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P.F. Surai and J.E.

Dvorska 93

Peter F. Surai and 2Julia. E. Dvorska
Avian Science Research Centre, Scottish Agricultural College, Auchincruive, Ayr,
Scotland, UK and 2Sumy National Agrarian University, Sumy, Ukraine

Effects of mycotoxins on antioxidant
A delicate balance between antioxidants and
pro-oxidants in the body in general and
specifically in the cell is responsible for
regulation of various metabolic pathways
leading to maintenance of immunocompetence, growth and development and
protection against stress conditions associated
with commercial poultry production (Surai and
Dvorska, 2001). This balance can be regulated
by dietary antioxidants, including vitamin E
(Surai et al., 1999), carotenoids (Surai and
Speake, 1998; Surai et al., 2001) and
selenium (Se) (Surai, 2000). On the other
hand, nutritional stress factors have a negative
impact on this antioxidant/pro-oxidant
balance. In this respect mycotoxins are
considered to be among the most important
feed-borne stress factors.
It is not clear at present whether
mycotoxins stimulate lipid peroxidation
directly by enhancing free radical production
or if the increased tissue susceptibility to lipid
peroxidation is a result of a compromised
antioxidant system. It seems likely that both
processes are at work. In most cases lipid
peroxidation in tissues caused by mycotoxins
was associated with decreased concentrations
of natural antioxidants. For example, in an
experiment with quail, levels of the primary
liver antioxidants (α−tocopherol, γ−
tocopherol, carotenoids and ascorbic acid)
were significantly decreased as a result of T-

2 toxin consumption (Dvorska and Surai,
2001; Figure 1).
Similarly, the presence of T-2 toxin in the
diet decreased the concentration of α−
tocopherol in the chicken liver (Hoehler and
Marquardt, 1996). T-2 toxin consistently
depressed concentrations of vitamin E in
chicken plasma (Coffin and Combs, 1981).
Addition of micelle-promoting compounds
(taurocholic, monoolein, and oleic acids)
alleviated depression in plasma vitamin E,
indicating interference of T-2 toxin with
micelle formation during vitamin E
absorption. Similarly, aflatoxin B1 (AFB1) in
the feed interfered with the accumulation of
carotenoids in chicken tissues (Schaeffer et
al., 1988) inducing pale bird syndrome in
birds. In fact, AFB 1 caused a significant
depression of lutein in the toe web, liver,
serum and mucosa (Schaeffer et al., 1988a).
Pigment restoration was accomplished by
feeding the same diet supplemented with
lutein (70 mg/kg). In young chickens AFB1
reduced the lutein content of jejunal mucosa
up to 35% while serum lutein was reduced
up to 70% (Tyczkowski and Hamilton, 1987),
suggesting that AFB 1 interfered with the
absorbtion, transport and deposition of
carotenoids. More precisely, AFB1 impaired
lutein absorption in chickens (Tyczkowski
and Hamilton, 1987a). In similar fashion,
ochratoxin A (OTA) was shown to affect

94 Effects of mycotoxins on antioxidant status and immunity

µg/g tissue













Figure 1. Effect of T-2 toxin with and without supplemental toxin adsorbents on antioxidant concentrations in
quail liver (adapted from Dvorska and Surai, 2001).

carotenoid assimilation in chickens. Again,
depression in uptake of carotenoids by
intestinal mucosa and depressed transport in
serum were considered to be important
mechanisms of AFB1 action on carotenoid
metabolism (Schaeffer et al., 1988; Huff and
Hamilton, 1975).
In general, malabsorption syndrome is
considered a common result of
mycotoxicoses. For example, aflatoxicosis,
ochratoxicosis and T-2 toxicosis were
produced by feeding diets containing graded
concentrations of the appropriate toxin to
broiler chickens from hatching until 3 weeks
of age (Osborne et al., 1982). In this
experiment AFB1, even at levels lower than
needed for growth inhibition, produced a
malabsorption syndrome characterized by
steatorrhea, hypocarotenoidemia, and
decreased concentrations of bile salts and
pancreatic enzymes. T-2 toxin also produced
malabsorption, but at concentrations higher
than required to inhibit growth. Ochratoxicosis produced mainly hypocarotenoidemia (Osborne et al., 1982). It is
postulated that the decreased level of vitamin
A in the quail liver as a result of T-2 toxin
consumption (Dvorska and Surai, 2001) is also

