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Oncotarget, 2017, Vol. 8, (No. 20), pp: 33933-33952
Review
T-2 mycotoxin: toxicological effects and decontamination
strategies
Manish Adhikari1, Bhawana Negi2, Neha Kaushik3, Anupriya Adhikari4, Abdulaziz
A. Al-Khedhairy5, Nagendra Kumar Kaushik1 and Eun Ha Choi1
1
Department of Electrical and Biological Physics, Plasma Bioscience Research Center, Kwangwoon University, Seoul, Republic
of Korea
2
Department of Molecular Biology and Genetic Engineering, G B Pant University of Agriculture and Technology, Pantnagar,
Uttarakhand, India
3
Department of Life Science, Hanyang University, Seoul, Republic of Korea
4
Department of Chemistry, Kanya Gurukul Campus, Gurukul Kangri Vishwavidyalaya, Haridwar, India
5
Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
Correspondence to: Eun Ha Choi, email: ehchoi@kw.ac.kr
Correspondence to: Nagendra Kumar Kaushik, email: kaushik.nagendra@kw.ac.kr
Keywords: trichothecenes, oxidative damage, apoptosis, herbal antioxidant compounds, decontamination
Received: December 22, 2016
Accepted: February 08, 2017
Published: February 16, 2017
Copyright: Adhikari et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ABSTRACT
Mycotoxins are highly diverse secondary metabolites produced in nature by a
wide variety of fungus which causes food contamination, resulting in mycotoxicosis
in animals and humans. In particular, trichothecenes mycotoxin produced by genus
fusarium is agriculturally more important worldwide due to the potential health
hazards they pose. It is mainly metabolized and eliminated after ingestion, yielding
more than 20 metabolites with the hydroxy trichothecenes-2 toxin being the major
metabolite. Trichothecene is hazardously intoxicating due to their additional potential
to be topically absorbed, and their metabolites affect the gastrointestinal tract, skin,
kidney, liver, and immune and hematopoietic progenitor cellular systems. Sensitivity
to this type of toxin varying from dairy cattle to pigs, with the most sensitive endpoints
being neural, reproductive, immunological and hematological effects. The mechanism
of action mainly consists of the inhibition of protein synthesis and oxidative damage
to cells followed by the disruption of nucleic acid synthesis and ensuing apoptosis.
In this review, the possible hazards, historical significance, toxicokinetics, and the
genotoxic and cytotoxic effects along with regulatory guidelines and recommendations
pertaining to the trichothecene mycotoxin are discussed. Furthermore, various
techniques utilized for toxin determination, pathophysiology, prophylaxis and
treatment using herbal antioxidant compounds and regulatory guidelines and
recommendations are reviewed. The prospects of the trichothecene as potential
hazardous agents, decontamination strategies and future perspectives along with
plausible therapeutic uses are comprehensively described.
that approximately 25% of the world’s agricultural
commodities are contaminated to some extend with
mycotoxins [2, 3]. Such studies revealing necessarily high
occurrences and concentrations of mycotoxins suggest
that mycotoxins are a constant concern. The synthesis
of mycotoxins very closely resembles those processes
that utilize primary metabolic pathways, such as amino
INTRODUCTION
Mycotoxins are a group of chemically assorted
compounds originating from the secondary metabolism of
molds (filamentous fungi) that causes many diseases. The
far, more than 300 mycotoxins have been found to induce
toxicological effects in mammals only [1]. It is estimated
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Table 1: Mycotoxins and its related fungus with contaminating foods.
Mycotoxin
Food Products
Related fungi
Cereals,
oil
seeds,
spices,
dry
fruits,
Aflatoxins
Aspergillus parasiticus, A. flavus
other nuts and corn
Fusarium moniliforme, F. culmorum, F. avenaceum, F.
Fumonisins
Mainly in cereals and corns
proliferatum, F. verticillioides, F. nivale, Gibberella fujikuroi
Ochratoxin
Cereals, legumes, coffee beans
Aspergillus ochraceus, Penicillium verrucosum/viridicatum
Aspergillus clavatus, A. giganteus, Penicillium expansum,
Patulin
Grapes, apples, other fruits
Botrytis, P. roquefortii, P. claviforme, P. griseofulvum, other
Penicillium and Aspergillus sp.
Fusarium moniliforme, F. equiseti, F. culmorum, F. solani, F.
Trichothecenes Wheat, corn
avenaceum, F. roseum, F. nivale Fusarium tricinctum, F. poae, F.
(T-2/toxins)
sporotrichiella, F. graminearum and other fungal species
acid and fatty acid metabolism. Toxin production and the
degree of contamination of feed and food commodities are
regulated by environmental factors such as the substrate
composition and the texture, temperature and humidity.
The genera of mycotoxin-producing fungi are Aspergillus,
Fusarium,
Penicillium,
Alternaria,
Phomopsis,
Emericella, Cephalosporium, Myrothecium, Trichoderma,
Trichothecium,
Neopetromyces,
Byssochlamys,
Neotyphodium and Claviceps. The adverse effect of fungal
products have instigated mass poisoning in both man and
farm animals in many countries [1]. The main mycotoxins,
the fungi producing them, and associated commodities are
presented in Table 1. T-2 toxins are agriculturally among
the most important mycotoxins that present a potential
hazard to health worldwide. These compounds are
derivatives of a ring system referred to as trichothecenes
[4]. T-2 toxins belong to a large family of chemically
related toxins produced by fungi in taxonomical genera
such as Fusarium, Myrothecium and Stachybotrys.
There are more than 20 naturally occurring compounds
produced by the Fusarium species with similar structures,
including diacetoxyscirpenol, nivalenol, deoxynivalenol,
the T-2 toxins, HT-2 toxin and fusaron X [5]. In this
review, we discuss the toxic effects of T-2 toxins on
agriculture, livestock and humans and also simultaneously
report safety information regarding survival against the
Figure 1: Schematic representation of T-2 toxin by its toxic and safe design.
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Figure 2: Structures of T-2 and HT-2 toxins (type A) and other trichothecenes (types B, C, and D).
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Table 2: Relative toxicity of different mycotoxins on different livestock species.
# = Slight toxicity ## = Adequate toxicity ### = High toxicity
Toxin
Poultry
Ruminants
Aflatoxins
###
#
Swine
##
T-2 toxins
##
###
###
Ochratoxin
###
#
#
Zearalenone
#
##
###
Fumonisin
#
#
###
Deoxynivalenol
#
##
##
harmfulness of these toxins (Figure 1).
very important in toxic-reducing pathway.
