepared or obtained from animals and they were fed by contaminated material. (Capriotti et al., 2012, Wu et al., 2015, Afshar et al., 2013, Pfliegler et al., 2015, Thielecke and Nugent, 2018) In addition to the digestive tract, which is the main route of exposure to mycotoxins, the risk of infection throughout inhalation and skin contact is also possible.(Pfliegler et al., 2015) It is essential to mention this point that, not only all fungal species cannot produce toxins; but also secondary fungal metabolites are not toxic (Zain, 2011, Afshar et al., 2013) Considering that, a single fungal species may have the ability to produce several different type of mycotoxins, and has possibility to produce a types of mycotoxins from more than one species fungi; therefore, it can be recognized as a reason for the various types of mycotoxins recognition in an initial substrate (simple or combination) contaminated food.(Oueslati et al., 2012) Mycotoxins are contaminated 30-100% of food and feed samples on a global level. (Pinotti et al., 2016) Many types of mycotoxins are resistant to a wide environmental factors spectrum and are remained stable in the 4

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final product, therefore, they underwent slow degradation. Some factors have been shown resistance to low pH of animal gastric juice including high temperature and high pressure (even in pasteurization and sterilization conditions), and other different stages of food preparation even the chemical structure. Due to the widespread distribution of fungi in the environment, mycotoxins are one of the main contaminants in foods and feeds and its role and side effects can be presented by consuming contaminated food. (Pfliegler et al., 2015) If several mycotoxins were presented in a foodstuff consumed simultaneously, especially in mycotoxins potentially produced by exactly same fungal species, they occasionally could be interacted amongst mycotoxins and side effects of their additive and synergistic. The severe side effects were observed, because of the consumption of those, food contaminated with mycotoxins with the amount of less than the maximum legal limit concentration, but it takes a long time especially in children, immunodeficiency, and high-risk patients. (Li et al., 2014, Streit et al., 2013, Bräse et al., 2009) Nowadays, more than 400 types of mycotoxins have been identified and most scientific topics and investigations are concentrated on carcinogens and/or toxic mycotoxin variety.(Miró-Abella et

al.,

2017)

In

this

regard,

Aflatoxins(AFs),

Ochratoxins(OTs),

Fumonisins(FBs),

Zearalenone(ZEA) and Deoxynivalenol(DON) have created widespread concerns about public health due to the highest prevalence and having teratogenicity, carcinogenicity, mutagenicity, genotoxicity and immunosuppression effects. (Afshar et al., 2013, Oueslati et al., 2012, Do et al., 2015, Hathout and Aly, 2014, Mansoreh Taghizadeh, 2017) The mycotoxins adverse effects are affected by various factors including; type, dose, and consumption toxin duration, recipient age (younger people are more sensitive); some environmental factors like stress, lifestyle, etc. the maximum level of toxin in food can play its own adverse effects Even with long-term 5

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consumption of below doses. Mycotoxins toxic effects induced with different patterns that are associated to their chemical structure. 3. Aflatoxins Aflatoxins are bis-furan metabolites and 20 different types of them have been identified, but the four main ones AFB1, AFB2, AFG1, and AFG2 are synthesized by toxigenic fungi naturally, while AFM1 and AFM2 are the hydroxylated metabolites of AFB1 and AFB2 and were produced from the animal and their products (Figure 1). Almost 0.3-6.2% of consumed AFB1 by an animal is metabolized to AFM1 and transformed to milk. Some other different factors, like animal hygiene, animal race, diet, milk production rate has some influences on this transformation. The other AFs P1, Q1, G2a, B2a, AFL, GM1, GM2, GM2A, B3, M2A, and Aflatoxicol (AFL) are microbial or animal metabolism products and has been reported in Figure 2. (Kumar et al., 2016, Gholami-Ahangaran et al., 2016, Ashiq, 2015, Carvajal-Moreno, 2015, Wochner et al., 2017, Adebo et al., 2017) AFs are difuranocoumarin derivatives composed by two furan rings, linked with each other to a coumarin moiety. AFs associated to a bisdihydrodifuran or tetrahydrobisfuran united to a coumarin replaced by a cyclopentanone or a lactone. The difurocoumarocyclopentenone group includes AFB1, aflatoxin B2, aflatoxin B2a, AFM1,

aflatoxin

M2,

aflatoxin

Q1

(AFQ1),

and

aflatoxicol

(AFL),

while

the

difurocoumarolactone group comprises aflatoxin G1, aflatoxin G2 and aflatoxin G2a. In aflatoxins biosynthesis pathway from Acetyl-CoA, at least 21 enzyme levels and 34 genes coding are recognized (with the regulatory role) and their enzymes (27 genes) are often clustered function. These genes are correlated to the wide range of genes and contributed to morphology, tinning, or the formation of sclerotia. (Yabe and Nakajima, 2004, Xing et al., 2017, Kumar et al., 2016, Carvajal-Moreno, 2015, Loi et al., 2017) Several investigations have indicated an order of 6