a reflection of the decreased intestinal
absorption of fat soluble nutrients.
The presence of OTA in the diet
significantly decreased the concentration of
α−tocopherol in the chicken liver (Hoehler
and Marquardt, 1996). Furthermore, aflatoxintreated barrows had decreased serum
tocopherol and retinol concentrations
compared with control and pre-test values,
and decreased tocopherol concentration in
cardiac tissue (Harvey et al., 1994).
Aurofusarin decreased vitamin E and
carotenoid concentration in quail egg yolk
(Dvorska et al., 2001a), in the liver, yolk sac
membrane and other tissues of newly hatched
quail (Dvorska et al., 2002; Dvorska et al.,
2003; Dvorska and Surai, 2004). It is
interesting to note that the carotenoid and
vitamin A concentrations in the quail liver
were also decreased when the maternal diet
was supplemented with aurofusarin.
A pro-oxidant effect of mycotoxins in
many cases could be mediated through
changes in reduced glutathione (GSH)
concentration. For example, Rizzo et al.
(1994) demonstrated that T-2 toxin decreased
GSH in rat liver. Treatment of fasted mice
with a single dose of T-2 toxin (1.8 or 2.8

P.F. Surai and J.E. Dvorska 95
mg/kg BW) by oral gavage led to a marked
decrease in hepatic GSH (Atroshi et al., 1997).
In male broiler chicks, hepatic GSH
concentration decreased after 7 days of
treatment (1.5 mg T-2 toxin/kg BW/day) (Leal
et al., 1999). Acute exposure of mice to T-2
toxin (4 mg/kg, s.c.) resulted in a progressive
decrease in hepatic GSH, reaching a minimum
6-8 hrs after toxin administration (Fricke and
Jorge, 1991). Intraperitoneal administration
of AFB1 to rats (2 mg/kg) was also associated
with decreased GSH in the liver. In contrast,
in 3-week-old male chickens daily aflatoxin
gavage (2 mg/kg BW, in corn oil) for 5 and
10 days elevated hepatic GSH; and renal GSH
was elevated after 10 days (Beers et al.,
1992a). Similarly, hepatic GSH increased 2
and 8 hrs following a single AFB1 dose and
continued to increase through five daily doses
of AFB1 (Beers et al., 1992b).
There was GSH depletion in cultured rat
hepatocytes as a result of AFB1 toxicosis (Liu
et al., 1999). Similarly, consumption of OTA
for two weeks was associated with a depletion
of GSH from the mouse liver (Atroshi et al.,
2000). The mycotoxin patulin also decreased
GSH concentration in rat hepatocytes (Busbee
et al., 1999). Considering that glutathione is
responsible for the maintenance of redox
status of the cell (Sies, 1999) and therefore
participates in regulation of gene expression
(Arrigo, 1999), changes in GSH status could
be detrimental.
One of the most important mycotoxin
actions is their effect on antioxidant enzymes.
Depending on experimental conditions
(species, doses, route and duration of
administration, concentrations of other
antioxidants etc.), antioxidant enzyme
activities can be increased in response to
oxidative stress or decreased by direct or
indirect action of mycotoxins. For example,
treatment of pig kidney cells with 50 mM
fumonisin B1 (FB1) for 24 hrs significantly
decreased cellular GSH and increased the
activities of glutathione reductase (Kang and
Alexander, 1996). The activities of
glutathione peroxidase (GSH-Px), catalase,



and Cu/Zn-superoxide dismutase (SOD) were
not changed by this treatment. Oral
administration of T-2 mycotoxin to rats (1.25
mg/kg) for 5 days decreased the activity of
liver glutathione-S-transferase (Ahmed and
Ram, 1986). In contrast, feeding a single dose
of T-2 toxin (2 mg/kg BW) to rats increased
activities of GSH-shuttle enzymes including
GSH-Px, glutathione reductase and glucose6-phosphate dehydrogenase (Suneja et al.,
1989), probably reflecting an adaptive
response to oxidative stress. On the other
hand, when male rats were given a diet
deficient in vitamins C and E and Se and were
administered orally a single dose of
deoxynivalenol (DON) or T-2 toxin, there was
a significant decrease in activities of GSHPx, catalase, SOD and glutathione reductase
(Rizzo et al., 1994). Activity of GSH-Px in
rat blood was decreased due to consumption
of AFB1 (Choi et al., 1995). Administration of
AFB1 to rats (2 mg/kg intraperitoneally) caused
a significant decrease in the activities of SOD,
catalase, GSH-Px, glutathione-S-transferase
and glutathione reductase in liver (Rastogi et
al., 2001). A significant increase in SOD
activity occurred in the liver following AFB1
exposure of the ducks (Barraud et al., 2001).
When considering detrimental effects of
mycotoxins on antioxidant systems it is
necessary to be aware that combinations of
several mycotoxins can be more toxic than
individual mycotoxins, as was shown for a
combination of T-2 toxin and OTA (Kubena
et al., 1989).
One of the most important targets for
mycotoxins is embryonic development. Since
chicken embryo tissues contain high levels
of PUFA, they are vulnerable to peroxidation
and oxidative stress caused by mycotoxins
could be lethal. As mentioned previously,
aurofusarin increased late mortality of quail
embryos (Dvorska et al., 2001a). Furthermore,
contamination of the diet with T-2 toxin
markedly decreased egg production and
impaired hatchability (Tobias et al., 1992).
Confirmation of a possible association of this
effect with oxidative stress came from data