CHEMICAL STRUCTURE OF T-2 TOXINS
CHEMICAL
SYNTHESIS
PROPERTIES OF THE T-2 TOXIN
Trichothecenes have a tetracyclic sesquiterpenoid
12,13-epoxytrichothec-9-ene ring in common (Figure
2), and the 12,13-epoxy ring which is responsible for
the toxicological activity [6]. Their chemical structure
is characterized by hydroxyl (OH) group at the C-3
position, acetyloxy (-OCOCH0) groups at the C-4 and
C-15 positions, hydrogen at the C-7 position, and an esterlinked isovaleryl [OCOCH2CH(CH3)2] group at the C-8
position [7].
On the basis of characterized functional groups,
trichothecenes can be classified into four groups. Type
A trichothecenes are mainly represented by T-2 toxins
(henceforth T-2 or the T-2 toxin) and the HT-2 toxin (HT2) and do not contain a carbonyl group at the C-8 position
(Figure 2). In type B trichothecenes, a carbonyl group is
present at the C-8 position. The main representatives of
type B trichothecenes are deoxynivalenol and nivalenol
(Figure 2). Trichothecenes of type C (e.g., crotocin and
baccharin) have a second epoxy ring between C-7 and
C-8 or between C-9 and C-10. Trichothecenes of type
D, such as satratoxin and roridin, contain a macrocyclic
ring between C-4 and C-15. The T-2 toxin has ability to
undergoes microbial transformation and converts into its
deepoxylated form [8] (Figure 3) in the intestine which is
AND
T-2 is nonvolatile and resilient to degradation in
diverse environments, such as those with different light
and temperature levels, but it is deactivated easily by
strongly acidic or alkaline conditions. The synthesis of
T-2 starts from trichodiene, isolated from T. roseum [9]
and F. culmorum [10,11]. T-2 toxin prepared through the
sequence of oxygenations, cyclizations, isomerizations
and esterification of trichodiene in several laboratories in
the United States, Canada and England. Chemically, the
T-2 toxin is insoluble in water but soluble in acetone, ethyl
acetate, chloroform, ethanol, methanol and propylene
glycol, though it is stable in diverse environmental
conditions, even when autoclaved. T-2 may also be
decreased by the presence of coexisting bacteria or fungi
that can detoxify it by altering its chemical structure [12,
13, 14]. In order to achieve inactivation, it should be
heated to 900°F for 10 min or 500°F for 30 min [15].
HISTORICAL SIGNIFICANCE
In 1940, Soviet scientists coined the term
stachybotryotoxicosis to describe an acute syndrome
consisting of a sore throat, bloody nasal discharge,
Figure 3: Microbial transformation of trichothecenes into their de-epoxylated forms.
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Table 3: LD50 values of T-2 toxin in different animals with different administration pathways.
LD50
Species
Mode of administration
References
(mg/kg bw)
Mice
Oral
10
Ueno 1984
Mice
Intraperitoneal
5.2
Ueno 1984
Mice
Subcutaneous
2.1
Ueno 1984
Mice
Intravenous
4.2
Ueno 1984
Rats
Intraperitoneal
1.5
Creasia et al. 1990
Rats
Subcutaneous
1.0
Bergmann et al. 1985
Rats
Intramuscular
0.85
Chan et al. 1984
Rats
Intravenous
0.9
Fairhurst et al. 1987
Rats
Inhalation
0.05
Creasia et al. 1990
Guinea Pigs
Intraperitoneal
1.2
Creasia et al. 1990
Guinea Pigs
Intravenous
1-2
Fairhust et al. 1987
Guinea Pigs
Inhalation
0.4
Creasia et al. 1990
Rabbits
Intramuscular
1.1
Chan et al. 1984
7-days-old broilers
Oral
4
Hoerr et al. 1981
Pigs
Intravenous
1.21
Weaver et al. 1978
dyspnea, cough, and fever resulting from inhalation
of the Stachybotrys mycotoxin. The potential use of
the T-2 mycotoxin as a biological weapon was realized
during World War II in Orenburg, Russia when civilians
consumed wheat that was unintentionally contaminated
with Fusarium fungi. The victims developed a protracted
lethal illness with a disease pattern similar to that of
alimentary toxic aleukia (ATA). Twenty years after of this
incident, the trichothecene mycotoxin was discovered and
the T-2 toxin was isolated [16].
factors that are important in the production of mycotoxins
during the pre-harvest and post-harvest handling of
agricultural products [20] are as follows:
i. Intrinsic factors consisting of the moisture content,
water activity, substrate type, plant type and nutrient
composition;
ii. Extrinsic factors such as the climate, temperature,
and oxygen level;
iii. Processing factors including drying, blending,
the addition of preservatives, and the handling of grains;
iv. Implicit factors such as mainly insect interactions,
fungal strains, and the microbiological ecosystem.
ECOLOGICAL PREVALENCE AND
FACTORS
STIMULATING
TOXIN
PRODUCTION
ROUTES
OF
TRANSMISSION
T-2 and HT-2 toxins are predominantly found in
grains, such as wheat, maize, barley, rice, soybeans and
particularly in oats and products thereof [17]. The fungal
propagation and production of mycotoxins is enhanced
in developing countries around the world due to tropical
conditions like high temperatures and moisture levels,
monsoons, unseasonal rains during harvests and flash
floods. It has been reported that cereals grown in the
humid subtropical climate regions of China, Thailand,
Vietnam and South Korea can show evidence of the
prevalent growth of Fusarium sp. The production of
mycotoxins is enhanced by factors such as the humidity of
the substrate (10 to 20%), the relative humidity (≥ 70%),
the temperature (0 to 50°C, depending on the fungus
species) and the availability of oxygen [18]. Researchers
have noted that crops in tropical and subtropical areas are
more susceptible to mycotoxin contamination as compared
to those in temperate zones due to the presence of high
humidity and temperatures in tropical areas, which provide
optimal conditions for toxin formation [19]. The major
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EXPOSURE
AND
The trichothecene mycotoxins are readily absorbed
by various modes, including the topical, oral, and
inhalational routes. As a dermal irritant and blistering
agent, it is alleged to be 400 times more intoxicating
than sulfur mustard. Respiratory ingestion of the toxin
indicates its activity being comparable to that of mustard
or lewisite [21]. The T-2 mycotoxin is distinctive in that
systemic toxicity can result from any route of exposure,
i.e., dermal, oral, or respiratory [16]. Some insects such as
Sitobion avenae (aphid) help in transmitting the Fusarium
langsethiae inoculum to infect humans [22]. Transmission
can occur by direct exposure of contaminated objects and
surfaces that have not been appropriately decontaminated.
TOXICITY OF THE T-2 TOXIN
The trichothecene family boasts of a wide range
of toxins, and T-2 is one of the earliest investigated
and amongst the most toxic members of the family as
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compared to other mycotoxins (Table 2). The toxicity and
deleterious effects of T-2 vary on the basis of numerous
factors, such as the route of administration; the time and
amount of exposure; the dosage administered; and the age,
sex and overall health of the animal along with presence
of any other mycotoxin [23]. Intoxication often occurs
after feeding on feed made from grain, hay and straw,
wintering in the open and becoming contaminated with
F. sporotrichiella and F. poae. Poisoning in humans is
known as alimentary toxic aleukia. The toxins produced
by these species (T-2 and Diacetoxyscirpenol) have
a local irritant effect and cause serous hemorrhagic
inflammation; necrosis and ulceration in the digestive
tract; and dystrophy in liver, kidney, heart, brain and
peripheral ganglia of the vegetative nervous system.