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severity amongst the acute and chronic toxicity of the various AFs. This order is AFB1 > AFG1 > AFB2 > AFG2, while AFM1 and AFM2 are less potent in comparison with their precursors. The less potency exhibited by the AFM groups is because of the steric hindrances, chirality and resonance energy of the AFBs cyclopentanone ring, as compared to the six-membered lactone ring of the AFGs. (Adebo et al., 2017) The IARC lists AflatoxinB1 as very toxic compounds with sufficient evidence of carcinogenicity in humans (Group Ι), AFM1 and the other metabolite of AFB1, as a possible human carcinogen (Group 2B), are produced mainly by strains of Aspergillus flavus and Aspergillus parasiticus. (Afshar et al., 2013, Caceres et al., 2017) The IARC lists AFM1, the metabolite of AFB1, are identified as a possible human carcinogen (Group 2B) 4. Aflatoxins maximum limitation allow Exposure to mycotoxin needs to be kept as low as possible in order to protect the consumer. Many countries have regulations governing mycotoxin in food with prescribed acceptable limits, and most of them have a maximum permitted or acceptable level for different foodstuffs. Aflatoxins damage health and business opportunities, and importing countries are increasingly imposing more regulations that are stringent. The Codex recommendations, Aflatoxins maximum acceptable level are of 1-20 µg/kg for AFB1, 10-30 µg/kg for total AFs (AFB1, AFB2, AFG1 and AFG2) and 0.05-0.5 µg/kg for AFM1 in milk and milk products based on the various world parts and foods type. Stringent limits like 2 µg/kg (for AFB1) and 4 µg/kg (for total aflatoxins) in adult’s human foods and 0.1 µg/kg in baby foods and 50 ng/kg for AFM1 in milk and milk products set in the European Community force producers, traders, and processors in other countries to incur more operating costs as they strive to meet them. (2015) 7

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5. Aflatoxins toxicokinetic effect Aflatoxins main biological effect is the acute or chronic liver disease, but they are also considered

as

hepatotoxicity,

carcinogenicity,

mutagenicity,

teratogenicity

and

immunosuppressant both cellular and humoral response. The Long-term consumption of food that were contaminated via mycotoxin may lead to adverse effects in the liver like damage to liver cells and other tissues, as well as occurring of obvious anomalies or microscopic in it.(Kazemi Darsanaki and Azizollahi Aliabadi, 2017, Gholami-Ahangaran et al., 2016, Stoev, 2013) . Because AFB1 is a low molecular weight compound, passive diffusion into the enterocyte was recommended as the absorption mechanism. (Gratz, 2007) Exposure to aflatoxins is typically throughout the contaminated foodstuff ingestion, while dermal exposure would result in slow and insignificant absorption. (Flores-Flores et al., 2015) The lactone and furfuran rings of AFs are responsible for the toxic and carcinogenic activity upon metabolic activation of the C8-C9 double bond to 8–9 epoxides. (Loi et al., 2017) Aflatoxins can induce cancer cells by conjunct to the water-insoluble guanine organic base of DNA strand, and create DNA-Adduct. (Hathout and Aly, 2014, IRANI et al., 2015, Caceres et al., 2017) Oxidative stress plays a remarkable role in the AFB1 toxic effects. The main Reactive oxygen species (ROS) generation effect induced by AFB1 are on DNA/protein/lipid peroxidation synthesis damage, mitochondrial lesions and inflammatory response (Figure 3). (Da Silva et al., 2018) AFB1 and AFG1 have a double bond at the 8,9 position that oxidizes and forms AFB1exo-8,9-epoxide (AFBO), an unstable molecule, and produces dihydrodiol AFB1 and is connected to the N7-guanine of DNA nucleases in order to create active carcinogens called AFB1-DNA adducts, and induce point mutations and DNA strand breaks. The guanine-thymine (GT) pair is evaluated in codon 249 of the p53 suppressor tumour gene and preferably guanine 8

