Mycotoxins and their impact on human and animal health

Mycotoxins are toxic substances produced naturally by filamentous fungi as secondary metabolites that can be found in food for humans and feed for livestock.

Cereals, nuts, corn, and rice can be contaminated in the field during harvest or storage, making them a common source of contamination.

The threat of mycotoxins

Mycotoxins are produced naturally as secondary metabolites with no known metabolic function by filamentous fungi (Edite Bezerra da Rocha et al., 2014).

⇰ They are considered toxic substances when present in human food or animal feed.

They can appear during pre-harvest, post-harvest, processing, storage, and feeding. Besides, they are commonly found in human and animal food derivatives (Sforza et al., 2006).

These toxins are produced by fungal species belonging mainly to:

• ⇰ Aspergillus
• ⇰ Fusarium
• ⇰ Alternaria
• ⇰ Penicillium
• ⇰ Myrothecium
• ⇰ Trichothecium
• ⇰ Verticimonosporium

(Zain, 2011)

Mycotoxins are one of the main classes of naturally occurring toxic substances contaminating food and feed worldwide (Hueza et al., 2014; Shetty et al., 2006; Taheur et al., 2017).

According to the Food and Agriculture Organization (FAO), about 25% of the food produced in the world is contaminated with at least one mycotoxin (Rogowska et al., 2019).

Contamination of animal and human food with mycotoxins occurs directly or indirectly.

⇰ Direct contamination occurs through the infection of the food by a toxigenic fungus with subsequent production of mycotoxins, whereas indirect contamination occurs through previous contamination of food ingredients by a toxigenic fungus, even though it has been eliminated during processing (Edite Bezerra da Rocha et al., 2014).

Factors enhancing mold growth and mycotoxin production include weather conditions, particularly humidity levels (above 70%) and temperature (20–30°C).

Additionally, the plant’s moisture content (above 15%), mechanical damage, damage to crops by insects, substrate composition, use of pesticides, plant variety, and spore load influence the production of mycotoxins (Streit et al., 2012).

Mycotoxin-containing ingredients used in preparing food and feedstuffs have less nutritional value and represent a risk for animal and human health (Matejova et al., 2017).

Major mycotoxins that pose a risk to human and animal health

Aflatoxins

Aflatoxins are difuranocoumarin derivatives that are produced in a variety of food, including maize, groundnuts, rice, sorghum (Kew, 2013), pistachio, groundnuts, tree nuts (almonds, walnut, hazelnut, brazil nuts), cottonseed, spices, dried fruits, cereals, soybean, cocoa, milk, milk products, and meat (Patriarca y Pinto, 2017; Vila-Donat et al., 2018).

⇰ They are produced mainly by Aspergillus flavus and A parasiticus and, to a lesser extent, A nomius, A bombycis, Aspergillus pseudotamari and Aspergillus ochraceoroseus (Varga et al., 2011).

Based on their blue or green fluorescence under ultraviolet light, the main known aflatoxins are B₁, B₂, G₁ and G₂.

AFB₁ and AFB₂ sare produced mainly by A. flavus, while others are produced by A. parasiticus (Dhanasekaran et al., 2011).

Other types of aflatoxins include P₁, Q₁, B₂A and G₂A, which are formed due to biotransformation or metabolism of aflatoxins in humans and animals (Doi et al., 2002).

Additionally, aflatoxin M1, a hydroxylated form of aflatoxin B1, is formed in animal tissues and fluids as a metabolite of AFB₁ (Neal et al., 1998), whereas aflatoxin M₂ is a metabolite of aflatoxin B₂ formed in cattle milk (Dhanasekaran et al., 2011).

Several factors enhance the production of aflatoxins.

For example, tropical and sub-tropical regions characterized by high temperatures and humidity, along with moisture content of the plants, have favorable conditions for the growth of Aspergillus and the production of aflatoxins (Kew, 2013).

The most favorable temperature for their production is 25-32˚C, as well as moisture contents over 12% and less than 16%, and relative humidity of 85%.