Damage is seen in the blood vessel walls, and hemorrhagic
diathesis is provoked [24]. The T-2 toxin also helps in
inducing cytotoxicity and damage in mouse immature
Leydig cells (TM3) [25]. The metabolic pathways are also
altered in different organs, such as the spleen, thymus,
stomach and liver in Wistar rats after T-2 toxin exposure
[26]. The increased elevation of glutathione disulfide and
3-hydroxybutyrate suggest that the T-2 toxin promotes
an anti-oxidative response in organ systems and helps
with free radical generation. In addition, the depletion of
urinary l-methylniconate and 1-methylnicotinamide can
occur during cysteine biosynthesis (Figure 4). The T-2
toxin caused reductions of succinate and citrate in urine
and a reduced level of fumarate in the liver, accompanied
by an increase in NAD at high levels in rats exposed to
T-2, suggesting that T-2 lowers the rate of the tricarboxylic
acid (TCA) cycle. The results in Figure 4 suggest that the
T-2 toxin induces oxidative stress in rats exposed to the
T-2 toxin.
Acute toxicological effects
As described above, the effects of the toxin can
be revealed through multifarious means of exposure.
It is the only toxin in this family of toxins that can be
absorbed directly through the skin. The chiefly illustrative
Figure 4: Diagrammatic representation of altered metabolic pathways in different organs of Wistar rats followed by
T-2 toxin treatment. Metabolites shown in red or blue denote a significant increase or decrease in T-2 toxin treated rats with respect to
control rats. Metabolites shown in black denote no marked change. (Reproduced from Wan Q et al. 2015 Mol. Biosyst. with permission of
The Royal Society of Chemistry).
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Table 4: Table 4: Estimated daily intakelevels and total T-2 and HT-2 toxins present in cereals and cereal-based
products by assuming a body weight of 55 kg.
Samples
Consumption (g/day) Total Toxins present (µg/kg)
Brown Rice
Barley
Mixed Grains
Corn
Wheat
Wheat flour
2.92
6.71
4.6
0.03
0.02
3.95
48.3
26.4
30.2
63.0
39.8
34.1
symptoms of T-2 toxicity are emesis, vomiting, skin
blistering, loss of appetite and weight loss. Table 3 depicts
the probable exposure routes and LD50 values of the toxin
in various experimental models.
Studies have been conducted to assess acute
toxicity levels in various experimental models, including
mice, guinea pig, pigeons and rats which have been
administered the T-2 toxin using different exposure
routes, viz. subcutaneous, intratracheal, intravenous,
intraperitoneal, and intragastric [27]. It was observed that
rats administered the T-2 toxin exhibited elevated brain
concentrations of tryptophan and serotonin, which led to
an upsurge in dopamine and a consequential decline in
3,4-dihydroxyphenylacetic acid levels [28]. Additionally,
it was observed that as the concentration of dopamine
increased, epinephrine levels declined in adrenal glands.
This cascade reaction indicates that T-2 induces the
elevation of indoleamine levels in the brain, causing
animals to show feed refusal behavior [29]. The T-2
mycotoxin alters the development of mouse blastocysts,
reduces the number of blastomeres, and increases
chromatin damage [30]. However, T-2 along with the
HT-2 mycotoxin in laboratory animals fed a commercial
feed were not detected if the levels are between 250 and
2000µg/kg body weight [31]. An analysis of acute toxicity
studies in a rabbit model displayed pathological and
histopathological changes in the GI tract, bone marrow and
lymphocytes. In contrast, subacute toxicity demonstrated
catarrhal gastritis involving inflammation of the stomach
lining, hypertrophy and emaciation of adrenal cortex [32].
2.56
3.22
2.53
0.03
0.01
2.45
other symptoms are also associated with chronic toxicity,
including emaciation, necrosis in the lymphoid tissue and
subacute catarrhal gastritis in rabbits [34]. Consumption
of feed contaminated with T-2 has shown to reduce weight
gain and egg production as well as the egg hatching ability
in chickens. In addition, substantial declines in serum
cholesterol and total protein levels as well as elevations
in lactate dehydrogenase and uric acid levels in serum
samples were also reported in various studies [35, 36, 37,
38]. Another phenotypic alteration stemming from T-2
toxicity includes feather alteration in chickens [39]. The
toxic effect of T-2 administration was also evident in a
study of white Pekin ducks, which demonstrated a marked
decline in their weight gain ability with increasing T-2
toxin dose concentrations [40]. The study also revealed
that the blastogenic response of lymphocytes against
specific and nonspecific mitogens was also strikingly
impaired [41]. Hence, it is evident that T-2 had toxic
effects in animals, such as weight loss, decreased blood
cell and leukocyte counts, decreased plasma glucose
levels, and certain pathological effects and lining changes
in the liver and stomach. Additionally, T-2 is linked to an
increased infection rate, DNA damage and the induction
of apoptosis [29, 42, 43, 44, 45].
Effects on dairy cattle
Ruminants are known to be relatively resistant
to the T-2 toxin in comparison to monogastric animals.
The primary cause of this phenomenon is principally
considered to be the de-epoxidation and de-acetylation
activity in the rumen for the protection of cows against
T-2-induced toxicity [46]. After absorption in stomach, the
toxic symptoms are dominated by the cytotoxic action on
the bone marrow. T-2 toxin exposure has been associated
with feed refusal, production losses, gastroenteritis lesions,
intestinal hemorrhages and death in dairy cattle. The
lesions in the oral cavity are weaker - only hyperaemia
and edema of the oral mucosa are usually seen, whereas
hyperaemia and hemorrhaging of the mucosa of the
abomasus are often present. Tremors and paralysis of the
hind limbs are often seen, but the haemorrhagic diathesis
is less pronounced than in cases involving other species
Chronic toxicological effects
Chronic effects of exposure to the T-2 toxin were
characterized in female rats as an upsurge in tyrosine and
serotonin levels in the cerebellar region. In addition, an
elevation in cortical tryptophan levels was also observed,
indicating variation in the T-2 toxin mode of action in
terms of chronic effects, in contrast to acute administration
behavior [33]. It was observed that while an acute
systemic T-2 treatment elevated tryptophan levels, a
decline in serotonin levels was noted simultaneously in
the cerebellar and brainstem regions [33]. Numerous
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Estimated daily intake [ng/kg bw/day]
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[47]. It has also been assumed to exert reduced immune
responses in calves. Various studies have reported that the
toxic effects of T-2 toxin result in bloody feces, enteritis,
abomasal and ruminal ulcers, and death. Symptoms such
as decreased milk production and the absence of estrus
cycles in cows have also been attributed to exposure of
T-2. Serum immunoglobulins, complement proteins, and
white blood cell and neutrophil counts were demonstrated
to be lower in calves exposed to the T-2 toxin [48].
