ChapterPDF Available

Mycotoxins-Induced Oxidative Stress and Disease


Abstract and Figures

Mycotoxins are produced in a strain-specific way, and elicit some complicated and overlapping toxigenic activities in sensitive species that include carcinogenicity, inhibition of protein synthesis, immunosuppression, dermal irritation, and other metabolic perturbations. Mycotoxins usually enter the body via ingestion of contaminated foods, but inhalation of toxigenic spores and direct dermal contact are also important routes. There is sufficient evidence from animal models and human epidemiological data to conclude that mycotoxins pose an important danger to human and animal health. Trichothecenes cause protein synthesis inhibition via binding to the 18s rRNA of the ribosomal large subunit as a major mechanism underlying induction of cell apoptosis. T-2 toxin triggers a ribotoxic response through its high binding affinity to peptidyl transferase which is an integral part of the 60 s ribosomal subunit and interferes with the metabolism of membrane phospholipids and increases liver lipid peroxides. SH is thought to induce caspase-3 activation and apoptosis through the activation of MAPK and JNK in a GSH-sensitive manner. FB1-induced inhibition of ceramide synthesis can result in a wide spectrum of changes in lipid metabolism and associated lipid-dependent pathways. OTA has complex mechanisms of action that include mitochondrial impairment, formation of OTA-DNA adducts and induction of oxidative stress and apoptosis through caspase activation. Accordingly, the strict control of food quality, in both industrialized and developing countries, is therefore necessary to avoid mycotoxicosis
Content may be subject to copyright.
Chapter 3
© 2013 Omar, licensee InTech. This is an open access chapter distributed under the terms of the Creative
Commons Attribution License (, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Mycotoxins-Induced Oxidative
Stress and Disease
Hossam El-Din M. Omar
Additional information is available at the end of the chapter
1. Introduction
Mycotoxins are pharmacologically active mold metabolites produced in a strain-specific
way that elicit some complicated toxicological activities [1]. More than 300 secondary
metabolites have been identified while only around 30 have true toxic properties [2]. The
chemical structures of mycotoxins vary significantly, but they are low molecular mass
organic compounds [3]. Mycotoxins are small and quite stable molecules which are
extremely difficult to remove and enter the food and feed chain while keeping their toxic
properties [4]. So, the occurrence of mycotoxins is regulated by legal limits in all developed
countries [5]. Mycotoxin contamination of the feed and food is a global problem because
more than 25% of world grain production is contaminated by mycotoxins [6]. The synthesis
of mycotoxins by moulds is genetically determined and closely related to primary metabolic
pathways, such as amino acid and fatty acid metabolism. However, the actual toxin
production is modulated by environmental factors such as substrate composition and
quality, humidity and temperature. The occurrence of mycotoxins in animal feed exhibits a
geographic pattern, for example Aspergillus species meet optimal conditions only in tropical
and subtropical regions, whereas Fusarium and Penicillium species are adapted to the
moderate climate. Worldwide trade with food and feed commodities results in a wide
distribution of contaminated material [7].
Plant selections for mycotoxin resistance have not created any significant results in
protection against grain mycotoxins. The major problem comes from the fact that there are
no safe levels of mycotoxins, because of synergistic interactions of many mycotoxins [2].
There is sufficient evidence from animal models and human epidemiological data to
conclude that mycotoxins cause an important hazard to human and animal health [1]. The
toxic effect of mycotoxins on animal and human health depends on the type of mycotoxin;
level and duration of the exposure; age, health, and sex of the exposed individual, genetics,
Mycotoxin and Food Safety in Developing Countries
dietary status, and interactions with other toxic insults. Thus, the severity of mycotoxin
toxicity can be complicated by factors such as vitamin deficiency, caloric deprivation,
alcohol abuse, and infectious disease [1,3,8].
Mycotoxins according to their chemical structure exert a broad variety of biological effects.
The nature and intensity of these effects depend on the actual concentration of an individual
mycotoxin and the time of exposure [7]. Cell proliferation of all mycotoxin treated blood
mononuclear cells was significantly decreased at the highest concentrations of mycotoxins,
but this decrease was significantly stronger for different mixtures of mycotoxins [9]. In
addition, feed commodities are often contaminated with more than one mycotoxin, as
mould species produce different mycotoxins at the same time. These co-occurring
mycotoxins can exert additive effects, as for example various trichothecenes, but may also
act antagonistically, as for example, observed with feeds containing trichothecenes and
zearalenone, and commodities, containing aflatoxins and cyclopiazonic acid [7].
Mycotoxicoses are more common in underdeveloped countries and often remain
unrecognized by medical professionals, except when huge numbers of people are involved
[3]. In general, mycotoxin exposure is more likely to occur in parts of the world where poor
methods of food handling and storage are common, where malnutrition is a problem, and
where few regulations exist to protect exposed populations. The incidence of liver cancer
varies widely from country to country, but it is one of the most common cancers in China,
Philippines, Thailand, and many African countries. Worldwide, liver cancer incidence rates
are 2 to 10 times higher in developing countries than in developed countries [10]. The
occurrence of fumonisin B1 was correlated with the occurrence of a higher incidence of
esophageal cancer in regions of Transkei (South Africa), China, and Northeast Italy [3]. In
Africa and Asia where the occurrence of mycotoxins is common and a high percentage of
the population is infected with hepatitis B or C mycotoxin reduction is obligatory [8]. One of
the strategies for reducing the exposure to mycotoxins is to decrease their bioavailability by
including various mycotoxins-adsorbing agents in the compound feed, which lead to
reduction of mycotoxins uptake as well as distribution to the blood and target organs.
Another strategy is the degradation of mycotoxins into non-toxic metabolites by using
biotransforming agents such as bacteria/fungi or enzymes [4].
Diagnosis of animal mycotoxicosis is based on experimental studies with specific toxins and
specific animals, very often under well-defined toxicological laboratory conditions, so that
the results of such studies can be far from real-life or natural situations. Furthermore, factors
such as breeding, sex, environment, nutritional status, as well as other toxic entities can
affect the symptoms of intoxication and may contribute to the significance of mycotoxin
damage on economic output and animal health [11]. The economic costs of mycotoxins are
impossible to determine accurately [12], but the US Food and Drug Administration (FDA)
estimated that in the US the mean economic annual cost of crop losses from the mycotoxins
aflatoxins, fumonisins, and deoxynivalenol are $932million USD [13]. While mycotoxin
associated losses in industrial countries are typically market losses as a result of rejected
crops, developing countries suffer additionally from health impacts [14]. Diagnosis is very
Mycotoxins-Induced Oxidative Stress and Disease
much dependent on receiving a sample of feed that was ingested prior to intoxication, but
also on data from another representative group of animals of the facility and the results of a
post-mortem examination [11, 13].
In the following table, the mycotoxins of major concern as feed contaminants are aflatoxins,
ochratoxin A, Fusarium toxins (trichothecenes like, deoxynivalenol, diacetoxyscipenol,
nivalenol, T2-toxin/HT2-toxin, zearalenone and fumonisins) [4]. Moreover, the most
predominant mycotoxigenic species in wheat grain were A. flavus with the ability to produce
mycotoxins (aflatoxins B1, B2, G1 and G2 and sterigmatocystin) [15].
Fungal species Mycotoxin
Aspergillus flavus; A. parasiticus Aflatoxins
A. flavus Cyclopiazonic acid
A. ochraceus; Penicillium viridicatum; P. cyclopium; Ochatoxin A
P. expansum Patulin
Fusarium culmorum; F. graminearum; F. sporotrichioides Deoxynivalenol
F. sporotrichioides; F. poae T-2 toxin
F. sporotrichioides; F. graminearum; F. poae Diacetoxyscirpenol
F. culmorum; F. graminearum; F. sporotrichioides Zearalenone
F. moniliforme Fumonisins
Acremonium coenophialum Ergopeptine alkaloids
Table 1. The major toxigenic species of fungi and their mycotoxins [16]
2. Route of mycotoxins exposure
The most common route of exposure to mycotoxins is ingestion, but it may also involve
dermal, respiratory, and parenteral routes, the last being associated with drug abuse [17]. In
general, animals are directly exposed to mycotoxins through the consumption of mouldy
feedstuffs, eating contaminated foods, skin contact with mould infected substrates and
inhalation of spore-borne toxins [1]. Human exposure can be via one of two routes; direct
exposure due to the consumption of mouldy plant products, or indirect exposure through
the consumption of contaminated animal products containing residual amounts of the
mycotoxin ingested by the food producing animals [18]. Human exposure to mycotoxins is
further determined by environmental or biological monitoring. In environmental
monitoring, mycotoxins are measured in food, air, or other samples; in biological
monitoring, the presence of residues, adducts, and metabolites is assayed directly in tissues,
fluids, and excretory products [19]. The risk of systemic toxicity resulting from dermal
exposure increases in the presence of high toxin concentrations, occlusion, and vehicles
which enhance penetration [20]. The main human and veterinary health load of mycotoxin
exposure is related to chronic exposure [2].
Mycotoxin and Food Safety in Developing Countries
3. Mycotoxins metabolism and induction of oxidative stress
Biodegradation of mycotoxins with microorganisms or enzymes is considered as the best
strategy for detoxification of feedstuffs. This approach is considered as environmental
friendly approach in contrast to physicochemical techniques of detoxification. Ruminants
are potential source of microbes or enzymes for mycotoxins biodegradation [21]. In
vertebrate, mycotoxin is metabolized by cytochrome P450 enzymes to metabolite-guanine-
N7 adduct (Fig 1). The carcinogenic potency is highly correlated with the extent of total
DNA adducts formed in vivo [22].
Figure 1. Mycotoxin metabolism in vertebrates [23]
Cytotoxicity and ROS generation are mechanisms of mycotoxins mediated toxicity. ROS are
chemically reactive molecules containing oxygen. They are highly reactive due to the
presence of unpaired electrons. ROS formed as a natural byproduct of the normal
metabolism of oxygen have important roles in cell signaling and homeostasis. However,
during times of environmental stress, ROS levels can increase dramatically as a result of
oxidative stress [24]. Oxidative stress occurs when the concentration of ROS generated
exceeds the antioxidant capability of the cell. In other words, oxidative stress describes
various deleterious processes resulting from an imbalance between the excessive formation
of ROS and limited antioxidant defenses [25]. Under normal conditions, ROS are cleared
from the cell by the action of superoxide dismutase (SOD), catalase (CAT), or glutathione
peroxidase (GPx). The main damage to cells results from the ROS-induced alteration of
macromolecules such as polyunsaturated fatty acids in membrane lipids, proteins, and
DNA. Additionally, oxidative stress and ROS can originate from xenobiotic bioactivation by
prostaglandin H synthase (PHS) and lipoxygenases (LPOs) or microsomal P450s which can
Mycotoxins-Induced Oxidative Stress and Disease
oxidize xenobiotics to free radical intermediates that react directly or indirectly with oxygen
to produce ROS and oxidative stress [26] as in Fig (2). Moreover, the cell can tolerate a small
to moderate amount of oxidative stress by producing antioxidant molecules e.g vitamin A,
C &E and GSH and activates enzymes e.g. CAT, SOD, GPx, glutathione reductase (GR) and
glutathione S transferase (GST) to counteract the excess oxidants [27]. LPO may bring about
protein damage and inactivation of membrane-bound enzyme either through direct attack
by free radicals or through chemical modification by its end products [28]. Reduction of
cellular viability by mycotoxins was correlated with increases of ROS generation and MDA
formation in concentration and time dependent manner [29]. The importance of oxidative
stress and LPO in mycotoxins toxicity was confirmed by the protective effects of natural
antioxidants [2]. Sporidesmin, the mycotoxin responsible for ‘facial eczema’ in ruminants,
contains a disulphide group which appears to be intimately involved in its toxic action. The
dithiol form of sporidesmin has been shown readily to undergo autoxidation in vitro in a
reaction which generates superoxide radical (O
) [30]. GST found in the cytosol and
microsomes catalyzes the conjugation of activated aflatoxins with GSH, leading to the
excretion of aflatoxin [31]. Variations in the level of the GST as well as variations in the
cytochrome P450 system are thought to contribute to the differences observed in
interspecies aflatoxin susceptibility [22, 32].
Figure 2. General pathways of ROS production and clearance [26]
Mycotoxin and Food Safety in Developing Countries
4. Mycotoxin toxicity
The amount of mycotoxins needed to produce adverse health effects varies widely among
toxins, as well as for each animal or person’s immune system. Two concepts are needed to
understand the negative effects of mycotoxins on human health: Acute toxicity, the rapid
onset of an adverse effect from a single exposure. Chronic toxicity, the slow or delayed onset
of an adverse effect, usually from multiple, long-term exposures. Mycotoxins can be acutely
or chronically toxic, or both, depending on the kind of toxin and the dose. Membrane-active
properties of various mycotoxins determine their toxicity. Incorporation of mycotoxins into
membrane structures lead to alterations in membrane functions. In general, mycotoxins
effects on DNA, RNA, protein synthesis and the pro-apoptotic action (Fig. 3) causing
changes in physiological functions including growth, development and reproduction [2].
Clinicians often arrange mycotoxins by the organ they affect. Thus, mycotoxins can be
classified as hepatotoxins, nephrotoxins, neurotoxins, immunotoxins, and so forth. Cell
biologists put them into generic groups such as teratogens, mutagens, carcinogens, and
allergens [1].
Figure 3. Mycotoxins affecting major sites in RNA and protein synthesis [33]
Mycotoxins-Induced Oxidative Stress and Disease
Aflatoxins occur in nuts, cereals and rice under conditions of high humidity and
temperature. The two major Aspergillus species that produce aflatoxins are A. flavus, which
produces only B aflatoxins, and A. parasiticus, which produces both B and G aflatoxins.