MECHANISMS OF TOXICITY AND EFFECTS

Aflatoxins are the most researched group of mycotoxins due to their carcinogenic and toxic effects in laboratory animals and livestock (Jha et al., 2013; Rotimi et al., 2017), as well as their acute and chronic hepatocarcinogenic and toxicological effects in human beings (Asim et al., 2011; Kew, 2013).

 

Aflatoxin toxicity arises mainly from the generation of intracellular reactive oxygen species (ROS), such as superoxide anion, hydroxyl radical, and hydrogen peroxide (H₂O2), during its metabolism by cytochrome P450 in the liver.

 

⇰ These ROS target cellular DNA, RNA, proteins, and cell membranes, leading to the impairment of cell function, oxidative stress, DNA damage, cytolysis, and apoptosis (Asim et al., 2011; Yang et al., 2016). In addition, they can target the p53 tumor suppressor gene causing hepatocarcinoma (Kew, 2013).

Hepatotoxicity

The metabolism of aflatoxins occurs mainly in the liver under the action of cytochrome P450s into electrophilic, reactive epoxide which, in turn, binds to DNA, RNA, and cellular macromolecules in the liver (Abrar et al., 2013). Aflatoxins are usually associated with the development of hepatocellular carcinoma (HCC) in humans due to their mutagenic and carcinogenic properties. In fact, they are considered a significant risk factor, alongside the hepatitis B virus (HBV) and the hepatitis C virus (HCV), for HCC (Bosetti et al., 2014).

AFB₁ is the most potent experimental hepatocarcinogen known (Humans and Cancer, 2002) and no animal model exposed to the toxin has failed to develop HCC.

It also accounts for approximately 9.2 % of all new cancers worldwide (Ferlay et al., 2010). Other liver diseases, including cirrhosis (Humans, 2014) and hepatomegaly (Gong et al., 2012), have also been reported as implications of aflatoxin-induced toxicity in humans.

Levels of serum liver enzymes were changed upon administration of AFB1 through intraperitoneal injection in 5-week-old male Wistar rats. It also increased malondialdehyde (MDA) and decreased glutathione, catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels (Ji et al., 2020).

Similar oxidative stress was represented by increased MDA levels and decreasing glutathione content (GSH) and altered liver enzyme levels in rats exposed to AFB₁ (Karaca et al., 2021; Vipin et al., 2017).

Nile tilapia (Oreochromis niloticus) exposed to AFB1 suffered from oxidative stress and hepatic damage indicated by liver damage biomarkers represented by decreased CAT activity, GPx, and SOD levels and increased MDA content (Ben Taheur et al., 2022).

LMatrinxã (Brycon cephalus) and Pacu (Piaractus mesopotamicus) showed fatty degeneration, liver damage and altered levels of liver enzymes following dietary exposure to AFB₁ (Michelin et al., 2021).

Immunosuppressive effects

The immunosuppressive effects of aflatoxins have been thoroughly investigated in human, poultry, and aquatic species.

AFB₁ is toxic to human lymphocytes and its cytotoxicity is mediated by apoptosis and necrosis (Al-Hammadi et al., 2014), and it has been shown to suppress the alternative pathway of complement activation (APCA) in ducks (Valtchev et al., 2015).

Lymphocyte percentage, avian influenza antibody titer relative to thymus weight, and immune response to phytohemagglutinin were decreased in broiler chickens exposed to AFB₁ (Rashidi et al., 2020).

Similarly, dietary exposure of broiler chickens to AFB₁ induced immune suppressive effects, including a reduction in the immune response to sheep red blood cells (SRBCs), phagocytic clearance of carbon particles, and PHA-P-mediated cutaneous basophilic hypersensitivity, along with degeneration, necrosis, and depletion of lymphoid tissue (Bhatti et al., 2021).

AFB₁ reduced bactericidal activity, lysozyme activity, and total serum protein level in yellow catfish (Pelteobagrus fulvidraco) (Wang et al., 2016).