Experimental evidence shows that lambs fed the T-2 toxin
develop symptoms of focal hyperemia and dermatitis at
the mucocutaneous junction of the commissure of the
lips, along with diarrhea, leukopenia, lymphopenia and
lymphoid depletion of mesenteric lymph nodes and the
spleen [46].
impairment of immune responses, destruction of the
hematopoietic system, declining egg production, the
thinning of egg shells, refusal of feed, weight loss and
altered feather patterns, abnormal positioning of the
wings, hysteroid seizures or an impaired righting reflex
[49, 50]. It has been reported that poultry are relatively
less susceptible to trichothecenes than pigs. The seroushaemorrhagic necrotic-ulcerative inflammation of the
digestive tract with thickening of the mucosa, a lurching
gait/step, and refusal of food due to oral lesions are the
main symptoms observed. It was observed that acute
intoxication of broiler chickens exhibits consequences
consisting of internal hemorrhaging, mouth and skin
lesions (necrohemorrhagic dermatitis), impaired feather
quality and neural disturbances [51]. Significantly
reduced levels of haemoglobin and the packed cell
volume in intoxicated broiler chicks have been observed
at low doses as well. Decreases in serum total protein and
cholesterol levels and increases in serum uric acid and
lactate dehydrogenase levels were also exhibited upon
T-2 exposure, hence conclusively indicating that toxic
Effect on poultry
In poultry, the T-2 toxin has been the causative
agent for mouth and intestinal lesions in addition to the
Figure 5: The impact of T-2 mycotoxins on the human intestinal gut region against infection by salmonella. (Reproduced
from Antonissen et al., 2014, with the permission of the Toxin Journal).
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effects of T-2 are evident on performance, biochemical
and immunological parameters even at very low levels
in broiler chicks [38, 52]. A patho-histological survey
usually reveals fatty changes/dystrophy and strong
granular degeneration in the liver, kidneys and rarely in
the heart. Necrosis in the digestive tract is superficial.
In chronic stages, interstitial nephritis, kidney sclerosis
and glomerulonephritis are seen, and the necroses in the
stomach and intestines become profound [47].
HT-2 toxin exposure causes oxidative stress which induces
apoptosis/autophagy in porcine oocytes [54]. Additionally,
toxin exposure can have reproductive and teratogenic
effects but exerts no carcinogenic effect [51].
Effects on horses
In addition to the described symptoms of ulceration
and necrosis of the mouth mucosis, gray-white coatings
on the tongue and palate, spasms and tremors of some
muscles, and occasional paresis of the hind limbs have
been seen [47]. Despite studies of the contamination of
cereals and animal feed with trichothecenes [55, 56], little
is known about the characteristics of equine exposure to
these mycotoxins [57, 58, 59]. The long-term effects of
the administration of T-2 toxins in mares were evaluated
with a daily oral dosage of 7mg of the pure T-2 toxin for
32-40 days. No effects on fertilization or ovarian activity
were detected in mares, though oral lesions were detected
in some cases [60].
Effects on pigs
Along with the serous-haemorrhagic necroticulcerative inflammation of the digestive tract, some
necroses are established on the snout, lips and tongue,
edema and mucous coatings of the mucosa of the stomach,
swelling in the region of the head, especially around the
eyelids and larynx, and rarely, paresis or paralysis are seen
[47].
Toxic effects of the T-2 toxin are usually manifested
in the form of alimentary toxic aleukia (ATA) in pigs.
The symptoms include vomiting, diarrhea, leukopenia,
hemorrhage, shock and death. Acute toxicological effects
are also characterized by multiple hemorrhages of the
serosa of the liver and along the intestinal tract, stomach
and esophagus (at necropsy). The presence of blood
was reported in intestines and in the abdominal cavity,
and a cream-colored paste was noted on the lining of
the esophagus and the ileum [18]. Low dosage chronic
exposure resulted in growth retardation, weight gain
suppression and feed refusal [51]. Variation in exposure
levels to the toxin also exerts diverse effects on the immune
system of animals. For instance, low concentrations
induce pro-inflammatory gene expression at the mRNA
and protein levels, whereas high concentrations have been
observed to promote leukocyte apoptosis [51].
Experimental evidence indicates that exposure to the
T-2 toxin results in lesions in the stomach associated with
congestion, hemorrhages and the presence of necrotic cells
in the isthmus and neck regions. Symptoms of submucosal
edema and necrotic crypt epithelial cells were observed
in the duodenum, jejunum, ileum, cecum and colon, with
the most severe lesions being in the colon. The same
study indicated higher lymphocyte depletion and necrosis
levels in the lymph node cortex region as compared to the
paracortex. Apoptotic bodies were observed in intestinal
crypt cells, lymphoid cells from the lamina propria, and
ileal Peyer’s patches, indicating apoptosis as the major
mechanism of action involved in intestinal lesions due to
T-2-induced toxicity [53]. T-2 contamination of feedstock
has been reported to result in decreased red blood cell
counts, and decreases in the MCV and hemoglobin levels
of red blood cells. A significant reduction in the number
of T lymphocytes was also observed. Feed contamination
also has an inhibitory effect on the ovaries, with
histological degeneration and accompanying atrophy [18].
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MECHANISM OF ACTION
The T-2 toxin have thiol group makes it a potent
protein and DNA synthesis inhibitor [23]. It also reduces
lymphocyte proliferation, alters the membrane function,
impairs the production of antibodies and alters the
development of dendritic cells [61]. The T-2 toxin causes
apoptosis in various cell types in vitro, such as human
liver cells, HL-60 cells, Jurkat cells, U937 cells, and Vero
cells. Deleterious effects are also manifested in a mice
model, exhibiting apoptosis in various tissues and organs
including the skin, kidney, brain and bone marrow [16].
The appearance of these manifestations constitutively
is mainly due to oxidative damage to cells that targets
biomolecules such as lipids, proteins and nucleic acids.
The main ROS involved in the oxidation of proteins,
lipids and DNA appear to be hydrogen peroxide, hydroxyl
radical and superoxide molecules. The mitochondrial
complex I and CYP450 have also been reported to be
involved in mycotoxin-induced ROS generation [62].
Furthermore, the T-2 toxin can decrease the function of
the innate immune system [63].