19/12/2004, 23:24

96 Effects of mycotoxins on antioxidant status and immunity
indicating that increased dietary vitamin E
during the first week of the experiment
significantly decreased the number of infertile
eggs and significantly improved the hatching
percentage (Tobias et al., 1992).

Increased lipid peroxidation as a
consequence of mycotoxicoses
As illustrated in Table 1, OTA has a
stimulating effect on lipid peroxidation. In
most of cases, accumulation of thiobarbituric
acid reactive substances (TBARS) was used
as a measurement of lipid peroxidation.
Ethane exhalation, EPR-registered free
radicals, hydroxyl radical formation, single-

strand cleavage DNA, DNA adduct formation
as well as LDH release were also used to
confirm pro-oxidant properties of OTA.
Various in vitro and in vivo systems were
also used including liver microsomes,
phospholipid vesicles, primary cell cultures,
whole organ and whole body measurements.
T-2 toxin was also shown to have prooxidant properties (Table 2). Those properties
were confirmed with rat, mouse and quail
liver tissue and yeast. TBARS accumulation
was the method used in most of the studies,
however, conjugate diene formation and DNA
fragmentation were also demonstrated. Effect
of AFB 1 on lipid peroxidation has been
studied in rat liver and kidney as well as in
cultured hepatocytes and in an in vitro model

Table 1. Stimulation of lipid peroxidation by ochratoxin A.


Lipid peroxidation

Protective effect References
of antioxidants

OTA in vitro

Rat liver



OTA in feed
OTA in feed

Ethane exhalation ↑
MDA in serum,
liver, kidney ↑
Phospholipid TBARS ↑, oxygen
uptake ↑
Bacillus brevis Free radical
generation (EPR) ↑
Chicken liver TBARS ↑

OTA in vitro
OTA and its
OTA in feed
OTA in vitro
OTA in diet
OTA in vitro
OTA in vitro
OTA in feed
OTA in feed
OTA in vitro


Vero cells in
Rat liver
A model oxidation system


OH• ↑, singlestrand cleavage
Astrocytes and TBARS ↑, LDH
release ↑
Mouse and rat DNA adduct
formation ↑
DNA adduct
formation ↑
Rat kidney


Rahimtula et al., 1988,
Gautier et al., 2001; Khan et
al., 1989
Rahmitula et al., 1988
Meki and Hussein, 2001


Omar et al., 1990

Vitamin E

Hoehler et al., 1996

SOD, catalase

Hoehler and Marquardt,
1996; Hoehler et al., 1997
Baudrimont et al., 1997a;
Hoehler et al., 1997
Gillman et al., 1999