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nucleotides. As a result of this adduct, and would cause point mutations mainly from GC to TA (94%) or AT (6%) that could increase the expression of the p53 gene, which was associated with an increase in cell apoptosis. a double bond AFB2 and AFG2 absence, which affects their toxicity with decrees to hundreds of times less. The bond changed the convert AFB1 to AFB2 and is identified, and the biotransformation and biosynthetic paths of AFB1 have been explained. (Carvajal-Moreno, 2015, Gratz, 2007, Heidtmann-Bemvenuti et al., 2011, Wang and Groopman, 1999, Da Silva et al., 2018) Lactone ring is hydrolyzed throughout ammonization, forming aflatoxin D1 (AFD1) and retains the 8, 9-dihydrofuran double bond; AFD1 lacks the strong in vivo DNA binding activity of AFB1, indicating that DNA alkylation depends upon both difuranocumarin and lactone moieties. (Loi et al., 2017) AFB1 uncouples mitochondrial oxidative phosphorylation, decreases the mitochondrial membrane potential (MMP), and leads to mitochondrial permeability.(Liu and Wang, 2016) The mitochondrial alterations associated with oxidative stress activate cytochrome C, modulate Bcl2 / Bax gene expression, and activate Caspase 9 and Caspase 3 are leading to cell.(Liu and Wang, 2016, Da Silva et al., 2018) Moreover, ROS generation induced by AFB1 inducing cytochrome P450 activity, increasing arachidonic acid metabolism, and activating the NADPH oxidase (NOX) dependent signaling pathway, thereby promoting the autophagy of pro-inflammatory macrophages M1, and modulates the inflammatory response through up-regulation of pro-inflammatory cytokines TNF-α, IL-1α, IL-1β and IL-6 and NO expression, by reducing anti-inflammatory cytokine IL-4 expression.(Da Silva et al., 2018) On the other hand, ROS causes changing in intracellular antioxidant

mechanisms such as SOD, GPx, CAT and

Nrf2 expression, inhibiting and

decreasing the enzymes Leads to an increase in lipid peroxidation (LPO) and in finally a decrease in GSH and increase in MDA levels(Da Silva et al., 2018). Due to the mycotoxins role 9

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in the development of some diseases, these toxins presence in food should be evaluate constantly. 6. Mycotoxins detoxification methods Different strategies have been developed to reduce or eliminate mycotoxin side effects like; the prevention of the mycotoxic fungi growth, detoxification food and feeds contaminated with toxins, the structure destruction and inhibition of absorption of mycotoxins in the gastrointestinal tract.(Hathout and Aly, 2014) Mycotoxins in contaminated food products can be used of the several traditional strategies physical (heat, ultraviolet light, solution absorption or ionizing radiation), and chemical (in addition to chlorination, oxidant or hydrolytic substances), Despite of being mentioned in various researches in order to remove or deactivate it. Although, harness of early plant pathogens colonization and creating an effective protective level in before or after of harvest stage of storage and warehousing, but most of these methods are associated with limited constraints as biosafety, dropping the quality of organic products and food flavour, limiting of efficiency, effectiveness and high-cost methods.(Sarlak et al., 2017, Pfliegler et al., 2015, Stoev, 2013, Zhang et al., 2014) In recent years, using some of the absorbent agents that have the ability to bind to mycotoxins in the animal digestive tract, have reduced their bioavailability and toxicity. The compounds have potential of industrial applications. There is a different efficacy of aflatoxins-induced poisoning amongst different available absorbent agent’s types. (Zain, 2011) Also crucial, the grains and foods contaminated via mycotoxin are urgently required in order to minimize potential losses to the farmer and toxicological hazards to the consumer. It is a need for finding new appropriate 10

