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Review Articles
A Brief Overview of our Current Understanding of Nivalenol:
A Growing Potential Danger yet to be Fully Investigated
Kongkapan, J.,1 Polapothep, A.,1 Owen, H.2 and Giorgi, M.3
Department of Veterinary Pharmacology, Faculty of Veterinary Medicine, University of Kasetsart, Bangkok 10900, Thailand.
Department of Veterinary Sciences, University of Queensland, Gatton, Brisbane, Australia.
3
Department of Veterinary Sciences, University of Pisa, Via Livornese (latomonte) 1, San Piero a Grado, 56122 Pisa, Italy.
1
2
* Corresponding author: Mario Giorgi, Chem. D., Spec. Pharmacol., Department of Veterinary Sciences, University of Pisa, Via Livornese (latomonte),
San Piero a Grado, Italy. Email: mario.giorgi@unipi.it
AB S T RAC T
Mycotoxins are secondary metabolites that are secreted by fungi into their direct environment. Recent
epidemiologic surveys indicate a significant increase in the global presence of fungal species. Nivalenol, a
mycotoxin belonging to trichothecenes type B, has been recently shown to possess one of the more potent
toxicities among mycotoxins of this group. It is critical that further research on the toxicological potential of
nivalenol on humans and animals be undertaken. This review reports on the studies conducted on nivalenol
thus far and in so doing serves to provide a basis for our current understanding of the mycotoxin.
Keywords: Mycotoxins; Nivalenol; Toxicity; Health Concern; Tricothecenes.
INTRODUCTION
Mycotoxins are secondary metabolites that are produced by
fungi into their direct environment. Recent epidemiologic
surveys indicate a significant increase in the global presence
of fungal species, probably as a consequence of global climate
change (1). Favorable temperature and moisture levels are
crucial for mycotoxicigenic fungi and mycotoxin production.
In general, tropical climates favor aflatoxin production while
ochratoxin A, patulin and Fusarium toxins (e.g. deoxynivalenol, nivalenol) are more of a concern in colder regions
(2). Mycotoxins are currently the most frequently detected
contaminants in animal feeds and certain plant-derived
foods (3). Mycotoxins originate from different biosynthetic
pathways, resulting in a large diversity of chemical structures
and biological effects (4). Fungal invasion and propagation
in living plants (pre-harvest contamination) is influenced by
various signaling molecules, and plant stress factors stimulate
mycotoxin production (3). Despite numerous efforts in the
areas of plant genetics and plant protection, the persistence
of fungal species in the environment and their complex life
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cycle makes it impossible to entirely avoid fungal invasion
and mycotoxin contamination of crops at the pre-harvest
stage under the current conditions of agricultural practice (5).
The actual ecological role of mycotoxins is still incompletely understood. Secondary metabolites, particularly those
of endophytic fungal species, exert antibiotic, anthelmintic
and insect repelling properties and may protect plant seeds
and plant tissues from external damage (1). At the same time,
the mycotoxins of many fungal species have a harmful effect,
competing with plants for nutrient resources and damaging
plant tissues sometimes leading to plant disease (e.g. Fusarium
head blight or FHB) (6). Plants react to fungal invasion using protective mechanisms, for example, some plants can
modify mycotoxins via conjugation reactions, predominantly
by glucoside binding (7). These modifications result in new
molecules with different physicochemical structures (modified mycotoxins) that have remained previously undetected
(masked mycotoxins, including Fusarium mycotoxins which
are not usually detected by routine testing) (8).