Belmadani et al., 1999

Retinol, ascorbic Grosse et al., 1997
acid, vitamin E
Creppy et al., 1998

Gautier et al., 2001

F. A balance between cell death and cell survival factors plays a major role in the decision process as to whether a cell should live or die (Ray et al. 1994 Ahmed and Ram. TBARS accumulation was substantially increased as well as conjugate diene production.P. Surai and J. such as initiation of death signals at the plasma membrane... This process is often referred to as programmed cell death or apoptosis..E. 1995. Several processes. 23:24 . Schuster et al. 2002 Atroshi et al. It is clear from these data that mycotoxins strongly promote lipid peroxidation in various in vitro and in vivo systems. When cell death is induced by osmotic. 2001 Chang and Mar.. There are also data indicating pro-oxidant properties of zearalenone (Karagezyan et al. This effect was obvious no matter which measurement was 05-Surai.. Liver MDA ↑ goose T-2 in feed T-2 in feed T-2 in feed T-2 in feed T-2 in feed system (Table 3). early disruption of external and internal membranes takes place with subsequent liberation of denatured 19/12/2004. primary rat hepatocytes. 1987. In those systems TBARS accumulation and DNA strand breaks were increased (Table 4).... Mycotoxin Tissue Lipid peroxidation measurement Protective effect References of antioxidants T-2 in feed Rat liver TBARS ↑ Se. 2004).. 1989. 1997). Dvorska and Surai. ascorbic acid. activation of death proteases.. ultimately coalesce to a common irreversible execution phase leading to cell demise. Dvorska 97 Table 2. At the same time GSH concentration and activities of antioxidant enzymes significantly declined as a result of AFB1 action. 1997 Dvorska and Surai. Ghedira-Chekir et al. Vero cells in culture and phosphatidyl choline (PC) bilayers.p65 97 - CoQ10 and vitamin E Lycopene Tsuchida et al... 1986 Karppanen et al. 1988 Leal et al. 1999) and citrinin (Ribeiro et al. Similar to the examples above. duck. 1999 Mezes et al. 1999 used to assess the process of lipid peroxidation. Mycotoxins and apoptosis The maintenance of tissue homeostasis involves the removal of superfluous and damaged cells. 1996). physical or chemical damage. Aurofusarin has been shown to decrease antioxidant defences and stimulate lipid peroxidation in quail egg and tissues of newly hatched quail (Dvorska et al. endonucleases etc. vitamin E T-2 in feed T-2 in feed T-2 in feed Rat liver nuclei TBARS ↑ Mouse liver TBARS ↑ Mouse MDA in liver after 24-48 hrs after supplementation↑ Mouse liver DNA fragmentation ↑ Quail liver TBARS ↑ Rat tissues Conjugate diene ↑ Chicken Liver MDA ↑ Chicken. 2003.. Stimulation of lipid peroxidation by T-2 toxin. expression of proapoptotic oncoproteins. 2000). rat liver nuclei fraction. since it is thought that cells activate an intrinsic death program contributing to their own demise (Sastre et al. Fumonisin B 1 also stimulated lipid peroxidation in rat liver.. Rizzo et al. Apoptosis is distinguishable from necrosis. 2002... 1989 Vila et al. DON increased TBARS formation in rat and mouse liver and decreased GSH in rat brain and spleen. 1984. Suneja et al.

apoptosis is characterised by cell shrinkage. SOD. 2000 change in the ratio of the two constitutes a trigger for apoptosis (Beaver and Waring. 1996).. chromatin condensation.98 Effects of mycotoxins on antioxidant status and immunity Table 3... 1999 Choi et al. Therefore. 2001 Verma and Nair. Reactive oxygen species (ROS) are thought to play a major role in apoptosis (Hockenbery et al. Ratan et al. Schaefer et al. 1995 Rastogi et al. hydrogen peroxide is considered a common mediator for the apoptosis induced by various anticancer drugs (Simizu et al. NO↑ melatonin loaded chitosan In feed Rat liver MDA ↑. vitamin E conjugated dienes ↑ In feed Rat liver MDA ↑. GSH depletion sensitises cells for intracellular induction of apoptosis (Zucker and Bauer.. Se . intracellular induction of apoptosis depends on ROS production and can be efficiently blocked by antioxidants (Langer et al.. GSH ↓. in many cases mycotoxins decreased cellular GSH. 1994)... In line with those findings there are data showing protective effects of catalase and SOD from different inducers of apoptosis (Sandstrom and Buttke. a decrease in GSH.. 2001 Rastogi et al. 1999 Souza et al. 1997). 2000). nuclear pyknosis. or an increase in GSSG or perhaps a References Shen et al.. 1997 Liu et al.. catalase hepatocytes release ↑ In feed Rat liver TBARS ↑ Semecarpus anacardium nut extract In vitro Cultured TBARS ↑ ROS Silvia primary rat formation ↑ miltorrhiza hepatocytes extract Intraperitoneally Rat liver TBARS ↑ Vitamin E. NO ↑ melatonin In feed Rat testis MDA ↑ Vitamin E In vitro Cultured rat TBARS ↑. vitamin E Intraperitoneally Rat liver and TBARS ↑ Picroliv kidney Intraperitoneally Rat liver GSH.. Catalase. LDH SOD. As previously mentioned.. 2003 Meki et al. Herdener et al. In fact. ternatin In feed Rat liver GSH-Px ↓ Se. 1993. 2001)... being involved in both initiation and execution of apoptosis (Herdener et al. For example ROS from mitochondria can cause apoptosis after GSH depletion (Zucker et al. Indeed. 2001 Shen et al. For example. 1996. 1995 Premalatha et al. hepatocytes ROS generation ↑ In feed Rat liver proteins into the cellular space and induction of an inflammatory response in the vicinity of the dying cell (Sastre et al. 1997).. 1993. and increased GSH concentration is shown to decrease the percentage of apoptosis in fibroblasts (Sastre et al. 1995). 1994 El-Gibaly et al. 1996). Stimulation of lipid peroxidation by aflatoxin.. DNA cleavage into fragments of regular sizes and activation of proteases called caspases (Dare et al. In contrast.. GSH depletion increases the percentage of apoptotic cells in a given population. 2001b Yang et al... apoptosis is induced by oxidative damage either directly from oxygen free radicals or hydrogen peroxide or from their generation in cells by injurious agents. GSH-Px ↓ In vitro Primary rat TBARS ↑. Mycotoxin Tissue Lipid peroxidation measurement Protective effect of antioxidants TBARS ↑. 2000).. 1998).. Therefore. which .. 1995).