Similarly, lysozyme activities, total immunoglobulin contents, and complement C3 and C4 activities were significantly decreased in the plasma of common carp fed with a diet containing aflatoxins (Bitsayah et al., 2018).

Effects on reproduction

The hepatotoxic and carcinogenic effects of aflatoxins in mammals and aquatic organisms have been intensively reviewed, unlike their effects on reproduction. The mechanism of reproductive toxicity of aflatoxin is not fully understood (Shuaib et al., 2010), but previous studies reported that exposure to aflatoxins induces toxic effects on testis and other reproductive organs with subsequent impairment of spermatogenesis.

It was found that abnormalities in semen parameters (volume, viscosity, pH, fructose, spermatozoa count, morphology, and motility) were evident in infertile men showing highly significant blood and semen aflatoxin levels when compared to their level in fertile men (Uriah et al., 2001).

Varieties of significant changes in reproduction indexes were detected in male Wistar rats injected intramuscularly with 20 μg AFB₁/kg body weight (Supriya et al., 2014).

Furthermore, AFB₁ was proved to cause pathological changes in the epididymis, such as degeneration and necrosis of epithelial cells of sperm tubules with decreased sperm number (Murad et al., 2015).

Fumonisins

Fumonisins are produced mainly by Fusarium verticillioides (also known as Fusarium moniliforme), Fusarium proliferatum, Fusarium nygamai, and other Fusarium species, such as Fusarium anthophilum, Fusarium dlamini, Fusarium napiforme, Fusarium subglutinans, Fusarium polyphialidicum and Fusarium oxysporum (Scott, 2012).

There are 16 known types of Fumonisins, referred to as B₁ (FB₁, FB₂, FB₃ and FB₄), A₁, A₂, A₃, AK₁, C₁, C₃, C₄, P₁, P₂, P₃, PH₁a and PH₁.

They are usually found in corn and corn-based foods (Marasas, 2001).

MECHANISMS OF TOXICITY AND EFFECTS

FB₁ has a neurotoxic effect in equines as it causes leucoencephalomalacia in horses (Vendruscolo et al., 2016), while its target organ in swine is the lungs as it causes porcine pulmonary edema in pigs (Freitas et al., 2012).

It is carcinogenic, hepatotoxic, nephrotoxic (Szabó et al., 2019; Szabó et al., 2018), and embryotoxic (Lumsangkul et al., 2019) in laboratory animals, while in humans, fumonisins are associated with oesophageal cancer (Yu et al., 2021) and neural tube defects (Copp et al., 2013).

Fumonisins exert their toxic effects mainly by inhibiting the ceramide synthase enzyme, which is essential for the synthesis of ceramide from sphinganine and sphingosine (Voss y Riley, 2013).

Ceramides are the basic structural components of all sphingolipids (found in the cellular membranes of animals and plants) (Engelking, 2015).

⇰ As a result, both sphinganine and sphingosine accumulate following enzyme inhibition causing apoptosis of renal tubule cells and hepatocytes (Voss and Riley, 2013).

It has been further suggested that the pathogenesis of pulmonary edema in swine and cardiotoxicity in horses exposed to FB₁ is partly due to inhibition of L-type calcium channels in the heart caused by the accumulated sphingosine and sphinganine, which then leads to left-sided cardiac insufficiency (Voss et al., 2007).

In addition, the carcinogenic effect of fumonisins in humans is related to impaired sphingolipid biosynthesis, which leads to impairment of cellular activity as they are part of cellular membrane composition and essential for cell-cell communication, intracellular and cell-matrix interactions, and growth factors (Edite Bezerra da Rocha et al., 2014).

Trichothecenes

Trichothecenes are toxic secondary metabolites produced in host plants, food, and other organic matrices by several fungal genera, including Fusarium, Microcyclospora, Myrothecium, Peltaster, Spicellum, Stachybotrys, Trichoderma, and Trichothecium. Among them, Fusarium trichothecenes are of most significant concern to food and feed safety (Proctor et al., 2018).