Trichothecenes are a large group of mycotoxins mainly
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produced by fungi of the Fusarium genus (9). Worldwide,
these toxins are commonly found in cereals, particularly
wheat, oats, barley and maize (10, 11). Cereals are commonly used in feed, and farm animals may therefore consume
relatively high amounts of trichothecenes. Trichothecenes
are toxic to animals and exposure has been linked to reproductive disorders in domestic animals (12). Because of their
effects on the immune system, exposure to trichothecenes
could also facilitate the development of infectious diseases in
humans and animals (13). Trichothecenes are closely-related
sesquiterpenoids (which all possess a ring structure) with a
12, 13 epoxy ring and a variable number of hydroxyl, acetoxy
or other substituents. Trichothecenes have been classified
into types A, B, C and D, based on their functional group
(14). Type A and type B trichothecenes have a wide range of
toxic effects on production animals and humans (15). Type A
trichothecenes are represented by T-2 toxin, HT-2 toxin and
diacetoxyscirpenol (DAS). Type B trichothecenes are most
frequently represented by deoxynivalenol (DON), nivalenol
(NIV) and fusarenon X (FX) (9) (Fig.1; Table A). C and D
types are not covered in this review as type C has not been
associated with adverse effects in livestock. In contrast to type
C trichothecenes, type D trichothecenes are potent cytotoxic
compounds however no naturally occurring toxicoses have
consistently been attributed to these mycotoxins (16).
NIV (12, 13-epoxy-3,4,7,15-tetrahydroxytrichothec9-en-8-one) belongs to trichothecene type B, produced by
Fusarium graminearum, F. crookwellense and F. nivale (17,
18). These fungi can inhabit various cereal crops (wheat,
maize, barley, oats and rye) and grain based food products
(bread, malt and beer) (11). The Fusarium species invade and
grow on crops, and may produce NIV under moist and cool
conditions. In recent reports, NIV has been detected in cereal
based products in European countries (19, 20, 21), Brazil
(22), Japan (23), Southeast Asia (24) and China (25). The
average concentration of NIV contamination is dependent
on the geographical area where the contamination occurred
(from 20–60 μg/kg in France, to 584–1780 μg/kg in China)
however no country has been found to be without some level
of contamination (26). The European Food Safety Authority
(EFSA) has issued guidelines on the risk to human and animal health related to the presence of NIV in food and feed in
the form of a tolerable daily intake (TDI) of 1.2 μg/kg bw/
day (27). In contrast, the Food Safety Commission in Japan
(FSCJ) has established a TDI of 0.4 μg/kg bw/day (28).
NIV is thought to act by binding to the ribosomal peptidyl transferase site to inhibit protein and DNA synthesis
(29). Consequently, exposure results in decreased cell proliferation (29) and apoptosis, particularly in organs containing
actively dividing cells such as the small intestine, thymus,
spleen, bone marrow and testes. It also causes decreased cell
proliferation and apoptosis in mitogen-stimulated human
lymphocytes, as observed with other trichothecenes (30, 31,
32, 33, 34). Several recent reports have described additive/
synergistic toxicity due to a combination of trichothecenes,
these situations have resulted due to the natural and common
co-occurrence of several different trichothecenes in crops
(e.g. NIV and DON) (4, 35). These same studies also detected
a greater toxicity of NIV on epithelial cells compared to other
well-known trichothecenes (36). Despite its relatively potent
toxicity, NIV has been poorly investigated in comparison to
other mycotoxins belonging to the same family.
To date, the data on toxicity of NIV are incomplete.
Limited data are available and its toxicokinetic profile has
only been reported in pigs and mice (37, 38). The aim of this
review is to collate the relevant literature about NIV. Given
the growing rate of NIV contamination and the likely serious
consequences of this, it is vital that we rapidly generate data
to increase our understanding of this mycotoxin. Hence, the
aim of this review is to stimulate scientists to perform research in this field and in addition, to help authorities gather
data for risk assessment in humans and animals.
METABOLISM
Figure 1: Chemical structure of trichothecenes type A and type B.
Substitutions R1 through R5 are given above.
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Once present in animal tissues, trichothecenes undergo a
variety of different metabolic reactions including hydrolysis
to split off side groups, hydroxylation and de-epoxidation.