1998 Fumonisin B1 Fumonisin B1 Abel and Gelderblom.. Morphological evidence of apoptosis was related to the toxicity of the mycotoxins and more toxic NIV and DON resulted in more late stage apoptotic events than FB1. 2002 TBARS ↑ Rizzo et al. Surai and J. deoxynivalenol.P. aurofusarin and citrinin. 1999 Rat liver TBARS ↑ - Ribeiro et al. For example. OTA and AFB 1. DNA fragmentation - Abado-Becognee et al. ascorbic acid.. the induction of apoptotic nuclear changes by various mycotoxins was investigated in HL-60 human promyelotic leukemia cells (Ueno et 05-Surai. Lemmer et al. However. 1994 Mouse liver TBARS ↑ Se. OTA. Dvorska. 1998 Fumonisin B1 Phosphatidyl choline bilayers Fumonisin B1 Vero cells Fumonisin B1 Glioma cells. Mycotoxin Tissue Lipid peroxidation measurement Protective effect References of antioxidants Fumonisin Rat liver nuclei Primary rat hepatocytes Rat liver TBARS ↑. Stimulation of lipid peroxidation by fumonisin.. 19/12/2004.. 2001 Dvorska et al. The results suggested that DNA damage and apoptosis rather than plasma membrane damage and necrosis may be responsible for the observed cytotoxicity.. 1989 Vero cells TBARS ↑ Vitamin E Ghedira-Chekir et al. based on the DNA fragmentation profile in gel electrophoresis and the morphological changes seen in electron microscopy. nivalenol (NIV).p65 - 99 al. Dvorska 99 Table 4. 1995 Fumonisin B1 DON in feed DON + 3-AcDON in feed Aurofusarin in feed Aurofusarin in feed Zearalenone injected IV Zearalenone in vitro Citrinin in feed Karppanen et al. AFB1 and some other mycotoxins induced DNA fragmentation. 1998.. 23:24 . mannitol Vitamin E Sahu et al. DNA strand breaks ↑ TBARS ↑ Catalase. Mouse fibroblasts Macrophage cell line Rat liver TBARS ↑.. DON...F. 2002 Dvorska and Surai. The results showed that T-2 toxin. In general. vitamin E - Quail egg yolk TBARS ↑ - Liver of newly TBARS ↑ hatched quail Rat liver TBARS ↑ - Dvorska et al... 1997 can trigger apoptosis. 2001b. citrinin. there are also reports indicating apoptosis caused by FB1. free radical Formation ↑. Acceleration of chain formation ↑ TBARS ↑ - Abel and Gelderblom. 1998 Mobio et al. T-2 toxin is the most potent apoptotic agent among mycotoxins.E. 2003 MDA↑ - Ferrante et al.. 1999 Yin et al... 1995). 1998 TBARS ↑ - Rate of peroxidation ↑. 2004 Karagezyan et al.