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methods for decontamination of mycotoxins that do not alter the nutritional quality of the product or these nutrients availability in products, which are intended for human consumption. Therefore, the biological detoxification measures development is essential in order to improve the human consumption foods safety. Particularly in liquid and processed milk and dairy products, highlights the significance of traceability of the raw material, because it has the nutrients needed for growth for all age groups, especially for children and patients with the immunecompromised system, and it is suggested to abundant consume. Thus, the nutritional quality of the dairy products must be increased and elevated the bioavailability of nutrients available for absorption; the products also maintain their organoleptic characteristics. (Wochner et al., 2017) There are very useful absorbing agents in order to prevent aflatoxins poisoning (Aflatoxicosis), but they are not effective for other mycotoxins. (Pitt, 2000) This point has great importance in the fruit and vegetables health, which are consumed by vegans.(Yang et al., 2014, Zheng et al., 2016, Hao et al., 2016) According to the consumers' demands and objections of avoiding from the use of chemical treatments, it is needed to find an effective technology with high sensitivity and specificity, which has minimum cost and is friendly with environment, in addition to the application and ability to run. (Rufino et al., 2013, Oliveira et al., 2013) This new strategy is biodetoxification and is a mycotoxins replacement via a nonpathogenic microbial or their enzymes and/or catabolic pathways. Their agents not only lead to reduce/ suppress toxins to no/less toxic compounds, but also to be Generally Regarded as Safe (GRAS) with some benefits end products manufacturing via bioadsorption or biodegradation mechanisms. These germs are called probiotics. (Ji et al., 2016, Alberts et al., 2016, Solis-Cruz et al., 2018, Niderkorn et al., 2009) 7. What is probiotics microorganism? 11

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The probiotics agents' definition is live microorganisms which when administered in adequate amounts causing numerous health beneficial effects on the host, which make them additives that are even more suitable to food and feed, according to the World Health Organization (WHO) and Food and Agriculture Organization of the United Nations (FAO). (Food et al., 2006, Oliveira et al., 2017) The probiotics include a wide variety of Non-pathogenic microorganisms bacterial, fungi, or algae and are mostly derived from human sources, animals and environmental, that only those human origin species are appropriates for the probiotic products that used human's production. (Czerucka et al., 2007, Hernandez-Mendoza et al., 2010) Nondairy probiotic products have high importance in all over the world, because of their high prevalence of lactose intolerance, and also the ongoing trend of vegetarianism in many populations all around the world. (Granato et al., 2010) These viable microorganisms help to maintain the digestive tract of mammals balance and would be useful for controlling and treating some diseases like diarrhea, urinary infections, candidiasis, lactose intolerance, hypercholesterolemia, immune disorders and any other food allergy throughout affecting the digestive enzymes, carcinogenic agents' inhibition and neutralizing cancer-inducing compounds. The probiotics application is also prevalent in the aquaculture industry in order to control the disease, improve the water quality, and decrease demand for the antibiotics or disinfectants use. (Zoghi et al., 2014, Kumar Bajaj et al., 2015, Zarei et al., 2017) The commonly used species of bacteria in probiotic foods and food supplements are A; Bacteria: (i) Lactobacillus: acidophilus, plantarum, sporogenes, rhamnosum, delbrueck, reuteri, fermentum, lactus, brevis, cellobiosus, casei, farciminis, paracasei, gasseri, crispatus; (ii)Bifidobacterium: bifidum, infantis, adolescentis, longum, thermophilum, breve, lactis, animalis; (iii) Streptococcus: lactis, cremoris, alivarius, intermedius, thermophilis, diacetylactis; 12

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(iv) Leuconostoc mesenteroides; (v) Pediococcus; (vi) Propionibacterium; (vii) Bacillus: subtilis, clausiic; (viii) Enterococcus faecium; (ix) Escherichia coli strain Nissle; B; Yeast and moulds: Saccharomyces cerevisiae, Saccharomyces bourlardii, Aspergillus niger, Aspergillus oryzue, Candida: krusei, pintolopesii and other yeasts. (Rathore, 2017, Amara and Shibl, 2015) Specific strains of probiotic bacteria have been earlier indicated in order to be effective in different poisons removal such as mycotoxins (Aflatoxins, Ochratoxins etc.).(Niderkorn et al., 2009) 8. Mechanism effect probiotic bacteria on mycotoxigenic fungi The antagonistic effect of probiotic agents on mycotoxigenic fungi is based on competition in the physical space and nutrients absorption that are needed for growth, antifungal metabolites production, the parasitism and parasitic role on fungi pathogen by creating a biofilm, and induction or stimulation of resistance in host plants, and also creating a defensive response throughout the release of free oxygen radicals (ROS). The required nutrients for these microorganisms obtained via lysis the living or dead cells or other microorganisms, which were available in the environment.(Ji et al., 2016, Sarlak et al., 2017, Streit et al., 2013, Zhang et al., 2014, Taylor and Draughon, 2001) Most studies have been accomplished on probiotic bacteria, yeasts, and after that in the form of fungi.(Streit et al., 2013, Ma et al., 2017) The most extensively used biological absorbents can be named as yeast and probiotic bacteria, which prevents from the toxins transfer in human and animal intestines, and it was removed with the availability of toxins reducing. This process can be influenced by various factors including; Pressure used, Aflatoxin concentration, pH, thermal processes, ionic strength, fermentation degree, protein content, acidity titration, and time and temperature of storage. (Sarlak et al., 2017, Arab et al., 2012) Most probiotics bacteria are susceptible to pH less than 4.2, and inactivated in these situations.(Arab et al., 2012) 13