Aflatoxins M1 and M2 are oxidative metabolic products of aflatoxins B1 and B2 produced by
animals following ingestion, and so appear in milk, urine and faeces. Aflatoxicol is a
reductive metabolite of aflatoxin B1. Aflatoxins are acutely toxic, immunosuppressive,
mutagenic, teratogenic and carcinogenic compounds (classified as group 1 carcinogens
according to the International Agency for Research on Cancer (IARC) [34]. Aflatoxins have
been detected in the blood of pregnant women, in neonatal umbilical cord blood, and in
breast milk in African countries, with significant seasonal variations [35]. The geographical
and seasonal occurrence of aflatoxins in food and of kwashiorkor shows a remarkable
similarity [36]. It has been hypothesized that kwashiorkor, a severe malnutrition disease,
may be a form of pediatric aflatoxicosis [37]. Aflatoxins exposure accounts for about 40% of
the load of disease in developing countries where a short lifespan is prevalent. Food systems
and economics in developed country make the advance in aflatoxins management
impossible [38]. The prevention of mycotoxins toxicity involves reduction of mycotoxin
levels in foodstuffs and increasing the intake of diet components such as vitamins,
antioxidants and substances known to prevent carcinogenesis [39]. The prevention of
mycotoxin contamination of human foods could have a significant effect on public health in
low-income countries due to enhanced food safety [40]. Chemoprotection against aflatoxins
has been confirmed with the use of a number of compounds that either increase an animal’s
detoxification processes [41] or prevent the production of the epoxide that leads to
cytotoxicity [42]. For the animal feed industries, a major focus has been on developing food
additives that provide protection from the mycotoxins. One approach has been the use of
esterified glucomanoses and other yeast extracts that provide chemoprotection by increasing
the detoxification of aflatoxin [41].
Figure 4. Metabolism of aflatoxin in liver [46]
Mycotoxin and Food Safety in Developing Countries
After the absorption, highest concentration of the toxin is found in the liver [43]. Once in
liver, aflatoxin B1 is metabolized by microsomal enzymes cytochrome P-450 3A4 to different
metabolites through hydroxylation, hydration, demethylation and epoxidation. Variations
in its catalytic activity of P-450 3A4 are important in issues of bioavailability and drug-drug
interactions [44]. As in Fig (4) the hydroxylation of AFB1 at C4 or C22 produces, AFM1 and
AFQ1, respectively. Hydration of the C2 – C3 double bond results in the formation of AFB2a
which is rapidly formed in certain avian species [45]. AFP1 results from o-demethylation
while the AFB1 – epoxide is formed by epoxidation at the 2,3 double bond Aflatoxicol is the
only metabolite of AFB1 produced by a soluble cytoplasmic reductase enzyme system [46] .
The putative AFB1 epoxide is generally accepted as the active electrophilic form of AFB1
that may attack nucleophilic nitrogen, oxygen and sulphur heteroatoms in cellular
constituents [47]. This highly reactive substance may combine with DNA bases such as
guanine to produce alterations in DNA [36]. However, both humans and animals possess
enzymes system, which are capable of reducing the damage to DNA and other cellular
constituents caused by the 8,9-epoxide. For example GST mediates the conjugation reaction
of the 8,9-epoxide to the endogenous compound GSH, this essentially neutralizes its toxic
potential (Fig. 5). Animal species such as the mouse that are resistant to aflatoxin
carcinogenesis have 3-5 times more GST activity than susceptible species such as the rat.
Humans have less GST activity or 8,9-epoxide conjugation than rats or mice suggesting that
humans are less capable of detoxifying this important metabolite [48].
Figure 5. Biomarkers of aflatoxin exposure in an internal dose and a biologically effective dose.
Biomarkers of exposure include aflatoxin M1, the internal dose includes the aflatoxin-mercapturic acid
and aflatoxinalbumin adduct, and the biologically effective dose is reflected by the excretion of the
aflatoxin-N7-guanine adduct formed by depurination leading to an apurinic (AP) site in DNA [49].
Mycotoxins-Induced Oxidative Stress and Disease
The diseases caused by aflatoxin consumption are called aflatoxicosis. Acute aflatoxicosis
results in death, however, chronic aflatoxicosis results in immune suppression and cancer
[19]. Suppression of the cell-mediated immune response was mediated by altered cytokine
expression [50]. Aflatoxins caused hepatotoxicity, nephrotoxicity and genotoxicity in
somatic and germ cells, resulted in mitotic and meiotic delay in mice [51]. An increase in
AFB1-8, 9-epoxide cause a significant increases in hepatic LPO level [52]. Peroxidation of
membrane lipids initiated loss of membrane integrity; membrane bound enzyme activity
and cell lysis [53]. LPO was significantly increased in the liver, kidney [54] and testis [55] of
aflatoxin-treated mice as compared to controls. However, GSH levels declined significantly
in the liver, kidney and testis after 45 days of aflatoxin treatment [56]. Moreover, AFB1
intake and expression of enzymes involved in AFB1 activation/detoxification may play an
important role in hepatitis B virus-related hepatocarcinogenesis [57]. The results of a clinical
trial suggest that chlorophyllin may have a role in preventing dietary exposure to aflatoxin
B1 by reducing its oral bioavailability [58].
Srategies for reducing exposure and risk from aflatoxin in developing countries should be
carefully tested and validated using clinical trial designs with biomarkers serving as
objective endpoints. Clinical trials and other interventions are designed to translate findings
from human and experimental investigations to public health prevention. Both primary (to
reduce exposure) and secondary (to alter metabolism and deposition) interventions can use
specific biomarkers as endpoints of efficacy. In a primary prevention trial, the goal is to
reduce exposure to aflatoxins in the diet. A range of interventions includes planting pest-
resistant varieties of staple crops, attempting to lower mould growth in harvested crops,
improving storage methods following harvest, and using trapping agents that block the
uptake of unavoidably ingested aflatoxins. In secondary prevention trials, one goal is to
modulate the metabolism of ingested aflatoxin to enhance detoxification processes, thereby
reducing internal dose and subsequent risk [49] (Fig. 6).
Ochratoxin A (OTA)
Ochratoxins are the first major group of mycotoxins identified after the discovery of the
aflatoxins [59]. OTA is found in a variety of plant food products such as cereals. Because of
its long half life, it accumulates in the food chain [60]. OTA is absorbed passively
throughout the gastrointestinal tract and actively in the kidneys. Highest amounts of OTA
could be found in the blood and it is distributed in kidney, liver, muscle and adipose tissue
in a decreasing order. The toxin is excreted primarily in the urine, and to a lesser degree in
bile and also in milk. The half-life of experimentally orally ingested OTA is shorter than
intravenously injected OTA [61]. According to IRAC [34] OTA is classified as group 1
carcinogens. Structure-activity studies suggested that the toxicity of OTA may be attributed
to its isocoumarin moiety and lactone carbonyl group. OTA reduces the expression of
several genes regulated by nuclear factor-erythroid 2 p45-related factor (Nrf2) and reduces
the expression of antioxidant enzymes through inhibition of Nrf2 [62, 63]. OTA toxicity may
be involved in the development of certain kidney diseases through generation of oxidative
stress [64]. Chronic administration of low dose of OTA caused morphological and functional
Mycotoxin and Food Safety in Developing Countries
changes in proximal tubules and administration of date extract protects against OTA-
induced tubule’s tissue damage [65]. However, antioxidant treatment failed to prevent the
development of OTA-induced tumors in animal models [66]. Indomethacin and aspirin
were found to prevent OTA genotoxicity in the urinary bladder and kidney of mice [67].
OTA causes acute depletion of striatal dopamine and its metabolites, accompanying
evidence of neural cell apoptosis in the substantia nigra, stratum and hippocampus [68].
Figure 6. Strategies for reducing exposure and risk from aflatoxin in developing countries [49]
OTA has complex mechanisms of action that include oxidative stress, bio-energetic
compromise, mitochondrial impairment, inhibition of protein synthesis, production of DNA
single strand breaks and formation of OTA-DNA adducts [69-71]. OTA induced renal
toxicity and carcinogenicity may be mediated by an Nrf2-dependent signal transduction
pathway [63]. It is a mitochondrial poison causing mitochondrial damage, oxidative burst,
LPO and interferes with oxidative phosphorylation [72, 73]. OTA was found to chelate ferric
ions (Fe
), facilitating their reduction to ferrous ions (Fe
), which in the presence of oxygen,
provided the active species initiating LPO [74]. OTA hydroquinone/ quinone couple was
generated from the oxidation of OTA by electrochemical, photochemical and chemical
processes resulting in redox cycling and in the generation of ROS [75]. OTA impairs the
antioxidant defense of the cells making them more susceptible to oxidative damage [62] and
a reduction in cellular antioxidant defense may contribute to the production of OTA-
dependent oxidative damage [76].
Studies carried out in several countries including Tunisia, Egypt and France, have indicated
a link between dietary intake of OTA and the development of renal and urothelial tumours
[77- 81]. OTA is known to affect the immune system in a number of mammalian species. The
type of immune suppression experienced appears to be dependant on a number of factors,
Mycotoxins-Induced Oxidative Stress and Disease
including the species involved, the route of administration, the doses tested, and the
methods used to detect the effects [82]. OTA causes immunosuppression following prenatal,
postnatal and adult-life exposures. These effects include reduced phagocytosis and
lymphocyte markers [83] and increased susceptibility to bacterial infections and delayed
response to immunization in piglets [9]. OTA induces apoptosis in a variety of cell types in
vivo and in vitro that mediated through cellular processes involved in the degradation of
DNA [84]. Moreover, the immunosuppressant activity of OTA is characterized by size
reduction of vital immune organs, such as thymus, spleen, and lymph nodes, depression of
antibody responses, alterations in the number and functions of immune cells, and
modulation of cytokine production (TNF-α and Il-6). The immunotoxic activity of OTA
probably results from degenerative changes and cell death following necrosis and apoptosis,
in combination with slow replacement of affected immune cells, due to inhibition of protein
synthesis [85]. Finally, it is proposed that a network of interacting epigenetic mechanisms,
including protein synthesis inhibition, oxidative stress and the activation of specific cell
signalling pathways is responsible for OTA carcinogenicity [86] (Fig.7)
Figure 7. Scheme to illustrate the oxidative stress-mediated mode of action proposed for OTA.
Increased production of ROS, RNS, and RCS is likely to originate either from direct redox reactions
involving OTA or through the inhibition of cellular defenses such as through the inhibition of
transcription factors as Nrf2 which regulates enzymes with antioxidant properties. The generation of
radicals will induce macromolecular oxidative damage such as oxidized DNA bases which may be
converted into mutation resulting into generation of transformed cells [66].
Trichothecenes (TCs) are mycotoxins produced mostly by members of the Fusarium genus
and other genera (e.g. Trichoderma, Trichothecium, Myrothecium and Stachybotrys). By now,
Mycotoxin and Food Safety in Developing Countries
more than 180 different trichothecenes and trichothecene derivatives have been isolated and
characterized [87, 88]. TCs were found in air samples collected during the drying and
milling process on farms, in the ventilation systems of private houses and office buildings
and on the walls of houses with high humidity [89-90]. They can be divided into four
categories according to both their chemical properties and their producer fungi;
1. Type A: functional group other than a ketone at C8 position (e.g.; T-2, HT-2, DAS);
2. Type B: carbonyl functions at C8 position (e.g.; DON, NIV, FUS-X, 3-acetyl-
deoxynivalenol, 15-acetyl-deoxynivalenol);
3. Type C: second epoxide group at C7, 8 or C9, 10; (e.g.; crotocin and baccharin);
4. Type D: macrocyclic ring system between C4 and C15 with two ester linkages (e.g.;
satratoxin G, H, roridin A and verrucarin A) [87, 91, 92].
TCs exposure leads to apoptosis both in vitro and in vivo in several organs such as lymphoid
organs, hematopoietic tissues, liver, intestinal crypts, bone marrow and thymus [91, 93].
Acute high dose toxicity of TCs is characterized by diarrhea, vomiting, leukocytosis,
haemorrhage, and circulatory shock and death, whereas chronic low dose toxicity is
characterized by anorexia, reduced weight gain, neuroendocrine and immunologic changes
[91, 94]. The myelotoxicity was considered highest for T-2 and HT-2 toxins and lowest for
DON and NIV [94]. TCs are toxic to many animal species, but the sensitivity varies
considerably between species and also between the different TCs [93]. Cellular effects on
DNA and membrane integrity have been considered as secondary effects of the inhibited
protein synthesis. The toxin binds to the peptidyl transferase, which is an integral part of the
60S ribosomal subunit of mammalian ribosome. TCs interfere with the metabolism of
membrane phospholipids and increase liver LPO in vivo. Also, some TCs are shown to
change the serotonin activity in the central nervous system, which is known to be related in
the regulation of food intake [88].
T-2 Toxin
T-2 toxin is a cytotoxic secondary fungal metabolite that belongs to TCs family produced by
various species of Fusarium (F. sporotichioides, F. poae, F. equiseti, and F. acuminatum), which
can infect corn, wheat, barley and rice crops in the field or during storage [95]. T-2 toxin is a
well known inhibitor of protein synthesis through its high binding affinity to peptidyl
transferase resulting in trigger of ribotoxic stress response that activate mitogen-activated
protein kinases [96]. Moreover, T-2 toxin interferes with the metabolism of membrane
phospholipids and increases liver LPO [97]. Also, T-2 toxin suppresses drug metabolizing
enzymes such as GST [98]. T-2 toxin treated mice showed a time-dependent increase in ROS
generation, depletion of GSH, increases in LPO and protein carbonyl content in the brain.
Moreover, the gene expression profile of antioxidant enzymes showed a significant increase
in SOD and CAT via the dermal route and GR and GPx via the subcutaneous route [99].
General signs of T-2 include nausea, emesis, dizziness, chills, abdominal pain, diarrhea,
dermal necrosis, abortion, irreversible damage to the bone marrow, reduction in white
blood cells and inhibition of protein synthesis [100, 101]. Moreover, the effects of T-2 toxins
on the immune system include changes in leukocyte counts, delayed hypersensitivity,
Mycotoxins-Induced Oxidative Stress and Disease
depletion of selective blood cell progenitors, depressed antibody formation and allograft
rejection [39]. Also, T-2 toxin has a direct lytic effect on erythrocytes [102]. T-2 toxin can
induce apoptosis in many types of cells bearing rapid rates of proliferation [103] and
increased the expression of both oxidative stress and apoptosis related genes in hepatocytes
of mice [104]. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain [68]. In
this aspect, it suggested that dysfunction of the mitochondria and oxidative stress might be
the main factor behind the T-2 toxin-induced apoptosis in the fetal brain [105]. ROS activate
caspase-2 which play a crucial role in the control of apoptosis [106, 107]. Moreover, it was
demonstrated that T-2 toxin induced cytotoxicity in HeLa cells is mediated by generation of
ROS leading to DNA damage and trans activation of p53 protein expression which leads to
shift in the ratio of Bax/Bcl-2 in favour of apoptosis and subsequent release of Cyt-c from
mitochondria followed by caspase cascade [99].