 

 

There are more than 150 toxins belonging to the trichothecenes family, but the most important ones are deoxynivalenol (DON), nivalenol (NIV), toxin T2, toxin HT2 and diacetoxyscirpenol (DAS) (Yang et al., 2015).

⇰ Like most mycotoxins, they are a significant food safety concern because of the harmful effects they induce from acute and chronic exposure to them (Sobrova et al., 2010). DON is the most commonly found trichothecene in cereal grains (Tian et al., 2016).

MECHANISMS OF TOXICITY AND EFFECTS

Trichothecenes are known for their capacity to inhibit eukaryotic protein synthesis by binding to the 60S subunit of the eukaryotic ribosomes and inhibiting peptidyl transferase activity, which eventually leads to inhibition of the initiation, elongation, or termination of the chain elongation step in protein synthesis (Arunachalam and Doohan, 2013).

These toxins can also inhibit DNA and RNA synthesis (Minervini et al., 2004), alter cellular membrane structure (Diesing et al., 2011), mitochondrial function, and arrest the cell cycle (Pestka, 2010a).

They can also induce oxidative stress via increasing lipid peroxidation and alteration of antioxidant defenses, which eventually impair protein synthesis and cause DNA damage (Doi and Uetsuka, 2011; Wu et al., 2014).

T-2 toxin significantly increased ROS levels, decreased GSH, and elevated lipid peroxidation leading to single-strand breaks in DNA In human cervical cancer cells (Chaudhari et al., 2009).

Elevated concentrations of DON increased ROS levels leading to cell death in a human cell line (Costa et al., 2009).

Dietary exposure of rainbow trout (Oncorhynchus mykiss) to 0.01 mg/ kg b.w. and 0.018 mg/kg b.w T-2 toxin increased lipid peroxidation and the activities of glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and decreased in catalase (CAT) activity (Modra et al., 2018).

In the same fish species, significant alterations in activities of GPx in the kidney, GR in the gill and kidney, CAT in the kidney and liver, and GST in the gill and liver followed dietary exposure to DON (Šišperová et al., 2015).

Trichothecenes are well known for inducing apoptosis and programmed cell death (PCD) via ROS- mitochondrial-mediated pathway (Zhuang et al., 2013).

T-2 toxin treatment of ovarian granulose cells of rats caused typical apoptotic morphological changes, such as nuclear fragmentation and reduction in mitochondrial membrane potential, due to the up-regulation of pro-apoptotic proteins p53 and Bax, higher Bax/ Bcl-2 ratio, and the activation of caspase 3 pathway (Wu et al., 2011).

It also induced increased ROS production and cell apoptosis, mainly in the tail areas of zebrafish embryos revealed by Acridine Orange staining (Yuan et al., 2014).

In human chondrocytes, T-2 toxin-induced apoptosis was associated with increased Fas, p53, pro-apoptotic factor Bax, and caspase 3, and downregulation of anti-apoptotic factor Bcl-xl expression (Chen et al., 2008).

Zearalanone

Zearalenone (ZEN), also referred to as the F-2 or RAL mycotoxin, is a non-steroidal estrogenic secondary metabolite biosynthesized mainly by Fusarium graminearum and to a lesser extent by Fusarium culmorum, Fusarium cerealis, or Fusarium equiseti (De Boevre et al., 2012; Taheur et al., 2017).

It has genotoxic (Braicu et al., 2016; Taranu et al., 2015), immunotoxic (Assumaidaee et al., 2020; Hueza et al., 2014), teratogenic, carcinogenic (Abassi et al., 2016), hematotoxic and hepatotoxic properties (Bai et al., 2018) but its toxicity to human and animal arises mainly from its xenosteroidal activities.