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9. Mechanism effect probiotic bacteria on detoxification Aflatoxins Several authors have described the biodetoxification of Aflatoxins presence based on native/standard probiotic bacterial strain (Table1). Probiotics can remove AFs using the biodegradation or bioadsorption mechanisms. AFs biodegradation is permanent and has longer duration in comparison with bioadsorption. Biodegradation modified AFB1 structure and would result in in undesirable metabolites (as AFL), which are probably harmful for the host. Bioadsorption involves direct binding of AFs in a short period and may be easily released that depends on the probiotic affinity toward AFs.(Solis-Cruz et al., 2018, Adebo et al., 2017, Luo et al., 2018) Two key sites affecting the AFs toxic activities are the furofuran and lactone rings. Changing in the coumarin structure has been reported in order to alter the AFs mutagenic properties too. Detoxification of the AFs molecule occurs when there is a cleavage of difuran ring of the mycotoxin (Adebo et al., 2017) that performed via often microorganism’s cells (bacteria and fungi) and their enzymatic metabolites (Table2). In bioadsorption, technique of AFs biodetoxification has been accomplished by specific strains of probiotics organisms of Bifidobacteria and Lactobacillus spp. bacteria, and yeast cell Saccharomyces cerevisiae. And with different unclear physical attach mechanism to the cell wall. (Adebo et al., 2017) Several studies indicated that probiotics bacteria can be removed AFB1 by physical adhesion, and could bind to the carbohydrate components of the bacterial cell wall, rather than by covalent bindings or metabolic degradation, consequently non-viable bacteria cells do not lose their binding ability..(Bueno et al., 2007, Hernandez-Mendoza et al., 2010) The probiotic bacteria cell wall is a complex arrangement of macromolecules same as other Gram-positive bacteria. It 14

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contained peptidoglycan (PG) sacculus that surrounds the cytoplasmic membrane and that is decorated with other glycopolymers like teichoic acids (TAs) or polysaccharides (PSs) and proteins.(Chapot-Chartier and Kulakauskas, 2014) These compounds have different functions. TAs, units are categorized into two groups: wall teichoic acids (WTAs), which are covalently linked to the PG molecule, and lipoteichoic acids (LTAs), which are anchored in the cytoplasmic membrane with a glycolipid moiety. WTAs has a high hydrophobic property and may constitute up to half of total dry weight of cell wall in certain bacterial species.(Chapot-Chartier and Kulakauskas, 2014, Swoboda et al., 2010) The microorganism efficiency as a AFs binder based (M ˟ Keq) could be determined with two parameters; the binding sites number per microorganism cell wall (M) that has difference in various microorganism and reaction equilibrium constant (Keq).(Bueno et al., 2007) AFs can be bound to the bacterial cell wall via non-covalent weak interactions that were associated with hydrophobic pockets on their surface like peptidoglycan and other polysaccharides cell wall or their compounds tightly associated with the bacteria peptidoglycan. These non-covalent interactions included Van der Waals interaction, electrostatic interactions, and hydrogen bonds respectively. Although, Van der Waals interaction is weaker in comparison with hydrogen bond, but they play major roles in the binding of AFB1due to their large number provide the possibility of maintaining the stability of the molecular structure. Hydrogen bonds have a small portion (3.8 kcal/mol) of the docking energy for the binding, however, hydrogen binding, may be considered as important in other AFs except for AFB1.(Haskard et al., 2001, Lahtinen § et al., 2004) The toxins removing and releasing is a fast and reversible physical process, without any chemical changes in the AFs, the adsorption capacity of removed toxin depends on the concentration, toxin, and bacterial cell types, and the total amount of cell wall 15