Typically, the T-2 toxin is hypothesized to bind
and inactivate peptidyl-transferase activity at the
transcription site [64], resulting in the inhibition of protein
synthesis [16]. The most prominent molecular target of
trichothecenes includes the 60S ribosomal unit, where it
prevents polypeptide chain initiation [51]. This inhibitory
effect is most prominent in actively proliferating cells,
for instance those of the skin and gastrointestinal tract,
the bone marrow and thyroid, and erythroid cells [65].
Moreover, the T-2 toxin is believed to disrupt DNA
polymerases, terminal deoxynucleotidyl transferase,
monoamine oxidase and several other proteins involved in
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the coagulation pathway [66]. This toxin has been shown
to decrease the colonization capacity of Salmonella in pigs
[67]. The T-2 toxin enhances the uptake of Salmonella
in macrophages via the activation of the mitogenactivated protein kinase (MAPK) extracellular signalregulated kinase (ERK1/2) pathway, which induces actin
reorganization and membrane ruffles (Figure 5).
The mechanism of action of trichothecenes
involves the interaction of the toxin with subcellular
structures, resulting in the disruption of the mitochondrial
morphology, rough endoplasmic reticulum and other
membranes [16]. They act upon and hinder the activity
of metabolically critical enzymes such as succinic
dehydrogenase, consecutively impeding cellular energetics
by decreasing the oxidation of succinate, malate and
pyruvate molecules and additionally inhibiting protein
synthesis in mitochondria [23]. Moreover, the ability
to cross the placenta and damage mouse fetuses via the
acceleration of cell death by apoptosis in the immune
system and other tissues has also been documented in the
trichothecenes family [68]. However, oxidative stress due
to the T-2 toxin in rat hepatocytes can be reduced using
l-carnitine [69]. It also regulates steroid hormone secretion
through the cAMP-PKA pathway in rat ovarian granulosa
cells [70].
GENOTOXIC AND CYTOTOXIC EFFECTS
The T-2 toxin is known to impact the synthesis
of biomolecules such as DNA, RNA and proteins, thus
inhibiting cellular functions such as the cell cycle and
resulting in apoptosis [42] [71]. Due to its structural
distinctiveness along with the HT-2 toxin, unlike other
trichothecenes, it impedes protein synthesis by inhibiting
the polypeptide chain initiation process. Toxicity of the
T-2 toxin on living beings has been stated in terms of its
deleterious effects on lymphoid cells and its diminishing
effects on the immune system [72].
The toxin primarily exerts effects similar to those of
a radiation injury by negatively impacting protein levels
and RNA and DNA synthesis processes [72, 61]. Studies
involving Chinese hamster V79 cells have indicated that
it induces micronuclei formation, gene mutations and
sister chromatid exchanges and also results in hindering
intercellular cross-talk.
Figure 6: Role of the T-2 toxin in causing ROS-mediated caspase-dependent and independent apoptosis in human cells.
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selenium chondroitin sulfate nanoparticles (SeCS) can
partly block apoptosis by decreasing the expressions of
ATF2, JNK and p38 mRNAs and the p-JNK, p-38, ATF2
and p-ATF2 proteins [79].
Apoptosis
The ERK1/2 pathway and the JNK/p38 MAP
kinase pathway activated by stress responses play a
pivotal role in determining the prospects of cell survival
or the undergoing of apoptosis. Hence, maintenance
of homeostasis amongst these pathways is essential
for cellular survival. However, the T-2 toxin and its
metabolites have been observed to induce apoptosis by
the activation of c-Jun N-terminal kinase 1 (JNK1) and/
or p38MAPK (SAPK2), also triggering the stimulation of
MAP kinases involved in regulating cellular proliferation
of, for instance, ERK1/2 [73]. Another group of scientists
found an additional pathway in which the T-2 toxin
generates pro-apoptotic conditions in the cellular milieu by
initiating a cascade reaction involving Fas up-regulation
on chondrocyte surfaces, followed by the up-regulation of
p53 proteins which in turn increases the Bax/Bcl-2 and
Bax/Bcl-xL ratios, simultaneously activating the caspase3-dependent apoptotic pathway [74]. T-2 toxin along with
satratoxin G induce DNA damage that involves activation
of ATM pathway which alter checkpoint kinase Chk2 [75]
and leads to apoptosis. A separate study has established
that deleterious effects of the T-2 toxin are intermediated
by ROS generation which contributes to DNA damage and
enhancement of the p53 protein expression in HeLa cells
(Figure 6).
This p53 protein activation causes an alteration
of the Bax/Bcl-2 ratio, leading to caspase-dependent
apoptosis mediated by a mitochondrial Cyt-c release [76].
In addition, Figure 6 demonstrates that HeLa cells exposed
to the toxin are damaged by the autonomous activation
of the AIF pathway independent of the caspase cascade,
subsequently causing DNA fragmentation, apoptosis and
eventually cell death [76].
DETERMINATION OF THE T-2 TOXIN:
METHODS AND TECHNIQUES
Several methods for the determination of the T-2
toxin based on traditional chromatographic, immunoassay,
or mass spectroscopy (MS) techniques have been studied
thus far [68]. Gas-liquid chromatography (GLC) and highpressure liquid chromatography (HPLC) with MS may be
used to assess the presence of T-2 and related trichothecene
mycotoxins in plasma and urine samples [80]. 50-75% of
the ingested toxin and metabolites are eliminated in the
urine and feces within 24 hours. Early post-exposure (024 hours) nasal or throat swabs and induced respiratory
secretions can be used for detection by HPLC/GLC/MS
and immunoassay methods. During the last decade, liquid
chromatography with mass spectrometry has become the
most recurrently used technique for the determination of
T-2 and HT-2 toxins, often within a multi-analyte approach
[17]. Hence, the estimated daily intakes were found to be
2.56, 3.22, 2.53, 0.03, 0.01 and 2.45 ng (kg bw), for brown
rice, barley, mixed grains, corn, wheat and wheat flour,
respectively (Table 4) [81].