Fumonisins produced by the fungus Fusarium verticillioides, a widespread fungal
contaminants of various cereals, predominantly corn [2, 108]. Fumonisn B1 (FB1) and B2 are
of toxicological significance, while the others (B3, B4, A1 and A2) occur in very low
concentrations and are less toxic [3]. FB1 is poorly absorbed and rapidly eliminated in feces.
Minor amounts are retained in liver and kidneys. FB1 does not cross the placenta and is not
teratogenic in vivo in rats, mice, or rabbits, but is embryotoxic at high, maternally toxic doses
[109]. FB1 has been linked to a number of diseases in humans and animals [1, 40]. FB1
increases oxidative DNA damage, as measured by increased DNA strand breaks and
malondialdehyde adducts in rat liver and kidney in vivo [111]. As shown in Fig. (9) an
alternative mechanism of action of FB1 involves the disruption of the de novo sphingolipid
biosynthesis pathway by inhibition of the enzyme ceramide synthase [68, 112]. The
inhibition of sphingolipid biosynthesis disrupts numerous cell functions and signaling
pathways, including apoptosis and mitosis, thus potentially contributing to carcinogenesis
through an altered balance of cell death and replication [113]. Disruption of sphingolipid
metabolism leads to changes in the sphinganine to sphingosine ratio [114] as demonstrated
in rat liver and mouse kidney at carcinogenic doses of FB1 [115].
FB1-induced DNA damage and hepatocarcinogenesis in experimental models can be
modulated by a variety of factors including nutrients, chemopreventive agents, and
other factors such as food restriction and viral infection, as well as genetic
polymorphisms [118]. In rat C6 glioma cells, FB1 inhibits protein synthesis, causes DNA
fragmentation and cell death, increases 8-hydroxy-2’-deoxyguanosine, induces LPO, and
cell cycle arrest [119]. Also, the signs of apoptosis were increased caspase-3 like protease
activity and internucleosomal DNA fragmentation [120]. Furthermore, the disruption of
membrane structure, the enhancement of membrane endocytosis, and the increase in
membrane permeability caused by FB1 in macrophages provide additional insight into
potential mechanisms by which the fumonisins might enhance oxidative stress and
cellular damage [121].
Mycotoxin and Food Safety in Developing Countries
Figure 8. Pathway of de novo synthesis (not in boxes) and turnover of sphingolipids (boxed) in animal
cells, and their inhibition by fumonisins. Fumonisns inhibit the synthesis of ceramides by specifically
binding to sphingosine and sphinganine [116, 117]
Zearalenone (ZEA) is produced mainly by Fusarium graminearum and related species,
principally in wheat and maize. ZEA and its derivatives produce estrogenic effects in
various animal species [3]. The structure of the ZEA similar to steroids and binds to ER as an
agonist. There are two major biotrasformation pathways for ZEA in animals (1)
hydroxylation catalyzed by 3α- and 3β- hydroxysteroid dehydrogenase (HSDs) resulting in
the formation of α- and β-ZOL; (2) conjugation of ZEA and its metabolites with glucuronic
acid, catalyzed by uridine diphosphate glucuronyl transferase. Consequently, ZEA is a
substrate for 3α-HSD and 3β-HSD present in many steroidogenic tissues, such as liver,
kidney, testis, prostate, hypothalamus, pituitary, ovary, intestine [122, 123]. The adverse
effects of ZEA are partly determined by the processes of elimination, because the biliary
excretion and entero-hepatic cycling are important processes affecting the fate of ZEA and
explaining a different sensitivity between animals [124]. α and β Zearalenol metabolites
caused cytotoxicity by inhibiting cell viability, protein and DNA syntheses and inducing
oxidative damage and over-expression of stress proteins. However, the ZEA metabolites
exhibited lower toxicity than ZEA, with β zearalenol being the more active of the two
metabolites [125]. In addition, oxidative damage is likely to be evoked as one of the main
pathways of ZEA toxicity which may initiate event at least in part contribute to the
mechanism of ZEA induced genotoxic and cytotoxic effects [126]. ZEA and its derivatives
compete effectively with 17 β-E2 for the specific binding sites of the oestrogen receptors
(ERs) occurring in different organs. Two subtypes of ER exist, ER-α and ERβ that are
differently distributed in the body. Binding of ZEA and its derivatives initiate a sequence of
Mycotoxins-Induced Oxidative Stress and Disease
events known to follow estrogen stimulation of target organs [127, 128]. So, the effect of ZEA
and its metabolites depends upon the reproductive status (prepubertal, cycling or pregnant)
of the affect animals [123]. ZEA do not induce apoptosis in porcine ovaries [129], however,
apoptosis is the principal mechanism contributing to germ cell depletion and testicular
atrophy following ZEA exposure [130]. Moreover, ZEA has potent effects on the expression
of chicken splenic lymphocytes cytokines at the mRNA level [131].
Patulin (PAT) is a toxic chemical contaminant produced by several species of mould,
especially within Aspergillus, Penicillium and Byssochlamys. It is the most common mycotoxin
found in apples and apple-derived products such as juice, cider, compotes and other food
intended for young children. Exposure to this mycotoxin is associated with immunological,
neurological and gastrointestinal outcomes [132]. PAT-induced nephropathy and
gastrointestinal tract malfunction have been demonstrated in animal models [133]. The toxic
effects of PAT on various cells related to its activity on SH groups [134]. Moreover, it
suggested that PAT-induced apoptosis is mediated through the mitochondrial pathway
without the involvement of p53 [12]. The interaction with sulfhydryl groups of
macromolecules by PAT and the subsequent generation of ROS plays a primary role in the
apoptotic process. The genotoxic effects might be related to its ability to react with
sulfhydryl groups and to induce oxidative damage [135]. PAT was found to reduce the
cytokine secretion of IFN-γ and IL-4 by human macrophages [136] and of IL-4, IL-13, IFN-γ,
and IL-10 by human peripheral blood mononuclear cells and human T cells [137]. The
clinical signs of PAT toxicosis are typical of the nervous syndrome. Animals present
hyperaesthesia, lack of coordination of motor organs, problems with ingestion and
digestion. At the molecular level, PAT alters ion permeability and/or intracellular
communication, causing oxidative stress and cell death (116).
Citrinin is a toxic metabolite produced by several filamentous fungi of the genera
Penicillium, Aspergillus and Monascus, which has been encountered as a natural contaminant
in grains, foods, feedstuffs, as well as biological fluids. Some analytical systems have been
developed for its detection and quantification [138]. As one of mycotoxins, citrinin possesses
antibiotic, bacteriostatic, antifungal and antiprotozoal properties. While it is also known as a
hepato-nephrotoxin in a wide range of species [139], in vitro studies have demonstrated that
citrinin produced multiple effects on renal mitochondrial function and macromolecule
biosynthesis that ultimately resulted in cell death [140]. Citrinin inhibited the oxygen
consumption rate by about 45 % and inhibited the glucose utilization of BHK-21 cells by
about 86 % due to alterations in mitochondrial function and in the glycolytic anaerobic
pathway [141]. Citrinin occurred frequently together with another nephrotoxin–ochratoxin
A in foodstuffs such as cereals, fruits, meat [142] and cheese [143]. Citrinin can act
synergistically with ochratoxin A to depress RNA synthesis in murine kidneys [144, 145].
The simultaneous exposure of rabbits to citrinin with OTA even at sub-clinical dietary levels
potentiated the OTA induced nephrotoxicity at ultrastructural level [146]. To avoid the
Mycotoxin and Food Safety in Developing Countries
direct/indirect intake of citrinin, it is important to develop detoxification methods for
citrinin during food processing. So far, there have been several reports on the detoxification
of citrinin. The investigation on thermal decomposition and detoxification showed that, in
the presence of a small amount of water, heating citrinin at 130oC caused a significant
decrease in its toxicity to Hela cells [147]; whereas heating at 150oC in water caused
formation of highly toxic compounds [148].
Ergot Alkaloids
The ergot alkaloids are among the most fascinating of fungal metabolites. They are classified
as indole alkaloids and are derived from a tetracyclic ergoline ring system [149]. These
compounds are produced as a toxic cocktail of alkaloids in the sclerotia of species of Claviceps,
which are common pathogens of various grass species. Ergotism is still an important
veterinarian problem. The principal animals at risk are cattle, sheep, pigs, and chickens.
Clinical symptoms of ergotism in animals include gangrene, abortion, convulsions,
suppression of lactation and hypersensitivity [150]. More recently, pure ergotamine has been
used for the treatment of migraine headaches. Other ergot derivatives are used as prolactin
inhibitors, in the treatment of Parkinsonism, and in cases of cerebrovascular insufficiency
[149]. The therapeutic administration of ergot alkaloids may cause sporadic cases of human
ergotism [151]. Ergotism is extremely rare today, primarily because the normal grain cleaning
and milling processes remove most of the ergot so that only very low levels of alkaloids
remain in the resultant flours. In addition, the alkaloids that are the causative agents of
ergotism are relatively labile and are usually destroyed during baking and cooking [3].
Satratoxin G
Satratoxin G is one of the most potent macrocylclic TCs produced by Stachybotrys chartarum
[152]. Roridin A is a commercially available macrocyclic TC used as a stratoxin G substitute,
and roridin L2 is a putative biosynthetic precursor of satratoxin [153]. Satratoxin G is potent
inhibitors of eukaryotic translation that are potentially immunosuppressive. It rapidly binds
small and large ribosomal subunits in a concentration- and time-dependent manner that
was consistent with induction of apoptosis [154]. A signal transduction pathway in
satratoxin-induced apoptosis in HL-60 cells involves, caspase-3 activation through
activation of both caspase-8 and caspase-9 along with cytosolic release of cytochrome c and
fragmentation of nucleosomal DNA by DFF-40/CAD [155].
Roridin E
Roridin E is a well-known macrocyclic trichothecene mycotoxin possessing potent anti-
proliferative activity against cancer cell lines [156]. Four new isolated from a marine-derived
fungus, Myrothecium roridum strain 98F42 [157]. One of them, 12-deoxy derivative of roridin
E, showed reduced cytotoxicity about 80-fold less than that of roridin E against human
promyelocytic (HL-60) and murine leukemia (L1210) cell lines [158]. Treatment of rats with
roridin E caused minimal toxicity on the hepatic and renal tissue, however, co
administration of linoleic acid with roridin E resulted in increase toxicity due to increased
incorporation to the cell membrane or inhibit its biotransformation [159].
Mycotoxins-Induced Oxidative Stress and Disease
5. Mmycotoxins and apoptosis
Apoptosis is a process for maintenance of tissue homeostasis. Several processes, such as
initiation of death signals at the plasma membrane, expression of pro-apoptotic
oncoproteins, activation of death proteases and endonucleases combine to cause cell
termination. ROS may play a major role in apoptosis. GSH depletion increases the % of
apoptotic cells [160]. In general, apoptosis is considered as a common mechanism of toxicity
of various mycotoxins [68]. TCs induce apoptosis response via mitochondrial and non-
mitochondrial mechanisms [161]. The amphophilic nature of TCs facilitates their cytotoxic
effect on cell membranes and inside the cell interact with ribosome and mitochondria
causing inhibition of protein synthesis [162]. FB1 and OTA are able to induce apoptosis and
necrosis in porcine kidney PK15 cells [163]. This is because the structure of FB1 resembles
sphingoid bases which regulate cell growth, differentiation, transformation and apoptosis,
and so it is not surprising that FB1 can alter growth of certain mammalian cells. The
involvement of the TNF signal transduction pathway in FB1 induced apoptosis in African
green monkey kidney fibroblasts has been shown [164]. Moreover, TNF-α production is
responsible for FB1 induced apoptosis in mice primary hepatocytes [165]. Over expression
of cytochrome P450-sensitized hepatocyte to TNFα-mediated cell death was associated with
increased LPO and GSH depletion [166]. FB1 was reported to increase induction of
cytochrome P450 isoforms and caused peroxidation of membrane lipids in isolated rat liver
nuclei as well as GSH depletion of in pig kidney cells [167-169]. GSH depletion is known to
activate c-Jun N-terminal kinase through redox inhibition of GST, which normally binds to
and inhibits stress kinases [170]. Stimulation of apoptosis and necrosis in porcine granulosa
cells by ZEA is dose-dependent manner via a caspase-3- and caspase-9-dependent
mitochondrial pathway [171]. At the molecular level, fumonisins inhibit ceramide synthase
and disrupt sphingolipid metabolism therefore influence apoptosis and mitosis [109]. The
immunotoxic activity of OTA probably results from degenerative changes and cell death
following necrosis and apoptosis in combination with slow replacement of affected immune
cells due to inhibition of protein synthesis [85]. Moreover, PAT induce DNA damage and
cell cycle arrest along with intrinsic pathway mediated apoptosis which may have dermal
toxicological implications [172].
Satratoxin H is thought to induce apoptosis of PC12 cells through the activation of p38
mitogen activated protein kinase and c-Jun N-terminal kinase in GSH-sensitive manner
[173]. Chemoprotective effects of flavonoid compounds against aflatoxins were confirmed in
hens [174]. Moreover, cysteine and GSH has protective effect against PAT in the incident of
rumen microbial ecosystem, however vitamin C and ferulic acid did not demonstrate an
effect [175]. Metallothioneins (MTs) are four major isoforms found in cytoplasm, lysosomes,
mitochondria and nuclei of mammalian cells [176]. MT-1 and 2 have ubiquitous tissue
distribution particularly in liver, pancreas, intestine, and kidney, whereas MT-3 is found in
brain and MT-4 in skin [177]. MT can play important role in the process of mycotoxins
detoxification probably by redistribution of significant ions to transcriptional factors and
interactions with oxygen radicals that may be generated by mycotoxins [23]. Nivalenol, a
Mycotoxin and Food Safety in Developing Countries
trichothecene mycotoxin induces apoptosis in HL60 cells and that intracellular calcium ion
plays a role in the nivalenol-induced secretion of IL-8 from this cell line [178].