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Table A: The chemical structures of the substituents R1-R5 are type A and type B trichothecenes (37)
Trichothecene
R1
R2
T-2 toxin
OH
OAc
Diacetoxyscirpentriol
OH
OAc
OH
OH
OH
H
OH
OAc
HT-2 toxin
Deoxynivalenol
Nivalenol
Fusarenon X
OH
OH
R3
Type A
R4
R5
OAc
OAc
H
OCOCH2CH(CH3)2
OAc
Type B
H
H
OCOCH2CH(CH3)2
H
OH
OH
OH
O
O
O
OH
OH
OH
NIV has been reported to be metabolized to a de-epoxidated
form by microorganisms in the gastrointestinal tract (39).
The intestinal microflora is important for the biotransformation of trichothecenes. The presence or absence of particular
intestinal microflora species can influence the extent to which
an animal is sensitive to NIV as it has been demonstrated that
the de-epoxidated products are less toxic than the parental
molecules (40). The removal of the epoxide oxygen at the
carbon 12 and 13 position has been reported to be a significant single step detoxification reaction for trichothecenes
(Fig.2). Indeed, the rate of de-epoxidation before absorption is an important factor in the toxicity of NIV and other
trichothecenes. The highest toxicity is expected in animals
with no de-epoxidation. For example, the deepoxy T-2 toxin
(DE T-2) metabolite of T-2 toxin demonstrated a toxicity
that was reduced 400 fold when compared to that of the
parental compound in the rat skin irritation bioassay (40).
The de-epoxides of NIV and DON were shown to be 51 and
24 times less cytotoxic than the corresponding toxins with an
intact epoxide ring (41).
Rodents
The first study concerning in vivo metabolism of NIV was
reported in rats (42). Male Wistar rats (n=5) were orally
administered with NIV (5 mg/kg bw) 12 times at 2- or
3-day intervals. Either urine or feces were collected daily for
39 days. The results showed a large amount of an unknown
metabolite in the feces. The unknown metabolite was then
identified as 3,4,7,15- tetrahydroxytrichothec-9, 12-dien8-one, namely de-epoxy NIV. Poapolathep et al. (38) studied
the fate of NIV and FX in mice using 3H-NIV and 3H-FX.
Radioactivity was measured mainly in the urine in mice given
3
H-FX, and mainly in the feces in mice given 3H-NIV. It
was demonstrated that the radioactivity was mainly due to
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Figure 2: Detoxification path way of NIV into deepoxy-NIV in animals.
NIV and in a small part, to an unknown metabolite (which
was never structurally identified). In addition, it was shown
that FX-to-NIV conversion mainly occurred in the liver and
kidney. Another study showed that NIV has potential to be
transferred in unchanged form to fetal or suckling mice via
the placenta and milk, respectively. It has been demonstrated
that the fraction of NIV in maternal milk is mainly due to the
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amount of FX previously converted to NIV in the maternal
body (35). According to these findings, mice (lacking the
de-epoxy-NIV) might be more sensitive to NIV toxicity
compared to rats.
Swine
In pigs fed twice a day for a week with a diet containing
NIV (0.05 mg/kg bw), NIV was mainly excreted in feces.
No metabolites of NIV, either as glucuronic acid or sulphate
conjugates, or as de-epoxy-NIV, were found in plasma,
urine, and feces, indicating a lack of metabolism. It has been
speculated that the inability of their intestinal microbes to
de-epoxidate trichothecenes might increase the sensitivity of
pigs to trichothecene toxicity. The high NIV concentrations
in feces (higher than in the feed) suggested a likely risk of
intestinal damage when microbial detoxification ability is
lacking (37). In order to investigate if the ability to form
de-epoxy-NIV was time – dependent, pigs were fed with
higher doses of NIV (2.5 or 5 mg/kg bw) for 3 weeks. The
results showed that all pigs were able to metabolize NIV to
de-epoxy-NIV after one week of treatment (not before) and
de-epoxy-NIV concentration was highest at the end of the
NIV treatment. From these results, it was concluded that pigs
are able to convert NIV into de-epoxy-NIV only if exposed
to this toxin for a prolong period (37).