Bio-distribution and pathophysiology
The T-2 toxin has widely been reported to be
toxic to plants, mammals including humans, and in the
dietary content for both vertebrates and invertebrates
[82]. The magnitude of toxin injury is dependent on the
administered dose and route of administration. It is readily
absorbed, metabolized and nearly entirely excreted (8090%) within 48 hours after ingestion and is uniformly
distributed thoroughly the body without specific affinity
for accumulation in any organ [62]. It has been observed
in rodents that plasma concentrations attain peak levels
after approx. 30 minutes. In one study, it was observed that
upon radioactively tagging of the T-2 toxin, its half-life is
less than 20 minutes in plasma. Furthermore, four hours
after IV administration in pigs, 15-24% of the radioactivity
was found in the GI tract and 4.7-5.2% in various other
tissues such as the liver and muscles. The rapid onset of
symptoms in minutes to hours supports a diagnosis of a
chemical or toxin attack. Symptoms of T-2 toxicity are
evidenced most frequently as reduced feed intake, weight
loss, skin irritation, itching, diarrhea, bleeding, feed
refusal, dyspnea, and vomiting [83,71] and range critically
to haemorrhages and necrosis in the GI tract, reproductive
organs and hematopoietic organs such as the bone marrow
and spleen [61]. T-2 has also been reported to exert an
important impact on reproductive performance in pigs
Inhibition of T-2-toxin-induced apoptosis
The T-2 toxin has been documented to induce
apoptosis in human chondrocytes via Bcl-2 and Bax
proteins. Additionally, it is well known that the Bax/Bcl-2
ratio pathway plays a pivotal role in determining cellular
susceptibility to undergo apoptosis. It has been found
that selenium can partly block chondrocyte apoptosis
induced by the T-2 toxin by reducing the Bax/Bcl-2 ratio
[77]. Another independent study ascertained that nanoSe-chondroitin sulfate can inhibit the T-2-toxin-induced
apoptosis of cultured chondrocytes derived from KashinBeck disease (KBD) patients in vitro [78]. A further
assessment of T-2-toxin-induced chondrocyte apoptosis
elucidated that increased levels of ATF2, JNK and p38
mRNAs and related protein expression levels play a vital
role in apoptosis induction. It was also noted that the JNK
and p38 pathways were involved in the apoptosis induced
by the T-2 toxin in chondrocytes. It was revealed that
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that are believed to be efficacious against the T-2 toxin.
The protective properties of antioxidants are most likely
due to their superoxide anion scavenging ability, thereby
protecting the cell membrane from mycotoxin induced
injury [87]. It has been described that lycopene protects the
liver against the T-2 toxin by reducing lipid peroxidation
and modulating GSH metabolism in vivo [88]. It has also
been reported that rutin can be used as an antioxidant
in cases of T-2 toxicity in the liver of rats, as it aided
in decreasing TBAR-induced lipid peroxidation, SOD,
GST, total lipids and elevated total thiol and catalase
levels as well as hemoglobin and hematocrit values
[89]. It has been reported that lipid peroxides are formed
in vivo by T-2 and that these effects can be partially
counteracted by antioxidants such as vitamin E, though
vitamin C is unable to exert the same protective effects
[90]. Independent investigations have revealed that
Hippophae rhamnoides (sea buckthorn) alone protected
the immunosuppressant action of the T-2 toxin, but sea
buckthorn and glucomannan in combination provided a
synergistic effect with regard to protection against T-2
toxicity [91]. Researchers have indicated that owing to its
natural healing potential, mucilage from quince seeds is a
potential treatment of T-2-toxin-induced dermal injuries
in rabbits [92].
If the toxin has been ingested orally, then superactivated charcoal can be utilized, as it adsorbs the
ingested toxin and removes it from the GI tract, thus
diminishing the ill effects of the toxin preventing it from
causing cellular damage. Despite the fact that a variety
of different strategies to combat mycotoxicosis have been
established, the basis of the most encouraging methods
consists of the addition of adsorbents to contaminated
feed. The adsorbent material selectively binds toxins
during digestion, preventing their absorption from the
gastrointestinal tract and therefore decreasing their toxic
effects. Researchers have demonstrated that a combination
of modified glucomannan with organic selenium provides
protection against the detrimental consequences of the
consumption of T-2-toxin-contaminated feed resulting in
toxin-induced antioxidant depletion and lipid peroxidation
in the livers of chicken or hepatocytic cells [93, 94]. It has
also been reported that small increases in the concentration
of sodium selenite can confer highly significant protection
against oxidative damage [95]. If natural remedies become
ineffective, antifungal treatments may be prescribed
on rare occasions. It has been reported that treating rats
with Goji extract or charcoal can ameliorate the adverse
effects of the T-2 toxin, but it was observed that Goji
extract can be used as an antioxidant and antidote in place
of charcoal against the T-2 toxin in mice [96]. However,
several other complex mechanisms can also be utilized,
which may involve modulation of metabolic detoxification
pathways intercepting the action and formation of stable
non-toxic complexes, and compounds having some degree
of structural similarity between mycotoxin and protective
[18]. Its toxicity varies according to its route of exposure,
whereby it is highly toxic when ingested through the lungs
as compared to other modes of ingestion [16]. Long-term
effects range from mycotoxicosis (domestic animals), ATA
(humans), inflammation of the GI mucosa, abdominal
pain, vomiting, diarrhea, headache, generalized weakness,
increased salivation, fatigue, and dizziness resulting in
opportunistic secondary infections such as pneumonia.
Effects on the immune system
T-2 toxin exposure results in leukopenia and
cell depletion in lymphoid organs. It also inhibits
erythropoiesis in the bone marrow and spleen and
significantly impairs antibody production, reducing the
proliferative response of lymphocytes and hindering the
development of dendritic cells [61]. The T-2 toxin is also
reported to inhibit IL-2 and IL-5 production by T cells.
In addition to lymphocyte precursors, trichothecenes
targets also include other hematopoietic progenitors,
such as granulocyte, monocyte and erythrocyte colonyforming cells [72]. It has been observed that CD4/CD8
double-positive T cells from the thymus of young mice
are highly sensitive to the T-2 toxin and that CD44low
and CD45low cells, which are B lymphocyte precursors,
are also highly sensitive to the T-2 toxin. Additionally, it
has been documented to diminish immunoglobulin and
cytokine levels. Studies have shown that prolonged lowdose exposure to this toxin can influence memory T cells
and can have an adverse effect on the humoral response
mediated by B lymphocytes and the secondary immune
response in pigs [61]. It has also been established that
the ingestion of low concentrations of the T-2 toxin alters
TLR activation by decreasing the pattern recognition
of pathogens, thus interfering with the initiation of
inflammatory immune responses against bacteria and
viruses [84]. The development of the immune-affinity 96spot monolith array and high-sensitive chemiluminescent
immunoassay investigation methods are highly promising
means of detecting multiple mycotoxins in food samples
[85, 86].
Prophylaxis against the T-2 toxin: exploring
herbal routes
The deleterious effects of exposure to the T-2 toxin
can be minimized by means of detoxification remedies
with natural substances. The consumption of a diet
rich in probiotics, nutrients consisting of amino acids,
enzymes, and lipids can aid in alleviating the symptoms
of T-2 toxin damage. Several natural compounds, such
as vitamins, provitamins, carotenoids, chlorophyll and
its derivatives, phenolics, and selenium and synthetic
compounds including butylated hydroxyanisole and
butylated hydroxytoluene, have antioxidant properties
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agent molecules could aid in protection if assisted by
competitive inhibition [87].
addition, the established value is 2 ppm for oat milling
products (husks) for feed and compound feed [99].