6. Mycotoxins as therapeutics compound
Cumulative knowledge about toxins structure and mechanism of action, as well as recent
progress in the fields of cell biology, immunology, molecular biology and nanotechnology,
enabled the development of different targeting strategies that are vital for converting a lethal
toxin into a therapeutic agent. Fig. 9 showed three targeting strategies in toxin based therapy.
i- Ligand targeted toxins upon administration to patients are internalized and intoxicate
diseased cells, sparing healthy cells that do not display the target on their surface. ii- protease
activated toxins: the toxin is engineered to be cleaved and activated by a disease-related
intracellular or extracellular protease. Toxin cleavage may enhance cell-binding and/or
translocation, stabilization or catalytic activity of the toxic moiety specifically in protease
expressing cells, leading to their suppression. iii- toxin based suicide gene therapy: a DNA
construct, encoding for a toxic polypeptide whose expression is regulated by a specific
transcription regulation element, is delivered to a heterogeneous cell population [179].
Figure 9. Three targeting strategies in toxin based therapy [179].
Because of their pharmacological activity, some mycotoxins or mycotoxin derivatives have
found use as antibiotics, growth promoters, and other kinds of drugs. Ergocryptine is an
ergot alkaloid that affects dopaminergic activity principally by interacting with D2-type
receptors [180]. The bromation derivative has increased dopamine agonist activity, and is
used against Parkinsonism and to reduce growth hormone secretion and milk production
[181]. Ergotamine was among the most effective available agents for relieving migraine
attacks [182]. Ergometrine and the semi-synthetic methylergometrine have been widely
used for the prevention and treatment of excessive uterine bleeding following birth and also
to initiate delivery [183]. Lysergic acid diethylamide is a serotonin receptor agonist [184] and
can also interact with dopamine receptors to make it a useful tool for probing the
Mycotoxins-Induced Oxidative Stress and Disease
biochemical basis for behaviour [185]. Methysergide a semi-synthetic ergot alkaloid is a
serotonin antagonist used in the treatment of migraine and is used for daily preventive
therapy rather than in acute cases [184]. The TCs have been associated with various
biological properties, such as antiviral especially as inhibitors of the replication of Herpes,
antibiotic, antimalarial, antileukemic and immunotoxic [59,186]. Mycoestrogenic
zearalenone is suspected to be a triggering factor for central precocious puberty
development in girls. Due to its chemical resemblance to some anabolic agents used in
animal breeding, ZEA may also represent a growth promoter in exposed patients [187].
Development of cyclosporine A as immunosuppressive drug has been traced back to the
stimulus derived from the first highly-active cyclopeptides from Amantia mushrooms [188].
7. Conclusion
Mycotoxins are produced in a strain-specific way, and elicit some complicated and
overlapping toxigenic activities in sensitive species that include carcinogenicity, inhibition of
protein synthesis, immunosuppression, dermal irritation, and other metabolic perturbations.
Mycotoxins usually enter the body via ingestion of contaminated foods, but inhalation of
toxigenic spores and direct dermal contact are also important routes. There is sufficient
evidence from animal models and human epidemiological data to conclude that mycotoxins
pose an important danger to human and animal health. Trichothecenes cause protein
synthesis inhibition via binding to the 18s rRNA of the ribosomal large subunit as a major
mechanism underlying induction of cell apoptosis. T-2 toxin triggers a ribotoxic response
through its high binding affinity to peptidyl transferase which is an integral part of the 60 s
ribosomal subunit and interferes with the metabolism of membrane phospholipids and
increases liver lipid peroxides. SH is thought to induce caspase-3 activation and apoptosis
through the activation of MAPK and JNK in a GSH-sensitive manner. FB1-induced inhibition
of ceramide synthesis can result in a wide spectrum of changes in lipid metabolism and
associated lipid-dependent pathways. OTA has complex mechanisms of action that include
mitochondrial impairment, formation of OTA-DNA adducts and induction of oxidative stress
and apoptosis through caspase activation. Accordingly, the strict control of food quality, in
both industrialized and developing countries, is therefore necessary to avoid mycotoxicosis.
Author details
Hossam El-Din M. Omar
Zoology Department, Faculty of Science, Assiut University, Egypt
8. References
[1] Bennett JW, Klich M. Mycotoxins. Clinical Microbiology Reviews 2003; 16 (3): 497–516.
[2] Surai PF, Mezes M, Melnichuk SD, Fotina TI. Mycotoxins and animal health: From
oxidative stress to gene expression. Krmiva 2008; 50: 35–43.
[3] Peraica M, Radic B, Lucic A, Pavlovic M. Toxic effects of mycotoxins in humans. Bull.
WHO 1999; 77:754–766.
Mycotoxin and Food Safety in Developing Countries
[4] EFSA (2009): Annual Report of European Food Safety Authority, ISBN: 978-92-9199-211-
9 doi:10.2805/3682.
[5] Reverberi M, Ricelli A, Zjalic S, Fabbri AA, Fanelli C. Natural functions of mycotoxins
and control of their biosynthesis in fungi. Appl Microbiol Biotechnol 2010; 87:899–911.
[6] Fink-Grenmels J, Georgiou NA. Risk assesment of mycotoxins for the consumer. In:
Ennen G, Kuiper HA, Valentin A, eds. Residues of Veterinary Drugs and Mycotoxins in
Animal Products. NL-Wageningen Press 1996 p 159-74.
[7] Fink-Grenmels, J . Mycotoxins: Their implications for human and animal health.
Veterinary Quarterly 1999; 21(4):115-120.
[8] Bryden WL.Mycotoxins in the food chain: human health implications. Asia Pac J Clin
Nutr 2007; 16(1):95-101.
[9] Stoev S, Denev S, Dutton M, Nkosi B. Cytotoxic effect of some mycotoxins and their
combinations on human peripheral blood mononuclear cells as measured by the MTT
assay. The Open Toxinology Journal 209; 2: 1-8.
[10] Henry SH, Bosch FX, Troxell TC, Bolger PM. Reducing liver cancer-global control of
aflatoxin. Science 1999; 286:2453–2454.
[11] Binder EM, Tan LM, Chin LJ, Handl J, Richard J. Worldwide occurrence of mycotoxins
in commodities, feeds and feed ingredients. Animal Feed Science and Technology,2007;
137: 265–282.
[12] Wu TS, Liao YC, Yub FY, Chang CH, Liu BH. Mechanism of patulin-induced apoptosis
in human leukemia cells (HL-60). Toxicology Letters 2008; 183:105–111.
[13] CAST Report. Mycotoxins: risks in plant, animal, and human systems. In: J.L. Richard,
G.A. Payne (Eds.), Council for Agricultural Science and Technology Task Force Report
2003; No. 139, Ames, Iowa, USA. ISBN 1-887383-22-0.
[14] Wu F. Mycotoxins risk assessment for the purpose of setting International Regulatory
Standards. Environ. Sci. Technol. 2004; 38 (15): 4049–4055.
[15] Afifi MM, Abdel-Mallek AY, El-Shanawany AA, Khattab SMR .Fangal populations and
myctotoxins of wheat grains imported to Egypt. Ass.Univ. Bull.Envir. Res.2012;
[16] D’mello, JPE, Macdonald AMC. Mycotoxins. Animal Food Sci. Technol. 1997; 69, 155-
[17] Peraica M, Domijan AM. Contamination of food with mycotoxins and human health.
Arh. Hig. Rada. Toksikol. 2001; 52: 23–35.
[18] Boutrif E, Bessy C. Global significance of mycotoxins and phycotoxins. In: Mycotoxins
and phycotoxins in perspective at the turn of the millennium. Koe, W.J., Samson, R.A., van
Egmond, H.P., Gilbert, J. and Sabino, M. (eds.). Ponsen and Looyen, Wageningen, The
Netherlands 2001,p. 3-16.
[19] Hsieh D . Potential human health hazards of mycotoxins. In: Natori S, Hashimoto K,
Ueno Y (Eds.). Mycotoxins and Phytotoxins. Third Joint Food and Agriculture
Organization/ W.H.O./United Nations Environment Program International Conference
of Mycotoxins. Elsevier, Amsterdam, The Netherlands 1988; p. 69-80.
[20] Kemppainen RJ, Thompson FN, Lorenz MD, Munnell JF, Chakraborty PK. Effects of
prednisone on thyroidal and gonadal endocrine function in dogs. Journal of
Endocrinology, 1983; 96:293-302.
Mycotoxins-Induced Oxidative Stress and Disease
[21] Upadhaya SD, Park MA, Ha JK. Mycotoxins and Their Biotransformation in the Rumen.
A review. Asian-Aust. J. Anim. Sci.2010; 23 (9): 1250-1260.
[22] Eaton DL, Groopman DJ, ed.; 1994). The toxicology of aflatoxins: human health,
veterinary, and agricultural significance. Academic Press, San Diego, Calif.
[23] Vasatkova A, Krizova S, Adam V, Zeman L, Kizek R. Changes in metallothionein level
in rat hepatic tissue after administration of natural mouldy wheat. Int. J. Mol. Sci., 2009;
10: 1138-1160.
[24] Devasagayam TPA, Tilak JC, Boloor KK, Sane Ketaki S, Ghaskadbi Saroj S, Lele RD
."Free Radicals and Antioxidants in Human Health: Current Status and Future
Prospects". Journal of Association of Physicians of India 2004; 52: 796.
[25] Sies H. Oxidative stress: from basic research to clinical application. Am. J. Med., 1991; 91:
[26] Tafazoli, S. Mechanisms of drug-induced oxidative stress in the hepatocyte
inflammation model, Doctor of Philosophy, Department of Pharmaceutical Sciences,
University of Toronto, 2008.
[27] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. Fourth Edition,
Oxford University Press, Oxford, UK, 2007.
[28] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine, 3rd ed.; Oxford
University Press: New York, NY, USA, 1999.
[29] Ferrer E, Juan-Garcia A, Font G, Ruiz MG. Reactive oxygen species induced by
beauvericin, patulin and zearalenone in CHO-K1 cells. Toxicology in Vitro; 2009, 23:
[30] Munday R. Studies on the mechanism of toxicity of the mycotoxin, sporidesmin. I.
Generation of superoxide radical by sporidesmin.Chemico-Biological Interactions; 1982,
41(3): 361-374.
[31] Raj HG, Prasanna HR, Mage PN, Lotlikar PD. Effect of purified rat and hamster hepatic
glutathione S-transferases on the microsome mediated binding of aflatoxin B1 to DNA.
Cancer Lett.; 1986, 33:1–9.
[32] Eaton DL, Ramsdel HS. Species and diet related differences in aflatoxin
biotransformation, p. 157–182. In D. Bhatnagar, E. B. Lillehoj, and D.K. Arora (ed.),
Handbook of applied mycology, vol. 5, mycotoxins in ecological systems. Marcel
Dekker, Inc., New York, N.Y.;1992.
[33] Kiessling KH. Biochemical mechanism of action of mycotoxins. Pure & Appl.
Chem.;1986, 58(2): 327-338.
[34] IARC. Overall evaluations of carcinogenicity: an updating of IARC Monographs
volumes 1 to 42. Report of an IARC Expert Committee. Lyon, International Agency for
Research on Cancer, 1987 (IARC Monographs on the Evaluation of Carcinogenic Risks
to Humans, Supplement 7).
[35] Maxwell SM, Apeagyei F, de Vries HR, Mwanmut DD, Hendrickse RG. Aflatoxins in
breast milk, neonatal cord blood and sera of pregnant women. J. Toxicol. Toxin. Rev.;
1989, 8: 19-29.
[36] Hendrickse RG. Kwashiorkor: the hypothesis that incriminates aflatoxins. Pediatrics;
1991, 88: 376-379.
Mycotoxin and Food Safety in Developing Countries
[37] Hendrickse RG. Of sick turkeys, kwashiorkor, malaria, perinatal mortality, heroin
addicts and food poisoning: research on the influence of aflatoxins on child health in the
tropics. Ann. Trop. Med. Parasitol.; 1997, 91:787– 793.
[38] Williams JH, Phillips TD, Jolly PE, Stiles JK, Jolly CM, Aggarwal D. Human aflatoxicosis
in developing countries: a review of toxicology, exposure, potential health
consequences, and interventions. Am.J.Clin.Nutr.; 2004, 80:1106-1122.
[39] Creppy EE. Update of survey, regulation and toxic effects of mycotoxins in Europe.
Toxicology Letters; 2002, 127: 9–28.
[40] Murphy PA, Hendrich S, Landgren C, Bryant CM. Food mycotoxins: an update. Journal
of Food Science; 2005, 71: 52-R65.
[41] Kensler TW, Davis EF, Bolton MG. Strategies for chemoprotection against aflatoxin-
induced liver cancer. In: Eaton D, Groopman JD, eds. The toxicology of
aflatoxins:humanhealth, veterinary, and agricultural significance. London: Academic
Press; 1993, p. 281–306.
[42] Hayes JD, Pulford DJ, Ellis EM, McLeod R, James RF, Seidegard J. Regulation of rat
glutathione S-transferase A5 by cancer chemopreventive agents: mechanisms of
inducible resistance to aflatoxin B1. Chem Biol Interact; 1998, 112:51–67.
[43] Mintzlaff HJ, Lotzsch R, Tauchmann F, Meyer W, Leistner L. Aflatoxin residues in the
liver of broiler chicken given aflatoxin-containing feed. Fleischwirtschaft; 1974, 54: 774-
[44] Guengerich FP. Cytochrome P450s and other enzymes in drug metabolism and toxicity.
The AAPS Journal ; 2006, 8 (1) Article 12 (
[45] Patterson DSP, Allcroft R. Metabolism of aflatoxins in susceptible and resistant animal
species. Fd. Cosmet. Toxicol 1970, 8: 43.