Ruminants
Trichothecenes are, to a large extent, de-epoxidised in the
rumen of the cattle before absorption into the blood, this is
regarded as a detoxification process (43, 44). Data available
for NIV in ruminants are scarce. To the best of the authors’
knowledge, only one study is reported. This study involved
the incubation of NIV with cow ruminal fluid and found
that a large fraction of NIV (78-82%) was transformed to
deepoxy-NIV (37).
Poultry
Broiler chickens were fed with NIV (2.5 or 5 mg/kg) for 3
weeks (37). De-epoxy-NIV was not detected in any samples
of feces. The unidentified metabolite of NIV was found in
the feces samples, this was nonspecifically identified as an
acetylated metabolite of NIV. A subsequent in vitro study
monitored the degradation of 12 trichothecenes (including
NIV) by chicken intestinal microbes (45). NIV was found
to be converted to de-epoxy-metabolite by the chicken large
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intestinal microbes. These studies are conflicting, and different processes of the intestinal microbes in vivo versus in vitro
might have triggered this difference. On the other hand, NIV
and de-epoxy-NIV were found in feces of laying hens at
levels up to 10% of the ingested NIV (5 mg NIV/kg diet for
50 days) (46).
TOXICIT Y
NIV and other trichothecenes are potent inhibitors of protein
synthesis and their toxicity is directed at RNA and DNA as
well as mitochondrial and electron transport chain functions
(9). In addition, NIV can stimulate lipid peroxidation, alter
cell membrane function and modulate immune responses.
It activates mitogen activated protein kinases (MAPKs)
through the ribosomal stress response, this could be another
mechanism of toxicity that operates via apoptotic and proinflammatory processes (9). Rapidly dividing cells, such
as intestinal epithelial cells or immune cells, are especially
sensitive to NIV and other type B trichothecenes. The 50%
lethal dose (LD50) values, which may differ based on route
of exposure and species exposed, can be used to compare the
toxicity of trichothecenes and are shown in table 1. Various
studies have commonly detected NIV, often together with
DON in cereals worldwide (20, 24, 44, 47). Furthermore,
the toxicity of NIV is higher than that of DON as showed
from the LD50 in mice (intra-peritoneal administration) of 4
mg/kg versus 70 mg/kg, respectively (Table 1). Incidentally,
human health authorities tend to assume that NIV toxicity is
similar to DON toxicity (27), since the chemical structures of
these two toxins are similar. NIV and DON also share toxicological properties, such as the inhibition of cell proliferation,
induction of interleukin-8 secretion, and the involvement of
stress-activated MAPKs and nuclear factor κΒ in the signal
transduction pathways of their toxicities (48). Therefore, NIV
should be of concern for food safety but in vivo information
for assessing the health risk remains scarce.
The intestinal epithelial cell is a recognized target for
NIV and damage is likely to result in impaired absorption
of nutrients (sugar and electrolyte) leading to the known
detrimental effect of trichothecenes on animal growth (49).
The exposure of intestinal epithelial cell to NIV may alter
their ability to proliferate and to ensure a proper barrier function. Several reports have shown that NIV has a greater toxic
impact on the gastrointestinal tract than DON. Cheat et al.
(50) reported that in vivo, proliferative cells of pig intestinal
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Tabel 1: Partial list of type A and B trichothecene toxins and their comparative toxicity (adapted from Haschek et al. (26))
Group
Main producer
A
Fusarium spp.
B
Fusarium spp.
Trichothecenes
Mouse i.v. or i.p.a
T-2 toxin
HT-2 toxin
Diacetoxyscirpenol
(DAS)
Deoxynivalenol
(DON, vomitoxin)
Nivalenol (NIV)
Fusarenon X (FX)
3.0-5.3
6.5-9.0
Acute LD50 values (mg/kg)
Fisher 344b
Mouse oral or p.oa Mice p.o
Rat p.o
3.8-10.5
9.6-23.0
15.5-46.0
70.0-76.7
46
4.0-6.4
3.4
4.5
38.9
19.5
Fisher 344 Rat
subcutaneousc
0.9
Summarized by Haschek and Beasley, (26)
Kawasaki et al. (32)
c
IARC. (29)
a
b
mucosa showed a 30% and 15% decrease (in number) after
NIV and DON exposure, respectively. Other recent studies
also concluded that NIV induced a strong dose-dependent
cytotoxicity on intestinal epithelial cells in vitro (36, 51, 52).