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components obtained from the viable or nonviable (heat-treated) bacteria. (Pfliegler et al., 2015) Therefore, only specific bacterial (species involved, individual strain, dose) likely can be appropriate for the certain toxins destruction in biodetoxification pattern. Viable probiotic bacterial have an auto-safety system, which does not allow all AFs around the cell to bind for activating cell walls. Due to that, bacterial resistance is limited in the toxin absence, and by concentration of toxins increasing, this self-efficacy is going to disturbing and being eliminated, as a result, could increase the cell wall ability to bind the toxin. 10. Conclusion Contamination with aflatoxins is one of the main foodborne diseases causes all over the world. The prevalence of these diseases is directly associated with a lack of knowledge and food and feed contaminated consuming. aflatoxins have a negative economic role in all food and feed industries and causing economic capital to be wasted, via reduced performance and the product production value, reduced animal productivity, and additional prevention, control, and detoxification costs to increase the humans and animal’s health level. Hence, it is very important to assess the food aflatoxins levels in industrial and non-industrial countries, regularly. To reducing, controlling and managing the aflatoxins have been used in various physical, chemical, biological and genetic engineering techniques in foods. Although the human body has, the innate antioxidant defense mechanisms aimed at preventing the reaction between excess free radicals and biological compounds but the use of exogenous antioxidant compounds has an essential role in regulating this mechanism, too. In environmental science using microorganisms, particularly an agent with probiotic properties, as a specific, effective, irreversible, environmentally friendly, cheap, and safe strategy. The generated promising results of this 16

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approach is for eliminating food and feed chemical pesticides and metals contaminants like mycotoxins, without any toxic residues, will create new opportunities for innovation and health outcomes. Probiotic elements (non-pathogenic bacterial/fungal microorganisms) and they're cellular metabolites/compounds are the most common exogenous antioxidant compounds. The natural antioxidants are a rational compound presented by nature in a logical approach to prevent ROS and RNS production via oxidative stress-induced aflatoxins that associated with DNA, protein synthesis and mitochondria toxic effects and restore oxidative balance destroyed by mycotoxins. Considering that, the sector is as major advances in the agricultural industry macro-politics and the humans and animal’s consequent health. Hence, it is required to perform more researches to formulate new and applicable strategies guideline regarding, decontamination probiotic mechanisms, dosage, time and how to use these new probiotic functional supplements, based on maximize benefits effects in preventing and treating different diseases such as cancers. Ethical Statement Non applicable Author Contribution P.A, M.S, L.R.N, SH.N.R, and A.G conceived the review. P.A., M.S, and L.R.N performed the bibliographic research, designed and wrote the manuscript. All authors reviewed and approved the manuscript content. Acknowledgment

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The authors wish to acknowledge the assistance of the members of the Mazandaran University of Medical Sciences, Sari, Iran and Department of Food Science and Technology, Ayatollah Amoli Branch, Islamic Azad University, Amol. Iran. Declaration of Interest This research has been supported by the grant (project 4715) of the Research Deputy of the Mazandaran University of Medical Sciences. The study approved by the Mazandaran University of Medical Science's Ethics Committee (Ethic Code IR. MAZUMS.REC.1398.4671). And with registration number of Department of Food Science and Technology, Ayatollah Amoli Branch, Islamic Azad University, Amol. Iran. The authors state no conflict of interest. Reference 2015.

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Table 1: Biodetoxification rate of Aflatoxins based on native/standard probiotic bacterial strains Table 2: Some microorganism’s cells (bacteria/fungi) and their enzymatic metabolites list effective on Aflatoxins detoxification Figure 1 Chemical structures of major dietary aflatoxins namely aflatoxin B1, G1 and M1 with the double bonds in 8-9 position and aflatoxins B2, G2 and M2 without the double bond(Gratz, 2007) Figure 2 Major metabolic pathways of AFB1(Gratz, 2007) Figure 3 indicated Summary of the intracellular lesions in food and feed contaminated, which are associated with oxidative stress induced by the Aflatoxin B1

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Ethical Statement Non applicable

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Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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Table 1: Biodetoxification rate of Aflatoxins based on native/standard probiotic bacterial strains