[46] Dhanasekaran D, Shanmugapriya S, Thajuddin N Panneerselvam A. Aflatoxins and
aflatoxicosis in human and animals. In aflatoxins - biochemistry and molecular biology,
Guevara-Gonzalez, R.G. (editor), ISBN 978-953-307-395-8, InTech, Published, 2011,
[47] Guengerich FP, Johnsen WW, Ueng YF, Yamazaki H, Shimada T. Involvement of
cytochrome P450, glutathione S-transferase and epoxide hydrolase in the metabolism of
aflatoxin B1 and relevance to risk of human liver cancer. Environ Health Persp, 1996,
104: 557-562.
[48] Verma RJ. Aflatoxin Cause DNA Damage. Int J Hum Genet; 2004, 4(4): 231-236.
[49] Groopman JD, Thomas W, Kensler TW, Wild CP. Protective interventions to prevent
aflatoxin-induced carcinogenesis in developing countries. Annu. Rev. Public Health;
2008, 29:187–203.
[50] Meissonnier GM, Pinton P, Laffitte J, Cossalter AM, Gong YY, Wild CP, Bertin G,
Galtier P, Oswald I. Immunotoxicity of aflatoxin B1: impairment of the cell-mediated
response to vaccine antigen and modulation of cytokine expression. Toxicol. Appl.
Pharmacol.; 2008, 231, 142–149.
[51] Deabes MM, Darwish HR, Abdel-Aziz KB, Farag IM, Nada SA, Tawfek N S. Protective
effects of Lactobacillus rhamnosus GG on aflatoxins-induced toxicities in male albino
mice. J Environment Analytic Toxicol.; 2012, 2:132. doi:10.4172/2161-0525.1000132.
Mycotoxins-Induced Oxidative Stress and Disease
[52] Toskulkao C, Taycharpipranai S, Glinsukon T. Enhanced hepatotoxicity of aflatoxin B1
by pretreatment of rats with ethanol. Res Comm Chem Pathol Pharmacol; 1982, 36: 477-
[53] Toskulkao C, Glinsukon T. Hepatic lipid peroxidation and intracellular calcium
accumulation in ethanol potentiated aflatoxin B1 toxicity. J Pharmacobio Dyn, 1988,
[54] Verma RJ, Nair A. Vitamin E prevents aflatoxin induced lipid peroxidation in liver and
kidney. Med Sci Res; 1999, 27: 223.
[55] Verma RJ, Nair A. Ameliorative effect of vitamin E on aflatoxin-induced lipid
peroxidation in the testis of mice. Asian J Androl; 2001, 3: 217.
[56] Patel JW. Stimulation of cyclophosphamide induced pulmonary microsomal lipid
peroxidation by oxygen. Toxicology; 1987, 45: 71.
[57] Yu MW, Lien JP, Chiu YH, Santella RM, Liaw YF, Cher CJ. Effect of aflatoxin
metabolism and DNA adduct formation on hepatocellular carcinoma among chronic
hepatitis B carriers in Taiwan. Journal of Hepatology; 1991, 27: 320-330.
[58] Sudakin DL. Dietary Aflatoxin Exposure and Chemoprevention of Cancer: A Clinical
Review. Clinical Toxicology; 2003, 41(2):195-204.
[59] Bra¨se S, Encinas A, Keck J, Nising CF. Chemistry and Biology of Mycotoxins and
Related Fungal Metabolites. Chem. Rev. 2009, 109, 3903–3990.
[60] Pfohl-Leszkowicz A, Manderville RA. Ochratoxin A: An overview on toxicity and
carcinogenicity in animals and humans. Mol. Nutr. Food Res. 2007, 51, 61–99.
[61] Marquardt RR, Frohlich AA. A review of recent advances in understanding
ochratoxicosis. Journal of Animal Science, 1992, 70, 3968-3988.
[62] Cavin C, Delatour T, Marin-Kuan M, Holzhauser D, Higgins L, Bezencon C, Guignard
G, Junod S, Piguet D, Richoz-Payot J, Gremaux E, Hayes JD, Nestler S, Mantle P,
Schilter B. Reduction in antioxidant defences may contribute to ochratoxin A toxicity
and carcinogenicity. Toxicol. Sci.; 2007, 96 (1), 30–39.
[63] Boesch-Saadatmandi C, Wagner AE, Graeser AC, Hundhausen C, Wollram S, Rimbach
G. Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus
cells. J. Anim. Phys. Anim. Nutr;.2009, 93: 547–555.
[64] Krogh P. Role of ochratoxin in disease causation. Fd Chem Toxic; 1992, 30: 213–224.
[65] Ali A, Abdu S.Antioxidant protection against pathological mycotoxins alterations on
proximal tubules in rat kidney. Functional Foods in Heals and Disease; 2011, 4:118-134.
[66] Marin-Kuan M, Ehrlich V, Delatour T, Cavin C, Schilter B. Evidence for a role of
oxidative stress in the carcinogenicity of ochratoxin A. Journal of Toxicolog, 2011: 1-15.
[67] Obrecht-Pumio S, Grosse Y, Pfohi-Leszkowicz A, Dirheimer G. Protection by
indomethacin and aspirin against genotoxicity of ochraoxin A, particularly in the
urinary bladder and kidney. Arch Toxicol. 1996; 70:244-248
[68] Doi K, Uetsuka K. Mechanisms of mycotoxin-induced neurotoxicity through oxidative
stress-associated pathways. Int. J. Mol. Sci.;2011, 12: 5213-5237
[69] Dirheimer G, Creppy EE. Mechanism of action of ochratoxin A, IARC Sci. Publ., 1991,
115: 171-175.
[70] Gautier JC, Holzhaeuser D, Markovic J, Gremaud E, Schilter B, Turesky RJ. Oxidative
damage and stress response from ochratoxin exposure in rats. Free Radic. Biol.
Med.,2001, 30: 1089–1098.
Mycotoxin and Food Safety in Developing Countries
[71] Bryan NS, Rassaf T, Maloney RE, Rodriguez CM, Saijo F, Rodriguez JR, Feelisch M.
Cellular targets and mechanisms of nitros(yl)ation: An insight into their nature and
kinetics in vivo. Proc. Natl. Acad. Sci. USA; 2004, 101: 4308–4313.
[72] Mantle PG. Risk assessment and the importance of ochratoxins. International
Biodeterioration and Biodegradation, 2000, 50: 143-146.
[73] Petzinger E, Ziegler K. Ochratoxin A from a toxicological perspective. Journal of
Veterinary Pharmacolocy Therapeutics, 2000, 23, 91-98.
[74] Omar RF, Hasinoff BB, Mejilla F, Rahimtula AD. Mechanism of ochratoxin A stimulated
lipid peroxidation. Biochemical Pharmacology, 1990, 40: 1183-1191.
[75] Dai J, Park G, Wright MW, Adams M, Akman SA, Manderville RA. Detection and
characterization of a glutathione conjugate of ochratoxin A. Chem. Res. Toxicol., 2002,
15 (12), 1581–1588.
[76] Stemmer K, Ellinger-Ziegelbauer H, Ahr HJ, Dietrich DR. Carcinogen- specific gene
expression profiles in short-term treated Eker and wild-type rats indicative of pathways
involved in renal tumorigenesis. Cancer Res., 2007, 67: 4052–4068.
[77] Abdelhamid AM. Occurrence of some mycotoxins (aflatoxin, ochratoxin, citrinin,
zearalenon and vomitoxin) in various Egyptian feeds. Archive in Animal Nutrition,
1990, 40, 647.
[78] Maaroufi K, Achour A, Hammami M, el May M, Betheder AM, Ellouz F, Creppy EE
Bacha H. Ochratoxin A in human blood in relation to nephropathy in Tunisia. Human
and Experimental Toxicology, 1995, 14, 609-614.
[79] Fillastre JP. Néphrotoxicité expérimentale et humaine des ochratoxines. Bulletin
Académie Nationale de Médecine, 1997, 181, 1447.
[80] Godin M, Fillastre JP, Le Gallicier B, Pauti MD. Ochratoxin-induced nephrotoxicity in
animals and humans, Semaine des Hopitaux, 1998, 74, 800-806.
[81] Wafa EW, Yahya RS, Sobh MA, Eraky I, El Baz H, El Gayar HAM, Betbeder AM,
Creppy, EE. Human ochratoxicosis and nehropathy in Egypt: a preliminary study.
Human and Experimental Toxicology, 1998, 17, 124-129.
[82] [82]- O’Brien E, Dietrich DR. Ochratoxin A: The continuing enigma. Critical Reviews in
Toxicology, 2005, 35:33–60.
[83] Müller G, Kielstein P, Rosner H, Berndt A, Heller M, Köhler H. Studies on the influence
of combined administration of ochratoxin A, fumonisin B1, deoxynivalenol and T-2
toxin on immune and defence reactions in weaner pigs. Mycoses, 1999, 42, 485–493.
[84] Seegers JC, Boehmer LH, Kruger MC, Lottering ML, De Kock M. A comparative study
of ochratoxin A induced apoptosis in hamster kidney and HELA cells. Toxicol. Appl.
Pharmacol., 1994, 129:1–11.
[85] Alanati, L., Petzinger, E. Immunotoxic activity of ochratoxin A. J. Vet. Pharmacol.
Therap., 2006, 29: 79–90.
[86] Marin-Kuan M, Cavin C, Delatour T, Schilt B. Ochratoxin A carcinogenicity involves a
complex network of epigenetic mechanisms. Toxicon, 2008, 52:195–202 .
[87] Sudakin DL. Trichothecenes in the environment: Relevance to human health. Toxicol.
Lett.,2003, 143: 97-107.
[88] Eriksen GS, Pettersson H. Toxicological evaluation of trichothecenes in animal feed.
Anim. Feed Sci. Technol., 2004, 114: 205-239.
Mycotoxins-Induced Oxidative Stress and Disease
[89] Croft WA, Jarvis BB, Yatawara CS. Airborne outbreak of trichothecene toxicosis.
Atmospheric Environment, 1986, 20, 549-552.
[90] Nikulin M, Pasanen AL, Berg S, Hintikka EL. Stachybotrys atra growth and toxin
production in some building materials and fodder under di!erent relative humidities.
Applied and Environmental Microbiology, 1994, 60: 3421-3424.
[91] Pestka JJ. Deoxynivalenol:toxicity, mechanisms and animal health risks. Anim. Feed
Sci.Technol., 2007, 137, 283-298.
[92] Yazar S, Omurtag GZ. Fumonisins, Trichothecenes and Zearalenone in Cereals. Int. J.
Mol. Sci.,2008, 9, 2062-2090.
[93] Eriksen GS. Metabolism and Toxicity of Trichothecenes, Doctoral thesis, Uppsala, Sweden,
[94] Larsen JC, Hunt J, Perin I, Ruckenbauer P. Workshop on trichothecenes with a focus on
DON: Summary report. Toxicol. Lett., 2004, 153: 1-22.
[95] Desjardins AE, Hohn TM, McComic SP. Trichothecene biosynthesis in Fusarium species:
chemistry, genetics, and significance. Microbiol. Mol. Biol. Rev., 1993, 57: 595–604.
[96] Shifrin VI, Anderson P. Trichothecene mycotoxins trigger a ribotoxic stress response
that activates c-jun N-terminal kinase and p38 mitogen-activated protein kinase and
induces apoptosis. J. Biol. Chem., 1999, 274: 13985–13992.
[97] Chang IM, Mar WC. Effect of T-2 toxin on lipid peroxidation in rats: Elevation of
conjugated diene formation. Toxicol. Lett., 1988, 40: 275–280.
[98] Guerre P, Eeckhoutte C, Burgat V, Galtier P. The effects of T-2 toxin exposure on liver
drug metabolizing enzymes in rabbit. Food Addit. Contam., 2002, 17, 1019-1026.
[99] Chaudhary M, Rao PV. Brain oxidative stress after dermal and subcutaneous exposure
of T-2 toxin in mice. Food Chem. Toxicol., 2010, 48: 3436–3442.
[100] Pacin A, Reale C, Mirengui H, Orellana L, Boente G. Subclinic effect of the
administration of T-2 toxin and nivalenol in mice. Mycotoxin Research, 1994, 10: 34-46.
[101] Moss MO. Mycotoxin review-2. Fusarium. Mycologist, 2002, 16, 158-161.
[102] Gyongyossy-Issa MIC, Khanna V, Khachatourians GC. Characterisation of hemolysis
induced by T-2 toxin. Biochim. Biophys. Acta.,1985, 838: 252-256.
[103] Shinozuka J, Suzuki M, Noguchi N, Sugimoto T, Uetsuka K, Nakayama H, Doi K. T-2
toxin-induced apoptosis in hematopoietic tissues of mice. Toxicol. Pathol.,1998, 26: 674–
[104] Shinozuka J, Miwa S, Fujimura H, Toriumi W, Doi K. Hepatotoxicity of T-2 Toxin,
Trichothecene Mycotoxin. In New Strategies for Mycotoxin Research in Asia (Proceedings of
ISMYCO Bangkok ‘06); Kumagai, S., Ed.; Japanese Association of Mycotoxicology:
Tokyo, 2007, pp. 62–66
[105] Sehata S, Kiyosawa N, Makino T, Atsumi F, Ito K, Yamoto T, Teranishi M, Baba Y,
Uetauka K, Nakayama H, Doi K. Morphological and microarray analysis of T-2 toxin-
induced rat fetal brain lesion. Food Chem. Toxicol., 2004, 42: 1727–1736.
[106] Annunziato L, Amoroso S, Pannaccione A, Cataldi M, Pignataro G, D’Alessio S,
Sirabella R, Second A, Sibaud L, DiRenzo GF. Apoptosis induced in neuronal cells by
oxidative stress: role played by caspases and intracellular calcium ions. Toxicol.
Lett.,2003, 139: 125–133.
Mycotoxin and Food Safety in Developing Countries
[107] Huang P, Akagawa K, Yokoyama Y, Nohara K, Kano K, Morimoto K. T-2 toxin
initially activates caspase-2 and induces apoptosis in U937 cells. Toxicol. Lett., 2007, 170:
[108] Wild CP, Gong YY. Mycotoxins and human disease: a largely ignored global health
issue. Carcinogenesis, 2010, 31(1):71–82.