A normal porcine jejunal epithelial cell line (IPEC-J2) was
exposed to various Fusarium mycotoxins and resulting cell
viability was observed: The results showed that the toxicological potency rank was NIV > DON > ZEA > FB1 and all
combinations of mycotoxins gave reduced cell viability (52).
Apoptosis is now recognized as a major mechanism for
trichothecene-induced toxicity (9). The induction of apoptosis by trichothecenes, especially T-2 toxin, FX and NIV have
been studied in animals (31, 38, 53, 54). The early morphologic changes in immune cells, such as those within lymphoid
tissues (thymus, spleen and Peyer’s patches) were described as
apoptosis caused by NIV. It was shown that, when NIV was
given orally to mice at the dose levels of 5, 10, 15 mg/kg bw,
the degree of apoptosis was dose-dependent (33). In another
study, NIV was incubated with human blood cells (human
K562 erythroleukemia cell line). The results showed that NIV
was toxic for human blood cells causing DNA damage and
apoptosis (55). NIV also produced polyribosomal degradation
in bone marrow cells and significant erythropenia and slight
leukopenia in mice treated with 30 mg/kg of NIV (29). Both
the in vivo and in vitro findings indicated that NIV induces
apoptosis in different immune cells, probably decreasing
their functional properties. Therefore the immune system
seems to be one of the targets of NIV. However, there is no
experimental evidence on mutagenic and/or carcinogenic
properties of NIV in animals as specified by International
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Agency Research on Cancer (IARC) (56). NIV was classified as group 3, indicating that the toxin is not considered
carcinogenic to humans (56).
Apart from these findings, NIV has reported effects on
the reproductive and developmental system. In a study by
Ito et al. (57), pure NIV was injected intra-peritoneally in
pregnant albino Switzerland (ICR) mice at dose levels of
0, 0.1, 0.5 or 1.5 mg/kg bw/day on days 7-15 of gestation.
The highest dose caused stillbirths after vaginal hemorrhage
in 6 out of 10 animals. High embryo lethality was recorded
in the two highest dose groups (88 and 48%). No fetal malformations were observed in the treated groups. A single
administration of 3 mg/kg bw on day 7 affected the embryo
within 10 hours, damaged the placenta within 24 hours, and
caused abortions at 48 hours.
The general toxicity and immunotoxicity/hematotoxicity
of NIV are considered to be significant. As discussed previously, these effects are similar to those of other trichothecenes. NIV has been shown to be more toxic than the other
type B trichothecene (DON) even though it is a less common
crop contaminant than DON (23).
It should be noted that the risk for animals and public
health relates to the presence of NIV in food. NIV-induced
health damage is regarded as a serious problem and NIV
is considered to be one of the mycotoxins that need to be
regulated.
In conclusion, animal exposure to NIV is primarily from
consuming cereal grains and cereal by-products. NIV can
also be a potentially dangerous mycotoxin for humans. The
available information on the toxicity of NIV is incomplete
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and it is critical this shortfall is remedied as soon as possible.
NIV is of significant and growing concern and it is the responsibility of the scientific community to propagate specific
information on its toxicity. It should be remembered however,
that the major challenge in mycotoxin risk assessment is
understanding the effects of the total mycotoxin exposure,
including being able to predict interactions between different
mycotoxins at the level of adsorption and effects on target
organs. While initially risk assessment focused on avoidance
of probable carcinogenic mycotoxins, animal health concerns
are now related to undesirable effects on intestinal health and
the immune system, reproductive performance and sensitivity
to vaccination and to the mitigation of adverse effects in farm
and companion animals.
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