 

Its chemical structure is similar to naturally occurring estrogen and it exerts its action by acting as an endocrine-disrupting compound (EDCs) (Rogowska et al., 2019), potentially changing the functions of the endocrine system in living creatures and causing adverse health effects. In fact, they are known to prompt alterations in hormonally monitored physiological functions (homeostasis, growth, development, and reproduction) (Kar et al., 2021).

MECHANISMS OF TOXICITY AND EFFECTS

Zearalenone exerts its action by imitating naturally occurring estrogens (leading to a similar outcome as natural estrogens) or competing with their receptors (leading to an antiestrogenic reaction).

⇰ Either way, reproductive impairment is the final outcome (Rogowska et al., 2019).

Dietary exposure of piglets to 1mg/kg ZEN induced reproductive impairment represented by an increase in the length, width, and area of the vulva, the genital organ coefficient, and a significant decrease in E2, LH, and FSH (Su et al., 2018).

Similarly, low doses of ZEN affected mice’s male reproductive capacity with a significant decrease in spermatogenic cells, sperm concentration, viability, motility, and hyperactive rate and a significant increase in the DNA double-strand break in spermatogenic cells, in addition to a significant increase in deformity and mortality rate of sperm (Pang et al., 2017).

In fish, several studies reported the effect of zearalenone on reproductive performance, including impaired reproduction of rainbow trout and induced high sperm concentration and high plasma vitellogenin levels in males, and induced early ovarian development in females (Woźny et al., 2020).

In the same line, zearalenone induced vtg-1 mRNA expression in zebrafish (Danio rerio) in a concentration-dependent manner following 120 h exposure (Bakos et al., 2013).

The mechanism of zearalenone-associated immunotoxicity arises because it is a xenoestrogen and EDC.

⇰ Estrogens not only function as reproductive hormones. They also have non-reproductive functions, also affecting immune functions. In this respect, estrogens act on immune cells via estrogen receptors (ERs) which enable them to act either in an immunomodulatory (Islam et al., 2017) or immunosuppressive way (Abbès et al., 2013; Zahran et al., 2021).

Ochratoxins

Ochratoxins are dihydroisocoumarin bonded to phenylalanine pentaketide metabolites. They are classified as ochratoxin A (OTA), produced by Aspergillus ochraceus, and ochratoxin A, B, and C, produced by other Aspergillus and Penicillium species (Marroquín-Cardona et al., 2014).

Ochratoxins have been found to contaminate various foods like grains, rice, wheat, dried fruit, coffee, cocoa, wine, beer, and foods of animal origin, particularly pork (Kumar et al., 2020).

 

MECHANISMS OF TOXICITY AND EFFECTS

OTA induces toxicity by binding to proteins, particularly serum albumins, with subsequent bioaccumulation in its target organs (Duarte et al., 2012).

It is also an inhibitor of the nuclear factor erythroid 2–related factor 2 (Nrf2), thus inducing physiological oxidative stress, further damaging the DNA (Limonciel and Jennings, 2014).

OTA is mainly nephrotoxic:

• ⇰ In humans, it is responsible for human Balkan endemic nephropathy (BEN) (Stiborová et al., 2016), chronic interstitial nephropathy (CIN) (Hassen et al., 2004), renal failure, and tumors (Chen y Wu, 2017; Hope y Hope, 2012).
• ⇰ In pigs, it causes endemic porcine nephropathy (Jørgensen y Petersen, 2002).

It is also carcinogenic, classified as a Group 2B possible human carcinogen (Marroquín-Cardona et al., 2014).

Ruminants and rodents are, to some extent, resistant to OTA because their microbiota can produce carboxypeptidase enzymes.

⇰ The enzyme can cleave the peptide bond and form less toxic OTα (Abrunhosa et al., 2006).

Despite that fact, OTA is hepatotoxic, teratogenic, immunotoxic, and carcinogenic in experimental models.

It induced hepatotoxicity in rats marked by a significant decrease in SOD, CAT, and GPx activities, a significant increase in MDA level, and histopathological lesions in the liver, including inflammation, steatosis, necrosis, and fibrosis (Damiano et al., 2021).