[109] Voss KA, Riley RT, Norred WP, Bacon CW, Meredith FI, Howard PC, Plattner RD,
Collins TF, Hansen DK, Porter JK. An overview of rodent toxicities: liver and kidney
effects of fumonisins and Fusarium moniliforme. Environ Health Perspect.,2001,109
[110] Howard PC, Eppley RM, Stack ME, Warbritton A, Voss KA, Lorentzen RJ, Kovach
RM, Bucci TJ. Fumonisin B1 carcinogenicity in a 2-year feeding study using F344rats
and B6C3 F1 mice. Environ. Health Perspect., 2001,109: 277–282.
[111] Abel S, Gelderblom WCA. Oxidative damage and fumonisin B1-induced toxicity in
primary rat hepatocytes and liver in vivo. Toxicology, 1998,131, 121 - 131
[112] Merrill AH, Sullards MC, Wang E, Voss KA, Riley RT. Sphingolipid metabolism: roles
in signal transduction and disruption by fumonisins. Environ. Health Perspect., 2001,
[113] Stockmann-Juvala H, Savolainen A. A review of the toxic effects and mechanisms of
action of fumonisin B1. Hum. Exp. Toxicol., 2008, 27: 799–809.
[114] Riley RT, Enongene E, Voss KA, Norred WP, Meredith FI, Sharma RP, Spitsbergen J,
Williams DE, Carlson DB, Merrill AH, Jr. Sphingolipid perturbations as mechanisms for
fumonisin carcinogenesis. Environ. Health Perspect., 2001, 109: 301–308.
[115] Voss KA, Howard PC, Riley RT, Sharma RP, Bucci TJ, Lorentzen RJ. Carcinogenicity
and mechanism of action of fumonisin B1: a mycotoxin produced by Fusarium
moniliforme (=F. verticillioides). Cancer Detect. Prevent., 2002, 26: 1-9.
[116] Riley RT. Mechanistic interactions of mycotoxins: theoretical consideration. In: Sinha
KK, Bhatanagar D (Eds.), Mycotoxins in Agriculture and Food Safety. Marcel Dekker,
Inc, Basel, New York, 1998, pp. 227–254.
[117] Yiannikouris A, Jouany JB. Mycotoxins in feeds and their fate in animals: a review.
Anim. Res., 2002, 51: 81–99.
[118] Wang JS, Groopman DJ. DNA damage by mycotoxins. Mutation Research,1999, 424:
[119] Mobio TA, Anane R, Baudrimont I, Carratū MR, Shier TW, Dano SD, Ueno Y, Creppy
EE. Epigenetic properties of fumonisin B1: cell cycle arrest and DNA base modification
in C6 glioma cells. Toxicol. Appl. Pharmacol. 2000, 164, 91–96.
[120] Stockmann-Juvala H, Mikkola J, Naarala J, Loikkanen J, Elovaara E, Savolainen K.
Fuminisin B1-induced toxicity and oxidative damage in U-118MG glioblastoma cells.
Toxicology, 2004, 202: 173–183.
[121] Ferrante MC, Meli R, Raso GM, Esposito E, Severino L, Carlo GD, Lucisano A. Effect
of fumonisin B1 on structure and function of macrophage plasma membrane.
Toxicology Letters, 2002, 129: 181–187.
[122] Olsen M. Metabolism of zearalenone in farm animals. In Fusarium mycotoxins,
taxonomy and pathogenicity, 1st Ed.; Chelkowsi, J., Ed.; Elsevier: Amsterdam-Oxford-
New York, 1989, pp. 167–177.
Mycotoxins-Induced Oxidative Stress and Disease
[123] Minervini F, Dell’Aquila MD. Zearalenone and reproductive function in farm animals.
Int. J. Mol. Sci, 2008, 9: 2570-2584.
[124] D’Mello JPF, Placinta CM, MacDonald AMC. Fusarium mycotoxins: A review of global
implications for animal health, welfare and productivity. Anim. Feed Sci. Technol.,
1999, 80: 183-205.
[125] Ben Othmen ZO, El Golli E, Abid-Essefi S, Bacha H. Cytotoxicity effects induced by
zearalenone metabolites, α zearalenol and β zearalenol, on cultured vero cells.
Toxicology, 2008, 252: 72–77.
[126] Hassen W, Ayed-Boussema I, Oscoz AA, Lopez AD, Bacha H. The role of oxidative
stress in zearalenone-mediated toxicity in Hep G2 cells: Oxidative DNA damage,
gluthatione depletion and stress proteins induction. Toxicology, 2007, 232: 294-302.
[127] Kuiper-Goodman T, Scott PM, Watanabe H. Risk assessment of the mycotoxin
zearalenone. Reg. Toxicol. Pharmacol., 1987, 7: 253–306.
[128] Kuiper-Goodman T, Hilts C, Billiard SM, Kiparissis Y, Richard ID, Hayward S. Health
risk assessment of ochratoxin A for all age-sex strata in a market economy. Food Addit.
Contam. Part A Chem. Anal. Control Expo. Risk Assess., 2010, 27: 212–240.
[129] Wasowiczi K, Gajecja M, Calka J, Jakimiuk E, Gajecki M. Influence of chronic
administration of zearalenone on the processes of apoptosis in the porcine ovary. Vet.
Med. Czech, 2005, 50 (12): 531–536.
[130] Kim II-H, Son HY, Cho SW, Chang-Su Ha, CS, Kang BH. Zearalenone induces male
germ cell apoptosis in rats. Toxicology Letters, 2003, 138: 185-192.
[131] Wang YC, Deng JL, Xu SW, Peng X, Zuo ZC, Cui HM, Wang Y, Ren ZH. Effects of
zearalenone on IL-2, IL-6, and IFN-γ mRNA levels in the splenic lymphocytes of
chickens. The Scientific World Journal, 2012: 1-5.
[132] Puel O, Galtier P, Oswald IP. Biosynthesis and toxicological effects of patulin. Toxins,
2010, 2: 613-631.
[133] Mahfoud R, Maresca M, Garmy N, Fantini J. The mycotoxin patulin alters the barrier
function of the intestinal epithelium: mechanism of action of the toxin and protective
effects of glutathione. Toxicol. Appl. Pharmacol., 2002, 181: 209–218.
[134] Liu F, Ooi V, Chang S. Free radical scavenging activities of mushroom polysaccharides
extracts. Life Sci., 1996, 60(10): 763- 771.
[135] [135]- Liu BH, Wu TS, Yu FY, Su CC. Induction of oxidative stress response by the
mycotoxin patulin in mammalian cells. Toxicol. Sci., 2007, 95(2):340-347.
[136] Wichmann G, Herbarth O, Lehmann I.: The mycotoxins citrinin, gliotoxin, and patulin
affect interferon-gamma rather than interleukin-4 production in human blood cells.
Environ. Toxicol., 2002, 17: 211–218.
[137] Luft P, Oostingh GJ, Gruijthuijsen Y, Horejs-Hoeck J, Lehmann I, Duschl A. Patulin
Influences the Expression of Th1/Th2 Cytokines by Activated Peripheral Blood
Mononuclear Cells and T Cells Through Depletion of Intracellular Glutathione.
Environ. Toxicol., 2008, 23: 84–95.
[138] Yu FY, Liao YC, Chang CH and Liu BH. Citrinin induces apoptosis in HL-60 cells via
activation of the mitochondrial pathway. Toxicology Letters, 2006,161: 143-151
[139] Berndt WO. Ochratoxin–citrinin as nephrotoxins. In Llewellyn GC, Rear PCO (Eds.),
Biodeterioration Research 3 New York, USA: Plenum Press, 1999, PP.55-56.
Mycotoxin and Food Safety in Developing Countries
[140] Chagas GM, Oliveira MBM, Campello AP, Kluppel MLW. Mechanism of citrinin-
induced dysfunction of mitochondria. III. Effects on renal cortical and liver
mitochondria swelling. Journal of Applied Toxicology, 1995, 15: 91–95.
[141] Chagas GM, Kluppel MLW, Oliveira MBM. Citrinin affects the oxidative metabolism
of BHK-21 cells. Cell Biochem and Function, 1995, 13(4):257-271.
[142] Nishijima, M. In Kurata H & Ueno Y (Eds.), Toxigenic fungi. Amsterdam,
Netherlands, 1984, PP.172-181.
[143] Vazquez BI, Fente C, Franco C, Cepeda A, Prognon P, Mahuzier G. Simultaneous
high-performance liquid chromatographic determination of ochratoxin A and citrinin in
cheese by time-resolved luminescence using terbium. Journal of Chromatography A,
1996, 727: 185–193.
[144] Sansing GA, Lillehoj EB, Detroy RW. Synergistic toxic effect of citrinin, ochratoxin A
and penicillic acid in mice. Toxicon, 1976, 14:213-220.
[145] Glahn RP, Shapiro RS, Vena VE, Wideman RF, Huff WE. Effects of chronic ochratoxin
A and citrinin toxins on kidney function of single comb white leghorn pullets. Poultry
Science, 1989, 68(9): 1205–1211.
[146] Kumar M, Dwivedi P, Sharma AK, Singh ND, Patil RD. Ochratoxin A and citrinin
nephrotoxicity in New Zealand White rabbits: an ultrastructural assessment.
Mycopathologia, 2007, 163: 21–30.
[147] Kitabatake N, Trivedi AB, Doi E. Thermal decomposition and detoxification of citrinin
under various moisture conditions. Journal of Agricultural and Food Chemistry, 1991,
39(12): 2240–2244.
[148] Trivedi AB, Doi E, Kitabatake N. Toxic compounds formed on prolonged heating of
citrinin under watery conditions. Journal of Food science, 1993, 58(1): 229–231.
[149] Bennett JW, Bentley R. Pride and prejudice: the story of ergot. Perspect. Biol. Med.,
1999, 42:333-355.
[150] Lorenz K. Ergot on cereal grains. Crit. Rev. Food Sci. Nutr., 1979, 11:311-354.
[151] Cabellero-Granado FJ, Viciana P, Cordero E, Gomez-Vera M.J, del Nozal M, Opez-
Cortes LF. Ergotism related to concurrent administration of ergotamine tartrate and
ritonavir in an AIDS patient. Antimicrob. Agents Chemother., 1997, 41:1297.
[152] Yang GH, Jarvis BB, Chung YJ, Pestka JJ. Apoptosis induction by satratoxins and other
trichothecene mycotoxins: Relationship to ERK, p38 MAPK, and SAPK/JNK activation.
Toxicol. Appl. Pharmacol., 2000, 164: 149–160.
[153] Nielsen KF. Mycotoxin production by indoor molds. Fungal Genetics Biology, 2003,
39: 103-117.
[154] Bae HK, Shinozuka J, Islam Z, Pestka JJ. Satratoxin G Interaction with 40S and 60S
Ribosomal Subunits Precedes Apoptosis in the Macrophage. Toxicol Appl Pharmacol.,
2009, 237(2): 137–145.
[155] Nagase M, Shiota T, Tsushima A, Murshedul M, Fukuoka S, Yoshizawa T, Sakato N.
Molecular mechanism of satratoxin-induced apoptosis in HL-60 cells: activation of
caspase-8 and caspase-9 is involved in activation of caspase-3. Immunology Letters,
2002, 84: 23-27.
[156] Oda T, Xu JKU, Nakazawa T, Namikoshi M. 12- -Hydroxyl group remarkably reduces
Roridin E cytotoxicity. Mycoscience, 2010, 51:317–320.
Mycotoxins-Induced Oxidative Stress and Disease
[157] Xu J, Takasaki A, Kobayashi H, Oda T, Yamada J, Mangindaan REP, Ukai K, Nagai H,
Namikoshi M. Four new macrocyclic trichothecenes from two strains of marine-derived
fungi of the genus Myrothecium. J Antibiot, 2006, 59:451–455.
[158] Namikoshi M, Akano K, Meguro S, Kasuga I, Mine Y, Takahashi T, Kobayashi H. A
new macrocyclic trichothecene, 12,13-deoxyroridin E, produced by the marine-derived
fungus Myrothecium roridum collected in Palau. J Nat Prod. 2001, 64:396–398.
[159] Omar HM, El-Sawi NM, Meki ARMA. Acute toxicity of the mycotoxin roridin E on
liver and kidney of rats. J. Appl. Anim. Res., 1997, 12:145-152.
[160] Kam PCA , Ferch NI. Apoptosis: mechanisms and clinical implicat. Anaesthesia, 2000,
55: 1081-1093.
[161] Rocha O, Ansari K, Doohan FM. Effects of trichothecene mycotoxins on eukaryotic
cells: A review. Food Additives and Contaminants, 2005, 22(4): 369–378.
[162] Pace JG, Watts MR, Canterbury WJ. T-2 mycotoxin inhibits mitochondrial protein
synthesis. Toxicon, 1988, 26:77–85.
[163] Klaric MK, Rumora L, Ljubanvic D, Pepeljnjak S. Cytotoxicity and apoptosis induced
by fumonisin B1, beauvericin and ochratoxin A in porcine kidney PK15 cells: effects of
individual and combined treatment. Arch Toxicol., 2008, 82:247–255.
[164] Jones C, Ciacci-Zanella JR, Zhang Y, Henderson G, Dickman M. Analysis of fumonisin
B1-induced apoptosis.Environ Health Perspect., 2001, 109 (2): 315–320.
[165] Sharma N, Suzuki H, He Q, Sharma RP. Tumor necrosis factor α -mediated activation
of c-Jun NH2-terminal kinase as a mechanism for fumonisin B1 induced apoptosis in
murine primary hepatocytes. J Biochem. Molecular Toxicology, 2005, 19 (6):359-367.
[166] Liu H, Jones BE, Bradham C, Czaja MJ. Increased cytochrome P-450 2E1 expression
sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α. Am J Physiol
Gastrointest Liver Physiol, 2002, 282:G257–G266.
[167] Martinez-Larranaga MR, Anadon A, Diaz MJ, Fernandez R, Sevil B, Fernandez-Cruz
ML, Fernandez MC, Martinez MA, Anton R. Induction of cytochrome P4501A1 and
P4504A1 activities and peroxisomal proliferation by fumonisin B1. Toxicol Appl
Pharmacol., 1996, 141:185–194.
[168] Kang YJ, Alexander JM. Alterations of the glutathione redox cycle status in fumonisin
B1-treated pig kidney cells. J Biochem Toxicol, 1996, 11:121–16.