Mycotoxins

Microorganism Lactobacillus plantarum MON03 Lactobacillus plantarum C88 Lactobacillus kefiri KFLM3 Saccharomyces cerevisiae KFGY7 Acetobacter syzygii KFGM1 Lactobacillus plantrium Lactococcus lactis Mixed(Lactobacillus plantrium and Lactococcuslactis) Lactobacillus acidophilus Lactobacillus brevis

AFB1

Lactobacillus rhamnosus yoba 2012 Lactobacillus rhamnosus TMU094 Lactobacillus fermentum TMU121 Pedioccus pentosaceus TMU457 Labacillus rhamnosus PTCC1637 Enterococcus faecium M74 Labacillus plantarum ŁOCK 0862 Labacillus brevis ŁOCK 1093 Labacillus rhamnosus ŁOCK 1087 Labacillus reuteri ŁOCK 1096 Labacillus casei ŁOCK 0911 Streptomyces cacaoi subsp. Asoensis K234 Streptomyces luteogriseus K144 Streptomyces rimosus K145 Bacillus licheniformis CFR1

Mechanism of detoxification

Cell count CFU/ml

Toxin level

Detoxification rate % (mean ± SD) 54.3±7.3a, c 82.3±8.3a,d 39.8±0.4b,d 57.6a,e 59.4b,e

Binding

108

50µg/ml

Binding

1010

2µg/ml

Adsorption 82% Biotransformation 31%

Unknown

1 μg/mL

82 74 65

(Taheur et al., 2017)

Unknown

1010

2.02 μg/ml

33.92±2.86 18.83±1.5 60.90±0.23

(Sezer, Güven, Oral, & Vatansever, 2013)

Binding

109

Unknown

50 28

Binding

108

1 μg/ml

83.5

(Bagherzadeh Kasmani, Torshizi, Allameh, & Shariatmadari, 2012)

References (Jebali et al., 2015) (Huang et al., 2017)

(Sadeghi, Ebrahimi, & Sadeghi, 2016) (Wacoo et al., 2019)

Binding

1010-15

5 µg/ml

75.06±1.60c 72.15±0.38c 63.21±3.04c 33.01±3.08c

Unknown

1010

5mg/L

30.5±1.87a,d 27.1±3.15b,d

(Topcu, Bulat, Wishah, & Boyacı, 2010)

(Chlebicz & Śliżewska, 2019)

Binding

Unknown

100 μg/ml

65 60 59 59 49

Degradation

Unknown

1 μg/ml

88.34 ± 15.62 79.93

(Harkai et al., 2016)

Degradation

Unknown

500 ppb

94.73 ± 1.09

(Rao, Vipin, Hariprasad, Appaiah, &

1

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Venkateswaran, 2017) Lactobacillus plantarum MON03 Lactobacillus rhamnosus GAF01

Binding

Lactobacillus plantarum MON03

Binding

Saccharomyces cerevisiae HR 125a (SC) Lactobacillus helveticu ATCC 12046 (LH) Lactobacillus plantarum NRRL B-4496 (LP) Lactococcus lactis JF 3102 (LL) Mixed (SC+ LP + LH + LP with 2:1:1:1 ratio) Lactobacillus rhamnosus 1637PTCC

AFM1

108

Binding

Binding

0.05 µg/ml 0.1 µg/ml 0.2 µg/ml

71.6±6.1 74±8.2 78.6±7.1 84.9±7.1 91.3±7.2 94.7±8.2 64.5±5.2a,c 89.1±6.2a,d 2 52.2±0.5b,d

(Abbès et al., 2013)

(Jebali et al., 2015)

108

50µg/ml

1010

0.05 µg/l 0.1 µg/l

100, 92 100, 85 80,77 76, 73 100, 87

(Ismail et al., 2017)

Unknown

0.1 ng/ml 0.5 ng/ml 0.75 ng/ml

99 92 93

(Tajalli, Sarabi Jamab, Adibpour, Mehraban Sangatash, & Karazhyan, 2016)

(Elsanhoty, Salam, Ramadan, & Badr, 2014)

Lactobacillus plantrium Lactobacillus acidophilus ATCC 20552 Lactobacillus rhamnosus TISTR 541 Lactobacillus bulgaricus Streptococcus thermophiles Bifidobacterium angulatum DSMZ 20098

Unknown

Unknown

50 mg/L

76.4±0.45 68.2 66.6 69.2 64.8 66.8

Lactobacillus casei-431

Unknown

Unknown

0.75 ppb

98.96

(Alidad, MOHAMADI, & Tajali, 2013)