The maximum EU permitted content of T-2+HT-2
mycotoxins in human food (EC Regulation No 1881/2006
and EC Recommendation 2013/165/EU) ranges from
0.015 ppm for cereal-based foods for infants and young
children; 0.025 ppm for bread and bakery wares, pastries,
biscuits, cereal snacks or pasta; and 0.075 ppm for
breakfast cereals including formed cereal flakes up to 0.05
ppm for cereal milling products and 0.1 ppm for cereal
bran apart from oat bran, oat milling products other than
oat bran, flaked oats and maize milling products, and
0.2 ppm for oat bran and flaked oats designed for direct
human consumption [99]. However, no monitoring limits
of T-2+ HT-2 coexist in North America, Latin America,
or in the Asia/Oceania regions, including South Korea.
T-2 and HT-2 toxin exposure levels in dietary contents
were calculated using occurrence data retrieved from this
study in 2009, mean body weights from the Korea Food
and Drug Administration, and food consumption data from
the Korean National Health and Nutrition Examination
Survey (KNHANES 2008). Estimated daily exposure
levels to T-2 and HT-2 toxins were calculated using the
following formula:
REGULATORY GUIDELINES AND
RECOMMENDATIONS
Due to the prevalence of the T-2 toxin in animal
feed, several countries have formulated guidelines
stipulating the maximal permissible limits of the toxin in
products for animal use. China has limited the presence of
the toxin in animal feed to 0.08 mg/kg, Iran and Canada
have set the value for cattle animal feed to 0.1 mg/kg,
while Canadian feed for poultry and swine has a maximal
limit of 1.0 mg/kg of the T-2 toxin [97]. Currently, biochip
array technology is in use for rapid multi-mycotoxin
screening, including the screening of the T-2 and HT-2
toxins [98].
In the European Union, the maximum permitted
content of T-2+HT-2 mycotoxins in feedstuffs (EC
Directive 2002/32/EC, and EC Recommendations
2006/576/EC and 2013/165/EU) ranges from 0.1 ppm
(mg/kg) for unprocessed wheat, rye and other cereals
and 0.2 ppm for unprocessed barley (including malting
barley) and maize up to 0.25 ppm for compound feed
with the exception of feed for cats and 0.5 ppm for other
cereal products designed for feed and compound feed. In
Figure 7: Three targeting strategies in a T-2-toxin-based therapy. (Reproduced from Shapira A 2010 with the permission of the
Toxin Journal).
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However, as compared to other mycotoxins, data
pertaining to the occurrence of T-2 and HT-2 toxins in
cereals and related products are very limited in South
Korea [100, 81].
A number of strategies have been developed in an
effort to inhibit the detrimental effects of the T-2 toxin.
These include reducing the growth of mycotoxigenic fungi
and reducing mycotoxin production, the detoxification
of contaminated feed, and lowering the systemic
availability level as soon as mycotoxins are ingested by
an animal. Different types of radiation, i.e., γ-irradiation,
X-rays, and ultraviolet light, have been explored for the
decontamination of some mycotoxins, including the T-2
mycotoxin [101], and for their ability to control the growth
of certain fungi [102,103], but these also have several
disadvantages because radiation is effective only when
applied to a thin layer of grain [104]. There are many
energy inhibitors like sodium azide, 2-deoxy glucose,
2-4 dinitrophenol, ouabain which are well known to
antagonize the uptake of T-2 toxin in murine lymphocytes.
The inhibitors decreased the toxin level upto 40% by
binding to High affinity site of T-2 toxin [105].
Additionally, post-harvest storage conditions
also play a pivotal role in preventing mold growth and
mycotoxin production. For instance, grains should be
stored under conditions with moisture content levels of
no more than 15% so as to avoid the formation of hotspots
with high moisture, thus encouraging mold growth [51].
Hence, mycotoxins pose a grave public health hazard
due to their deleterious side effects and the fact that they
pose a severe threat to humans upon the consumption of
residual traces in animal-derived food products originating
from animals feeding on contaminated feedstuff [97].
symptoms in cases of lethal casualties include necrosis of
the affected skin area accompanied by leathery blackening
and sloughing off of exposed skin areas.
Interaction with the respiratory system initiates upon
nasal contact and causes itching, pain, epistaxis, sneezing
and rhinorrhea, which further advances the manifestation
of pulmonary/tracheobronchial toxicity by exhibiting
difficulty in breathing and coughing and wheezing. Oral
and throat exposure to the toxin causes pain and bloodladen saliva and sputum. Ingestion of the toxin via the
GI system leads to symptoms such as nausea, vomiting,
anorexia, diarrhea associated with cramps and abdominal
pain. If the toxin comes into contact with the eyes, it may
result in redness and pain in the eyes, blurry vision, and
a feeling of foreign body sensation. Following immediate
effects, symptoms displaying systemic toxicity are
manifested as generalized prostration, fatigue, weakness,
dizziness, loss of coordination and ataxia. Fatal cases
are the consequences of symptoms such as hypothermia,
tachycardia, and hypotension resulting in death in a short
span of time ranging from minutes to days [97].
Isolation and decontamination
After T-2 toxin exposure, standard precautions
should be taken according to set guidelines so as to
minimize secondary exposure and damage. These consist
of the removal of outer clothing and decontamination of
exposed skin areas using soap and water. Eye contact
with the toxin should be treated with profuse washing
of the eyes with saline. Subsequently, isolation is nonessential after adequate exhaustive decontamination.
Decontamination of the surrounding environments
involves treatment with an alkaline hypochlorite solution
(viz. 1% sodium hypochlorite and 0.1M NaOH) for
a sufficient contact time interval. Porous substances
with human exposure can be decontaminated only by
meticulous UV light and an ozone exposure treatment.
A RSDL (reactive skin decontamination lotion) kit
is a topical decontamination solution that minimizes
toxic effects from exposure to chemical warfare agents
(VX and HD) and the T-2 toxin [106]. T-2 and other
fabricated mycotoxins were assessed with immune-affinity
monolithic arrays, which were proved as a sensitive, stable
and economical tool to be used with food samples [85]. An
alternative approach to lessen the degree of toxin exposure
in feed is to decrease the level of bioavailability via the
inclusion of mycotoxin detoxifying agents (mycotoxin
detoxifiers) in the feed. These detoxifiers are mainly
categorized into two different classes, i.e., mycotoxin
binders (agents that adsorb the toxin in the gut, resulting
in the excretion of the toxin-binder complex in feces)
and mycotoxin modifiers or mycotoxin biotransforming
agents (including microbes such as bacteria, fungi, yeast
and enzymes that transform the toxin into non-toxic
metabolites biologically) [51]. The adverse effects of the
Potential hazardous agent
The T-2 toxin can act as a hazardous agent given
that it can be absorbed via intact skin and cause blistering,
irritation and systemic toxicity. The promptness of the
toxic effect is evident by the fact that symptoms can
begin to appear within seconds of exposure, though the
demonstration of lethal effects requires a larger dosage
of the T-2 toxin. It is a potentially critical biological
warfare agent candidate, as the mode of ingestion of the
T-2 toxin ranges diversely from food or water sources to
various air-dispersal modes, including aerosols, droplets
or smoke emanating from explosions. The LD50 of the T-2
toxin has been reported to be approximately 1 mg per kg
of body weight. The T-2 toxin has been documented to
have been used worldwide in various military conflicts
during the period of 1975-81, and the aerosolized form
has since widely become known as “yellow rain,” having
been causally linked to thousands of casualties [97].