[169] Sahu SC, Eppley RM, Page SW, Gray GC, Barton CN, O’Donnel Lmw. Peroxidation of
membrane lipids and oxidative DNA damage by fumonisin B1 in isolated rat liver
nuclei. Cancer Lett, 1998, 125:117–121.
[170] Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M,
Henderson CJ,Wolf CR, Davis RJ, Ronai Z. Regulation of JNK signaling by GSTp.
EMBO J; 1999, 18:1321–1334
[171] Zhu L, Yuan H, Guo C, Lu Y, Deng S, Yang Y, Wei Q, Wen L, He Z. Zearalenone
induces apoptosis and necrosis in porcine granulosa cells via a caspase-3- and caspase-
9-dependent mitochondrial signaling pathway. Journal of Cellular Physiology, 2012,
[172] Saxena N, Ansari KM, Kumar R, Dhawan A, Dwivedi PD, Das M. Patulin causes DNA
damage leading to cell cycle arrest and apoptosis through modulation of Bax, P53 and
P21/waf1 proteins in skin of mice. Toxicology and Applied Pharmacology, 2009,
Mycotoxin and Food Safety in Developing Countries
[173] Nusuetrong P, Pengsuparp T, Meksuriyen D, Tanitsu M, Kikuchi H, Mizugaki M,
Shimazu KI, Oshima Y, Nakahata N, Yoshida M. Satratoxin H generates reactive
oxygen species and lipid peroxides in PC12 cells. Biol. Pharm. Bull., 2008, 31: 1115-1120.
[174] Coulombe RA, Guarisco JA, Klein PJ, Hall JO. Chemoprevention of aflatoxicosis in
poultry by dietary butylated hydroxytoluene. Anim. Feed Sci. Technol., 2005,121: 217-
[175] Morgavi DP, Boudra H, Jouany JP, Graviou D. Prevention of patulin toxicity on rumen
microbial fermentation by SH-containing reducing agents. J. Agric. Food Chem., 2003,
51: 6906-6910.
[176] Eckschlager T, Adam V, Hrabeta J, Figova K, Kizek R. Metallothioneins and Cancer.
Curr Protein Pept Sci, 2009, 10: 360–375.
[177] Davis SR, Cousins RJ. Metallothionein expression in animals: A physiological
perspective on function. J. Nutr., 2000, 130: 1085-1088.
[178] Nagashima H, Nakagawa H, Iwashita K. Mycotoxin nivalenol induces apoptosis and
intracellular calcium ion-dependent interleukin-8 secretion but does not exert
mutagenicity. In Ikura K et al. (eds.), Animal Cell Technology: Basic & Applied Aspects,
2009, pp.301-306.
[179] Shapira A, Benhar I. Toxin-based therapeutic approaches. Toxins, 2010 2: 2519-2583.
[180] Rowell PP, Larson BT. Ergocryptine and other ergot alkaloids stimulate the release of
[3H] dopamine from rat striatal synaptosomes. Journal of Animal Science, 1999, 77(7):
[181] Samuelsson G. Drugs of natural origin. 4th ed. Apotekar societeten. Stockholm, 1999.
[182] Eadie MJ. Ergot of rye-the first specific for migraine. Journal of Clinical Neuroscience,
20, 11 (1): 4-7.
[183] De Costa C. St Anthony's Fire and living ligatures: a short history of ergometrine. The
Lancet, 2002, 359: 1768-70.
[184] Nichols CD, Garcia EE, Sanders-Bush E. Dynamic changes in prefrontal cortex gene
xpression following lysergic acid diethylamide administration. Molecular Brain
Research, 2003, 111 (1-2): 182-188.
[185] Nichols CD, Sanders-Bush EA. Single dose of lysergic acid diethylamide influences
gene expression patterns within the mammalian brain. Neuropsychopharmacology,
2002, 26 (5): 634-642.
[186] Hart C. Forged in St. Anthony’s Fire: drugs for migraine. Modern drug discovery,
1999, 2 (2): 20- 31.
[187] Kupchan SM, Streelman DR, Jarvis BB, Dailey RG, Jr, Sneden ATJ. Isolation of potent
new antileukemic trichothecenes from Baccharis megapotamica. J Org Chem., 1977,
[188] Hughes BJ, Hsieh GC, Jarvis BB, Sharma RP. Effects of macrocyclic trichothecene
mycotoxins on the murine immune system. Arh. Environ. Contam. Toxicol, 1989, 18:
[189] Massaer F, Meucci V, Saggese G, Soldani G. High growth rate of girls with precocious
puberty exposed to estrogenic mycotoxins. J Pediatr; 2008, 152: 690-695.
[190] Kapoor VK. Natural toxins and their therapeutic potential. Indian Journal of
Experimental Biology., 2010, 8: 228-237.
... Aflatoxins undergo Phase I metabolism by oxidation reactions including epoxidation, hydration, hydroxylation and O-demethylation reactions involving the CYP 450 mainly in the liver to produce AFB 1 -exo-8,9-epoxide (AFBO), AFB 2a , AFM 1 , AFQ 1 and AFP 1 that are excreted in bile and urine after conjugation (Figure 1) [5,[8][9][10]. ...
... The depletion is also affected by aflatoxin due to uncoupling of metabolic processes due to the lack of GSH for GSH-peroxidase catalysis of O 2 to H 2 O 2 thus affecting the integrity of the cell membranes. Its reduction further enhances the damage to critical cellular components (DNA, lipids, proteins) by the AFB-8,9-epoxides that form adducts [10,14,24]. Aflatoxin-B 1 -8,9-oxide is also a substrate for several isoforms of human glutathione S-transferases (GSTs), which yield a stable, nontoxic, polar product that is excreted in the bile. ...
... There are two types of interaction recognized especially with nucleic acids involving non-covalent, weak and reversal binding and the other involving irreversible covalent binding requiring mammalian metabolizing enzyme systems. Aflatoxins targets protein synthesis pathways especially the DNA template, RNA template (mRNA, tRNA, rRNA), proteins, transcription, translation and cellular metabolic reactions ( Figure 5) [10,24,[32][33][34]. ...
Chronic consumption of aflatoxin-contaminated foods is a global problem in both developing and developed countries especially where there is poor regulation of their levels in foods. In the body, aflatoxins (AFBs) mainly AFB 1 are bio-transformed to various metabolites especially the active AFB 1-exo-8,9-epoxide (AFBO). The AFB, AFBO and other metabolites interact with various biomolecules in the body including nucleic acids such as DNA and RNA and the various metabolic pathways such as protein synthesis , glycolytic pathway and electron transport chain involved in ATP production in body cells. The AFB interacts with DNA to form AFB-DNA adducts causing DNA breakages. The AFB and its metabolites induce the up regulation of nuclear receptors such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR) through gene expression that regulates the metabolizing enzymes such as CYP450 involved in Phase I and Phase II metabolism of xenobiotics. AFB activates these nuclear receptors to produce the metabolizing enzymes. The AFB 1 is metabolized in the body by cytochrome P450 (CYP450) enzyme isoforms such as CYP1A2, CYP1A2, CYP3A4/ CYP3A5, and CYP3A7 in fetus, glutathione S-transferase, aflatoxin B 1-aldehyde reductase leading to reactive metabolites, some of which can be used as aflatoxin exposure biomarkers. These enzymes are involved in the Phase I and Phase II metabolic reactions of aflatoxins. The CYP1A2 is the principal metabolizer of aflatoxin at low concentrations while the reverse is true for CYP3A4. The accumulation of AFB and its metabolites in the body especially the AFB 1-exo-8,9-epoxide depletes the glutathione (GSH) due to the formation of high amounts of epoxides and other reactive oxygen species (ROS). The AFB, AFB 1-exo-8,9-epoxide and other metabo-lites also affect the epigenetic mechanisms including the DNA methylation, histone modifications , maturation of miRNAs as well as the daily formation of single nucleotide polymorphism (SNP) where AFB exposure may facilitate the process and induces G:C to T:A transversions at the third base in codon 249 of TP53 causing p53 mutations reported in hepatocellular carcinoma (HCC). The changes in epigenetic mechanisms lead to either epigenetic inactivation or epige-netic derepression and all these affect the gene expression, cellular differentiation and growth. AFB also through epigenetic mechanisms promotes tumorigenesis, angiogenesis, invasion and metastasis in hepatocellular carcinoma. However, the formation of the small amounts of AFB 1 from AFB 2 is suspected to cause the carcinogenicity of AFB 2 in humans and animals. Chronic afla-toxins exposure leads to formation of reactive AFBO metabolites in the body that could activate and deactivates the various epigenetic mechanisms leading to development of various cancers.
... The regulation of redox homeostasis includes different defense mechanisms to remove free radicals, such as enzymatic or non-enzymatic antioxidants [16]. These enzymatic antioxidants mainly use nicotinamide adenine dinucleotide phosphate (NADPH), which is primarily produced by the oxidative phase of the pentose phosphate pathway (PPP) [17], as a reducing agent to remove free radicals. Thus, current studies have linked aging with the oxidative phase of PPP since NADPH has been reported to protect species from redox stress, improve oxidative stress tolerance, and extend lifespan [18]. ...
Full-text available
Deregulation of redox homeostasis is often associated with an accelerated aging process. Ribose-5-phosphate isomerase A (RPIA) mediates redox homeostasis in the pentose phosphate pathway (PPP). Our previous study demonstrated that Rpi knockdown boosts the healthspan in Drosophila. However, whether the knockdown of rpia-1, the Rpi ortholog in Caenorhabditis elegans, can improve the healthspan in C. elegans remains unknown. Here, we report that spatially and temporally limited knockdown of rpia-1 prolongs lifespan and improves the healthspan in C. elegans, reflecting the evolutionarily conserved phenotypes observed in Drosophila. Ubiquitous and pan-neuronal knockdown of rpia-1 both enhance tolerance to oxidative stress, reduce polyglutamine aggregation, and improve the deteriorated body bending rate caused by polyglutamine aggregation. Additionally, rpia-1 knockdown temporally in the post-developmental stage and spatially in the neuron display enhanced lifespan. Specifically, rpia-1 knockdown in glutamatergic or cholinergic neurons is sufficient to increase lifespan. Importantly, the lifespan extension by rpia-1 knockdown requires the activation of autophagy and AMPK pathways and reduced TOR signaling. Moreover, the RNA-seq data support our experimental findings and reveal potential novel downstream targets. Together, our data disclose the specific spatial and temporal conditions and the molecular mechanisms for rpia-1 knockdown-mediated longevity in C. elegans. These findings may help the understanding and improvement of longevity in humans.
... Ochratoxin A binds plasma protein (albumin) which inadvertently aids its absorption [25]. e) Tricothecenes Trichothecenes are a large group of related chemical mycotoxic sesquiterpene compound produced by some species of Fusarium, Myrothecium, Trichoderma, Trichothecium, Cephalosporium, Verticimonosporium, and Stachybotrys [26]. These mycotoxins contain the 12, 13-epoxy ring with hydroxyl or acetyl groups in their structures that confers biological activities on them. ...
Full-text available
Abstract— Food shortage and contamination of the little available had been a challenge facing the African continent for centuries. Mycotoxins produced by fungi on agricultural produce all over the world are poisonous compounds, and these metabolites are stable under most food processing stages, and responsible for reduced food quality and value in addition to causing mycotoxicosis and other health conditions in man and animals, while the farmer loses huge profit due to rejected produce. It is generally accepted that the best way to eliminate the problems caused by mycotoxins is to engage in an effective prevention technique, while other methods such as detoxification and deactivation of already contaminated agricultural goods is another route that must be charted so as to be able to halt fungal infections and the resulting mycotoxicoses from the consumption contaminated feed, crops, and food products by animals a nd man. The use of high technique molecular equipment though ensures dependable results but are not readily accessible in quantifying the resulting outcomes in the African continent. The review is to raise the need for concerted effort at mitigating the losses and wastages resulting from fungal contamination
Full-text available
According to some estimates, at least 70% of feedstuffs and finished feeds are contaminated with one or more mycotoxins and, due to its significant prevalence, both animals and humans are highly likely to be exposed to these toxins. In addition to health risks, they also cause economic issues. From a healthcare point of view, zearalenone (ZEA) and its derivatives have been shown to exert many negative effects. Specifically, ZEA has hepatotoxicity, immunotoxicity, genotoxicity, carcinogenicity, intestinal toxicity, reproductive toxicity and endocrine disruption effects. Of these effects, male reproductive deterioration and processes that lead to this have been reviewed in this study. Papers are reviewed that demonstrate estrogenic effects of ZEA due to its analogy to estradiol and how these effects may influence male reproductive cells such as spermatozoa, Sertoli cells and Leydig cells. Data that employ epigenetic effects of ZEA are also discussed. We discuss literature data demonstrating that reactive oxygen species formation in ZEA-exposed cells plays a crucial role in diminished spermatogenesis; reduced sperm motility, viability and mitochondrial membrane potential; altered intracellular antioxidant enzyme activities; and increased rates of apoptosis and DNA fragmentation; thereby resulting in reduced pregnancy.
Conference Paper
Full-text available
Epstein-Barr virus (EBV) is a common human virus that was first identified in 1964 in Burkitt's lymphoma cells. It is estimated that over 90% of the population is infected with it, which plays a key role in the emergence and progression of many diseases of various etiology. This virus, after the acute phase of infection, persists in the human body until its death. Primary EBV infection is usually asymptomatic and in many cases occurs in childhood. EBV belongs to oncogenic viruses and is strongly correlated with the occurrence of Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal cancer or post-transplant lymphoproliferative disease. The aim of the conducted research is the detection of the virus in the inhabitants of Szczecin who lead different lifestyles. For this purpose, oral swabs were taken from the residents of Szczecin who are students of the University of Szczecin, and using the ready EXTRACTME DNA SWAB & SEMEN KIT (Blirt company), genetic material in the form of DNA was isolated. Then, the obtained material was subjected to qualitative tests using the Real-Time PCR technique. A total of 47 people samples were examined; the reaction was carried out in duplicate. An increase in fluorescence was observed during the reaction which meant that the results were positive. EBV gene expression is present in part of the samples.