Binding

3×1010

0.05 ppb 0.25 ppb 0. 5 ppb

76.09 52.26 76.19

(Kate Shamshiri Marzieh, 2014)

Lactobacillus acidophilus Pool strains (Lactobacillus delbrueckii spp. Bulgaricus LB340, Lactobacillus rhamnosus HOWARU and Bifidobacterium lactis FLORA-FIT BI07) Saccharomyces cerevisiae Mixed(Pool strains and Saccharomyces cerevisiae) Lactobacillus rhamnosus 1637PTCC

1010 109 1010

Binding

Binding

Unknown

2

11.7±4.4 0.5 ng/ml 92.7±0.7 100

0.1 ng/ml 0.5 ng/ml 0.75 ng/ml

99 92 93

(Corassin, Bovo, Rosim, & Oliveira, 2013)

(Tajalli et al., 2016)

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Lactobacillus bulgaricus Streptococcus thermophiles Mixed (Lactobacillus bulgaricus and Streptococcus thermophiles)

Binding

106

50 μg/ml

58.5 37.7 46.7

Lactobacillus rhamnosus GG ATCC 53103

Binding

5×108

50μg/L

63

Lactobacillus acidophilus LA-5

Binding

109

0.500 ppb

99

(El Khoury, Atoui, & Yaghi, 2011) (Assaf, Atoui, Khoury, Chokr, & Louka, 2018) (Sarlak et al., 2017)

AFB1: aflatoxins B1; AFM1:Aflatoxin M1; a:viable; b:nonviable; c:12 hours; d:24 hours; e:7 hours.

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microorganism’s enzymatic metabolites

microorganism’s cells

Table 2: Some microorganism’s cells (bacteria/fungi) and their enzymatic metabolites list effective on Aflatoxins detoxification Gram positive Bacteria Bacillus spp. (Rao, Vipin, Hariprasad, Appaiah, & Venkateswaran, 2017) Bifidobacteria (Mahmood Fashandi, Abbasi, & Mousavi Khaneghah, 2018) Streptococcus thermophiles (Chen, Kong, Chi, Shan, & Guan, 2015) Rhodococcus spp. (Risa, Divinyi, Baka, & Krifaton, 2017) Cellulosimicrobium (J. Liu et al., 2017) Corynebacterium (Intanoo, Pattarajinda, Bernard, & Callaway, 2018) Streptomyces spp. (Harkai et al., 2016) Actinomycetes (Eshelli, Harvey, Edrada-Ebel, & McNeil, 2015) Gram negative Bacteria Klebsiella spp (Ning, Zhang, Xie, Wang, & Gao, 2019) Pseudomonas spp (Song, Zhang, Xie, & Li, 2019) Escherichia coli (L. Wang et al., 2018) Enterobacter spp. (Topcu, Bulat, Wishah, & Boyacı, 2010) Stenotrophomonas spp. (Liang et al., 2008) Brevundimonas spp. (Kim et al., 2017) Mycobacterium spp. (Teniola et al., 2005) Myxococcus fulvus (S. Guan et al., 2010) Fungi Saccharomyces. cerevisiae (Bueno et al., 2007) Candida utilis (Jakopović et al., 2018) Rhizopus spp. (Hackbart, Machado, Christ-Ribeiro, Prietto, & Badiale-Furlong, 2014) Aspergillus niger (Zhang et al., 2014) Trichoderma spp. (Hackbart et al., 2014) Phoma spp. (Shcherbakova, Statsyuk, Mikityuk, Nazarova, & Dzhavakhiya, 2015) Phanerochaete chrysosporium (J. Wang, Ogata, Hirai, & Kawagishi, 2011) Pleurotus ostreatus (Loi et al., 2016) Intracellular Enzyme AF-detoxifizyme(ADTZ) (L.-z. Guan et al., 2015) AF oxidase (AFO) (Cao, Liu, Mo, Xie, & Yao, 2011) Extracellular Enzyme Laccase (J. Alberts, Gelderblom, Botha, & Van Zyl, 2009) Peroxidase (Zaid, 2017) Reductase (C.-H. Li et al., 2019) Lactoperoxidase (Karim & Kamkar, 2000) Manganese peroxidase (Yehia, 2014) Myxobacteria AF Degradation enzyme (MADE) (S. Guan et al., 2010)