Primary symptoms of affected individuals immediately
after exposure include skin blistering, a burning sensation,
pain, pruritus, tenderness, and inflammation, and advanced
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T-2 toxin are also reversed by the potential use of selenium
and vitamin E on peripheral blood B lymphocytes [107].
that are biologically and ethically appropriate for
industrial-scale enzyme production and purification.
The development of host resistance strategies and
characterization studies can also be employed to realize
efficient methods which target T-2 toxin decontamination.
RNAi gene silencing and gene mapping can prove to
play a pivotal role in building strategies to increase the
contribution of selected resistance-associated proteins in
seed/crop resistance to T-2 contamination [111].
Methods for decontamination
Oxidation
Chemical methods for the oxidation of
trichothecene toxins include a treatment with 0.25%
NaOCl-0.025 mol/L NaOH for four hours. This has been
shown to inhibit the biological activity of the T-2 toxin,
and NaClO has also been acclaimed as a decontamination
agent for the T-2 toxin and other trichothecenes [80].
Biological oxidation has proven to be more specific
than chemical oxidation. It was observed that oxidation
by means of hydroxylation in animal bodies resulted in
the addition of a hydroxyl group at the C-3’ position of the
C-8 substituent of type A trichothecenes. Various animal
species such as mice, rats, monkeys, rabbits, chicken,
swine, cows and even the shrub Baccharis spp. have
exhibited oxidation of the T-2 toxin via hydroxylation
to the 3’-hydroxy T-2 toxin (3’-OH T-2) and/or the
3’-hydroxy HT-2 toxin (3’-OH HT-2). It was observed
that the formation of 3’-OH T-2 and 3’-OH HT-2 toxins
took place in microsomes in the presence of NADPH [80].
Plausible therapeutic uses
T-2 mycotoxin and their derivatives have been
attributed a diverse range of abilities, including their
application as growth promoters, antibiotics, and a
range of other drugs. The trichothecene family has been
credited with numerous biological properties consisting of
antiviral abilities (chiefly as Herpes replication inhibitors),
immunotoxic activities, antileukemic and antimalarial
capabilities [23]. This vast amount of the aggregated
understanding of mycotoxins has opened a new era of
applications utilizing an amalgamation of toxin dexterity
factors with progress made with scientific techniques
in various fields such as immunology, biotechnology,
molecular biology, cell biology and nanotechnology in
order to develop target-specific strategies that can adapt a
fatal toxin into a potential therapeutic agent.
The major strategies developed in this area include
toxins which target ligands being administered, which
upon internalization, target and attack diseased cells while
specifically sparing unexposed cells that do not display
receptors on their surfaces. Another approach follows a
protease-activated toxin strategy whereby the toxin is
cleaved via biotechnological engineering and activated
upon interaction with a disease-related intracellular/
extracellular protease. This cleavage is hypothesized
to enhance cell binding, which may lead to a signal
transduction cascade, translocation, stabilization or
increased catalytic activity of the toxin moiety in targeted
cells, resulting in their suppression. Amongst potential
therapeutic usage strategies, toxin-based suicide gene
therapies are also promising. These consist of a toxin
polypeptide-encoding DNA construct being delivered
to an assorted cell population (Figure 7). A specific
transcription regulator oversees the regulation of the DNA
construct expression [112, 23]. Thus, advancements of
such strategies could prove to be beneficial and provide
us with a tangible solution to the ever-increasing medical
challenges and applications related to these toxins.
Conjugation by glycosidation
Trichothecene mycotoxins can be conjugated by
glycosidation to yield glucuronides and glucosides. The
most important biochemical pathway is glucuronidation
for the metabolism of the T-2 toxin and the HT-2 toxin
in animal and human systems. The glucuronidation of
trichothecenes has reported to be achieved by microsomal
glucuronyl transferase or glucuronidase from the rat liver
[108].
Bentonite
Studies have reported that bentonite feeding (510%) inhibits the toxic effects of T-2 by decreasing
intestinal absorption and increasing fecal excretion of the
toxin [109]. Bentonite has shown the potential to bind
aflatoxin, sterigmatocystin, zearalenone and the T-2 toxin
[110].
Future perspectives
The identification of detoxification agents against
T-2 mycotoxicosis is more important, and its side effects
need to be assessed. Future potential applications of
the detoxification of mycotoxin by microorganisms,
enzymes and genes could prove to be beneficial. These
detoxification enzymes should have pronounced
capabilities to eliminate mycotoxins from human and
animal systems and from foods and feedstocks. Beneficial
detoxification genes used could be cloned and expressed in
microorganisms to develop recombinant microorganisms
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CONCLUSIONS
Fungal secondary metabolites such as the T-2 toxin
have had severe adverse effects and continue to poison
farm animals worldwide. The T-2 toxin and its metabolites
exist in various countries but are mainly found in tropical
and subtropical regions, such as South Korea. These toxins
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contaminate animal feedstuff and their production is aided
by the grain moisture content and weather conditions in
the affected areas. The symptoms of toxicity are diverse,
affecting the GI tract mucosa and digestion process and
causing skin blistering, edema, irritation, necrosis and
apoptosis. These all present bio-related threats to humans
and can induce oxidative stress, causing DNA damage,
inhibiting protein synthesis, and damaging lipids.
These lethal properties of the toxin support its
candidature as a fatal biological warfare agent. Despite
various guidelines and regulations established regarding
its usage and detection strategies pertaining to maximum
permissible limits in feed and food stocks, its presence
can prove to be toxic. Presently, T-2 toxin treatments of
induced damage emphasize mainly the use of natural
substances, probiotics, and amino acids, and the quest
for a precise antidote against the toxin continues to date.
Therefore, stringent regulations must be established and
quarantine activities need to be undertaken in order to
prevent planned/unplanned exposure on a large scale.
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Abbreviations
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trichothecene-2; LD50, lethal dose to kill 50 percent of
test sample; MAPK, mitogen activated protein kinase;
ERK ½, extracellular signal-regulated kinase ½; ATF,
activating transcription factor; JNK, c-Jun NH2-terminal
kinases.
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This work was supported by a grant from the
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is funded by the Korean Government, Ministry of
Science, ICT and Future Planning (MSIP) (NRF-20100027963), (NRF-2016K1A4A3914113) and Kwangwoon
University in 2017. Authors would like to thank Twasol
Research Excellence Program (TRE Program), King Saud
University, Saudi Arabia for support.
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