This study assessed the removal of aflatoxin M1 (AFM1) and ochratoxin A (OTA) from artificially contaminated whole UHT milk and red grape juice, respectively, using biofilms from Lactobacillus rhamnosus GG. Using ELISA, the level of AFM1 and OTA removal from beverages was determined depending on various factors. Biofilms of various ages demonstrated varying degrees of AFM1 removal capacity from phosphate-buffered saline (PBS). Different levels of AFM1 contaminated whole UHT milk (0.1, 0.2, and 1 μg/L) and OTA contaminated red grape juice (2 and 4 μg/L) were tested in the detoxification process. The binding ability of mycotoxins was improved by increasing the biofilm surface area up to 70 cm². L. rhamnosus GG biofilm was effective in removing mycotoxins within a short contact time ranging from 1 to 10 min. The proportion of bound AFM1 and OTA by L. rhamnosus GG biofilm was 64.6 and 98.3% respectively. A new machine has been proposed and used as a trial for detoxication purposes which would be a promising application in liquid food industries.
Full-text available
Aflatoxin B1 (AF) is an unavoidable environmental pollutant that contaminates food, feed, and grains, which seriously threatens human and animal health. Arabic gum (AG) has recently evoked much attention owing to its promising therapeutic potential. Thus, the current study was conducted to look into the possible mechanisms beyond the ameliorative activity of AG against AF-inflicted hepatic injury. Male Wistar rats were assigned into four groups: Control, AG (7.5 g/kg b.w/day, orally), AF (200 µg/kg b.w), and AG plus AF group. AF induced marked liver damage expounded by considerable changes in biochemical profile and histological architecture. The oxidative stress stimulated by AF boosted the production of plasma malondialdehyde (MDA) level along with decreases in the total antioxidant capacity (TAC) level and glutathione peroxidase (GPx) activity. Additionally, AF exposure was associated with down-regulation of the nuclear factor erythroid2–related factor2 (Nrf2) and superoxide dismutase1 (SOD1) protein expression in liver tissue. Apoptotic cascade has also been evoked following AF-exposure, as depicted in overexpression of cytochrome c (Cyto c), cleaved Caspase3 (Cl. Casp3), along with enhanced up-regulation of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappa-B transcription factor/p65 (NF-κB/p65) mRNA expression levels. Interestingly, the antioxidant and anti-inflammatory contents of AG may reverse the induced oxidative damage, inflammation, and apoptosis in AF-exposed animals
Full-text available
Abstract: Aflatoxin B1 (AF) is an unavoidable environmental pollutant that contaminates food, feed, and grains, which seriously threatens human and animal health. Arabic gum (AG) has re�cently evoked much attention owing to its promising therapeutic potential. Thus, the current study was conducted to look into the possible mechanisms beyond the ameliorative activity of AG against AF-inflicted hepatic injury. Male Wistar rats were assigned into four groups: Control, AG (7.5 g/kg b.w/day, orally), AF (200 µg/kg b.w), and AG plus AF group. AF induced marked liver damage expounded by considerable changes in biochemical profile and histological architecture. The oxidative stress stimulated by AF boosted the production of plasma malondialdehyde (MDA) level along with decreases in the total antioxidant capacity (TAC) level and glutathione peroxidase (GPx) activity. Additionally, AF exposure was associated with down-regulation of the nuclear factor erythroid2–related factor2 (Nrf2) and superoxide dismutase1 (SOD1) protein expression in liver tissue. Apoptotic cascade has also been evoked following AF-exposure, as depicted in overexpression of cytochrome c (Cyto c), cleaved Caspase3 (Cl. Casp3), along with enhanced up-regulation of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappa-B transcription factor/p65 (NF-κB/p65) mRNAexpression levels. Interestingly, the antioxidant and anti-inflammatory contents of AG may reverse the induced oxidative damage, inflammation, and apoptosis in AF-exposed animals.
Full-text available
Cinnamaldehyde (Cin) is a natural product obtained from cinnamon and is reported to have a potential anti-fungal, anti-oxidant, anti-inflammatory and anticancer effect. The present study investigated the possible protective role of Cin against tenuazonic acid-induced mycotoxicity in the murine model. Tenuazonic acid (TeA), a toxin produced by Alternaria is a common contaminant in tomato and tomato-based products. Here, Swiss male mice were administered with TeA isolated from Paradendryphiella arenariae (MW504999) (source-tomato) through injection (238 µg/kg BW) and ingestion (475 µg/kg BW) routes for 2 weeks. Thereafter, the prophylaxis groups were treated with Cin (210 mg/kg BW). The experiment was carried out for 8 weeks. The treated groups were compared to the oral and intra-peritoneal experimental groups that received the toxin solely for 8 weeks. Haematological, histopathological and biochemical aspects of the experimental and the control mice were analysed. Sub-chronic intoxication of mice with TeA showed elevated malondialdehyde (MDA), reduced catalase (CAT) and superoxide dismutase (SOD) production; abnormal levels of aspartate transaminase (AST) and alanine transaminase (ALT). Treatment with Cin reversed TeA-induced alterations of antioxidant defense enzyme activities and significantly prevented TeA-induced organ damage. Thus, cinnamaldehyde showed therapeutic effects and toxicity reduction in TeA induced mycotoxicosis.
Full-text available
Background:Ochratoxin A (OTA) was one of the mycotoxins and received attention worldwide because of the hazard it posed to human and animal health, where the kidney was the primary target organ for OTA toxicity. In the other hand, dates served as a good source of natural antioxidants and could potentially be considered as a functional food. Methods:The study was performed in the department of biology in King Abdulaziz University. Animals were gavage administrated and divided into four groups: first group received (sodium bicarbonate), second group received (289 μg OTA /kg B.W. /day), third group received (1mg Ajwa/kg B.W. / day) and fourth group received (289 μg OTA /kg B.W./day+ 1mg Ajwa /kg B.W. / day).Serum (creatinine -urea)levels were measured in each group at the time of tissue collection , some biopsies were fixed in 10% buffered formalin solution for light microscopy processing stained with Haematoxylin and Eosin (H& E.), Periodic Acid-Schiff (PAS) and Masson ́s Trichrome (M.T.).Other biopsies were immediately collected into electron microscopy processing. Results:After 28 days, a significant decrease in body weight, kidney weight and relative weight was detected inOTAtreated group.Also, Serum(creatinine-urea) level were elevated .The normal cyto-architecture of proximal tubules were lost exhibiting damaged bruch border, degenerated, binucleated and karyomegalic cells. The most destructed ultra-structure was the mitochondria which severely swollen with disintegrated membranes. In Ajwa Date extract-group the proximal tubules were normal, whereas in Ajwa date extract +OTA-group the severity of the lesions was significantly reduced. Conclusion:The present results indicated that, Ajwa date have protective effects and ameliorated the lesions of Ochratoxin nepherotoxicity which might lead to kidney failure. Keywords: Ochratoxin A., Ajwa date, proximal tubules, light –structure, ultra –structure, biochemical analysis, morphometry.
Full-text available
The effects of sub-acute exposure (7 days) to aflatoxins and the potential protective effects of Lactobacillus rhamnosus GG ATCC53013 (LGG) were studied in male Albino mice. Four experimental groups were used, each comprising 30 mice; control group, LGG-treated group (1 × 1010 CFU), AFs-treated group (0.7 mg/kg b.w.), and a group given LGG two hours before AFs intoxication. The malondialdehyde (MDA), glutathione (GSH) levels and superoxide dismutase (SOD) activity were measured in liver and kidney tissues. Chromosomal aberrations in bone marrow and in spermatocytes, as well as mitotic and meiotic activities were performed to assess the genotoxicity; besides sperm parameters were evaluated. Results showed that AFs significantly elevated the tissue levels of MDA, whereas the levels of GSH as well as SOD activity were significantly decreased in liver and kidney. AFs increased significantly the frequencies of structural and numerical chromosome aberrations in bone marrow and spermatocytes. In addition, mitotic and meiotic activities of somatic and germ cells were declined significantly. Also, AFs caused a high significant reduction in cauda epididymal sperm count, sperm motility and significant increase sperm abnormalities, as compared to control. Mice received LGG before AFs gavage, showed a significant amelioration in oxidative status in both liver and kidney, by increasing the contents of GSH and SOD activity. Cytogenetic analyses revealed that LGG administration before AFs gavage significantly reduced frequencies chromosomal aberrations in bone marrow and spermatocytes, and recovered mitotic and meiotic activities as well. Moreover, gavage LGG before AFs intoxication caused significant recovery in all sperm parameters studied. In conclusion, LGG was found to be safe and successful agent counteracting the oxidative stress and protected against the genotoxicity induced by AFs, in addition to reduction in spermatotoxic alterations.
Several species of the genus Fusarium and related fungi produce trichothecenes which are sesquiterpenoid epoxides that act as potent inhibitors of eukaryotic protein synthesis. Interest in the trichothecenes is due primarily to their widespread contamination of agricultural commodities and their adverse effects on human and animal health. In this review, we describe the trichothecene biosynthetic pathway in Fusarium species and discuss genetic evidence that several trichothecene biosynthetic genes are organized in a gene cluster. Trichothecenes are highly toxic to a wide range of eukaryotes, but their specific function, if any, in the survival of the fungi that produce them is not obvious. Trichothecene gene disruption experiments indicate that production of trichothecenes can enhance the severity of disease caused by Fusarium species on some plant hosts. Understanding the regulation and function of trichothecene biosynthesis may aid in development of new strategies for controlling their production in food and feed products.
The mycotoxins are a diverse group of secondary fungal metabolites. The diversity of chemical structure suggests that toxic mold metabolites may have the potential to cause diseases either after ingestion or contact on the skin. The mycotoxicoses that result from exposure to these compounds may be expressed as dysfunction of nervous system, the liver, the kidneys or potentially many other organs. Clearly, fungal infestation is not a requirement for the production of mycotoxicoses. Although the ability of certain mycotoxins to alter renal function in man has been debated only relatively recently, human contact with fungal toxins is not a new experience. Bagger (1931) had suggested that the earliest encounter of human mycotoxicoses were the ergotism episodes of the Middle Ages. It is likely that earlier occurrences also happened, but undoubtedly the frequency of such occurrences has decreased considerably in modern times. With the development of modern storage techniques for food, fungal contamination, as well as contamination by other microorganisms, has been greatly reduced and often is not considered a serious problem. Indeed, although human mycotoxicoses have not been ignored in recent times, it is nonetheless true that a much greater effort has been expended to address the problem of fungal contamination of animal feeds.
Ochratoxin A is a dihydroisocoumarin derivate linked to an L-beta phenylalanine group that is produced by a number of Aspergillus and Penicillium species and is commonly found as a contaminant in a broad range of foods for human and animal use. In addition to being teratogenic, carcinogenic, mutagenic, and immunosuppressive, ochratoxin A is nephrotoxic. Porcine nephropathy due to ochratoxin A is a naturally-occurring disease characterized by proximal tubular dysfunction. Proximal tubular dysfunction also occurs in many other animals after administration of ochratoxin A. Histologic features consist of degenerescence of the tubular epithelium, interstitial fibrosis, pycnosis, karyorrhexis, and karyomegaly. Whether ochratoxin A is nephrotoxic in humans remains unsettled, although a case of acute renal failure has been reported recently. Two cases of chronic renal failure probably due to chronic exposure to ochratoxin A are described herein. Ochratoxin A may play a role in chronic karyomegalic interstitial nephropathy and in Balkan endemic nephropathy. More recently, ochratoxin A has been implicated in the occurrence of chronic interstitial nephropathy in North Africa.
Erogt, a potent neurotoxin and vasoconstriotor found in a fungus that grows on rye, was one of the first effective migraine medications and has been a spring-board for further migraine drug development.
This chapter discusses metabolism of zearalenone in farm animals. The subcellular distribution of the hepatic zearalenone-reducing activity in various female domestic animals has been investigated by incubating liver homogenate and its subcellular fractions with zearalenone and coenzymes (NADH or NADPH) + regenerating systems. The zearalenone-reducing activity was found to be distributed mainly to the microsomal and cytosol fraction. The distribution of the activities differed among female domestic species. In the pig, both α- and β-zearalenol formation were located mainly in the microsomal fraction, independently of coenzyme requirement. Cow and hen had the NADH- and NADPH-dependent α-zearalenol formation located in the microsomal fraction, but differed sharply from pig as regards the formation of β-zearalenol. With NADH as coenzyme, cow and hen did not form any detectable amounts of β-zearalenol and with NADPH the formation occurred only in the cytosol fraction. The distribution patterns of α- and β-zearalenol formation in the goat were similar to that found in the pig. Sheep differed from pig and goat as regards to the distribution of NADPH-dependent α-zearalenol formation, which was located mostly in the cytosol fraction.
Five-week-old female ICR:CD-1 mice were inoculated orally with 10 mg/kg b.w. of T-2 toxin. Hematological and blood biochemical examinations and histopathological examination of the liver were done up to 48 hours after treatment (HAT). In addition, microarray analysis was done on the gene expression profile of the liver at 0.5, 3 and 24 HAT. In the T-2 toxin-treated group, the levels of AST and ALT increased while those of total cholesterol, total protein, blood glucose and fibrinogen decreased at and after 3 HAT. The coagulation test revealed the prolongation of both prothrombin time (PT) and activated partial thromboplastin time (APTT). Histopathologically, dead hepatocytes were sporadically observed at and after 3 HAT. Dead hepatocytes at the early stage were characterized by cellular swelling and those at the late stage by pyknosis with condensed eosinophilic cytoplasm, respectively. Microarray analysis on the liver revealed the up-regulated expression of oxidative stress-, cell cycle- and apoptosis-related genes and the down-regulated expression of lipid metabolism-, glycogen metabolism-, drug metabolism- and blood coagulation-related genes. Especially, c-fos and c-jun mRNAs expression was significantly elevated immediately after T-2 toxin-treatment and kept high level until 24 HAT. The present study clarified that T-2 toxin affects liver function including blood coagulation system and that morphological characteristic of dead hepatocytes shifts from cellular swelling (necrosis) to pyknosis with condensed eosinophilic cytoplasm (apoptosis). From the results of microarray analysis, T-2 toxin was considered to damage hepatocytes mainly through oxidative stress and apoptosis.