In another study, OTA exposure was associated with a significant increase in pro-inflammatory and DNA oxidative-damage biomarkers and a significant increase in nitric oxide (NO) levels in kidneys and liver (Longobardi et al., 2021).

The carcinogenic effect of OTA was reported in rats represented by increased mRNA levels of clusterin in kidneys, increased proliferation of cell nuclear antigen (PCNA) in liver and kidney, down-regulation of reactive oxygen species (ROS) and p53 gene, and up-regulation of vimentin and lipocalin in the kidney (Qi et al., 2014).

Furthermore, Liver and kidney impairment was evident in Nile tilapia exposed to OTA (Mansour et al., 2015), while it induced hepatic failure and antioxidative suppression in Thinlip Mullet (Liza ramada) (Magouz et al., 2022).

Decontamination of mycotoxins in experimental models

Mycotoxins in feed necessitated the development of novel technologies that would be useful, environmentally friendly, and cost-effective in their removal.

Examples of some compounds used to ameliorate mycotoxin toxicity are described as follows.

• Sodium selenite exhibits protective effects on AFB₁-induced toxicity by inhibiting oxidative stress and excessive apoptosis in broilers’ spleen (Wang et al., 2013), decreasing DNA damage and histological alterations in ducklings’ liver (Shi et al., 2015), and ameliorating reproductive toxicity in mice (Cao et al., 2017).
• Silymarin administration alleviates elevated Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression levels and diminishes liver damage induced by FB₁ in mice (Sozmen et al., 2014).
• Lactobacillus paracasei alleviates genotoxicity, oxidative stress status, and histopathological damage induced by FB₁ in mice (Ezdini et al., 2020), while Lb. delbrueckii subsp. lactis (LL) and P. acidilactici (PA) strains induced a protective effect against antigenotoxicity and precancerous lesions caused by FB₁ in Sprague-Dawley Rats (Khalil et al., 2015).
• Dietary supplementation of rutin in Nile tilapia improves growth, elevated liver antioxidant capacity, and reduced liver and myofiber damage induced by T-2-toxin (Deng et al., 2019).
• Oxidative damage and hepatopancreas immune responses induced by T-2 toxin in Chinese mitten crab (Eriocheir sinensis) are reduced following dietary supplementation with arginine (Zhang et al., 2020).
• Vitamina C supplementation diminishes reproductive, immune, and hematological toxicity in piglets exposed to ZEN (Su et al., 2018).

• Resveratrol (RSV) is able to decrease or reverse ZEN-induced toxicity in adult male Wistar rats, enhancing antioxidant enzyme activity and improving immune parameters in exposed rats (Virk et al., 2020).
• Curcumin modulates nitrosative stress, inflammation and DNA damage, hepatotoxicity, and nephrotoxicity induced by Ochratoxin A in Rats (Longobardi et al., 2021).
• Green tea-mediated zinc nanoparticles ameliorate the hepatotoxicity and nephrotoxicity induced by OTA in albino rats (Mansour et al., 2015).
• Selenium-enriched probiotics (SP) enhance kidney functions, growth performance, and antioxidant parameters in piglets intoxicated with OTA (Gan et al., 2021).
• Whey supplementation ameliorates ochratoxicosis in Nile tilapia (Mansour et al., 2015) and dietary Bacillus subtilis protects against hepatic failure, and antioxidative suppression induced by ochratoxin A in Thinlip Mullet (Liza ramada) (Magouz et al., 2022).
• The protective role of Minazel^® Plus on fish health is evidenced in growth performance, hematological parameters, innate immune and antioxidant responses, bioaccumulation of mycotoxins in liver and musculature, and histopathological assessment of liver and kidney tissues (Zahran et al., 2020).

CONCLUSIONS

Toxigenic secondary fungal metabolites, known as mycotoxins, are regarded as a threat to human health and food safety.

Due to their presence in a wide range of agricultural and food products, they continue to pose a serious threat to the health of animals and humans alike.

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