Electron microscopic characteristics of damaged lymphocytes were shrinkage of the cell body. protein kinase and intracellular Ca2+ level might be involved in the cellular apoptosis induction by Fusarium mycotoxins (Wang and Zhang. 3-acetyldeoxynivalenol.. Ultrastructural changes characteristic of .. 2000). The number of apoptotic lymphocytes in the thymus increased dramatically from 9 to 24 hrs after treatment and began to increase in the spleen at 12 hrs after treatment indicating that thymus was more sensitive to apoptosis than spleen. since such changes were observed in the gastric mucosa. These changes could impair nutrient assimilation as well as decrease defences against enteric pathogens and endotoxin. gastrointestinal epithelial cells and immunological cells as well as several cell lines. It seems likely that sphingol. p21 gene. 1998a). In another experiment. fusarenon-X.. moderate in the Peyer’s patches. roridin A >> diacetoxyscirpenol > baccharin B-5 >> nivalenol. Development of apoptosis and changes in lymphocyte subsets were examined in thymus. 1997). T-2 toxin. 1997). and somewhat mild in the mesenteric lymph nodes (Nagata et al. It should be noted that the gastrointestinal tract is also sensitive to trichothecene-induced apoptosis. Cytocentrifugation and light microscopy of leukocyte-enriched cell samples from the pronephros (the primary hematopoietic compartment in the fish) demonstrated T-2-related increases in apoptotic bodies and the apoptotic probes confirmed apoptosis in fish (Gogal et al. Female mice were treated orally with T-2 toxin (10 mg/kg BW) and thymus and spleen were examined to detect apoptotic changes (Shinozuka et al. 1997). T-2 toxin was the most potent agent to induce apoptosis in the thymus in young female mice (Islam et al. 2003). Massive cellular destruction was observed in the thymus and spleen and electron microscopy revealed the presence of apoptotic bodies. Of nine trichothecene mycotoxins tested. 1998). 2000). pregnant mice were dosed orally with T-2 toxin (3 mg/kg BW) at 11 days of gestation (Ishigami et al. 2000).. kidney cells.. deoxynivalenol. 1998). satratoxin G. mice were given 5 mg/kg BW of T-2 toxin and were killed 12 hrs later (Ihara et al... To examine the effect of T-2 toxin on the developing embryo. 1998. The authors showed that T-2-induced apoptosis involved activation of caspase-3 through cytosolic accumulation of cytochrome c along with caspase-9 activation. The degree of lymphocyte apoptosis was prominent in the thymus. It is interesting that both the acetyl group at the C-4 position and the isovaleryl or 3′-hydroxy isovaleryl group at the C-8 position of the T-2 toxin molecule are important for inducing apoptotic changes in the thymus (Islam et al.100 Effects of mycotoxins on antioxidant status and immunity Fumonisin B1. nuclear chromatin condensation and fragmentation (Li et al. the induction of apoptotic cellular lesions was observed.. 2001). in the liver of mice given 2.5 mg/ kg T-2 toxin and killed 2 hrs later. Both T-2 and HT-2 induced apoptosis after 24 hrs in HL-60 cells. T-2 TOXIN The rank order of the potency of trichothecene mycotoxins to induce internucleosomal DNA fragmentation was found to be T-2. fusarenon-X and DON could induce apoptosis of liver cells. 2001).. The possible mechanisms of apoptosis induction are not well understood. Similarly. T-2 toxin was shown to induce apoptosis in the hematopoietic (bone marrow) tissues of female mice (Shinozuka et al. gastric glandular epithelium and intestinal crypt cell epithelium (for review see Bondy and Pestka.. baccharin B-4 vehicle control (Nagase et al. mesenteric lymph nodes and Peyer’s patches of mice up to 24 hrs after oral inoculation with T-2 toxin (10 mg/kg).. with T-2 being somewhat more potent than HT-2 and the apoptotic process was almost completely blocked in the presence of a caspase inhibitor (Holme et al. 1999).

E. cytotoxicity of trichothecene mycotoxins is mediated through an apoptotic process. they released nucleosomal DNA fragments into the medium 2-3 days after exposure to 0. T-2 toxin-induced apoptosis was detected. T-2 toxin could directly cause fetal apoptosis (Ishigami et al.. Primary mouse embryo fibroblasts underwent apoptosis following FB1 treatment (Ciacci-Zanella et al. Recently genes that inhibit FB1induced apoptosis in African green monkey kidney fibronlasts (CV-1 cells) and two mouse embryo fibroblasts have been identified (Jones et al. Using DNA fragmentation and fluorescence microscopy assays Yang et al. However. Molecular mechanisms of T-2 stimulation of apoptosis are not clear at present. 2003). and ultimately evokes apoptosis. 2002). 2001). 1999). Therefore. 1999).. the pathway leading from the activation of these kinases to the activation of caspases and apoptosis has not been elucidated and needs further research.. The authors suggested that the Ca2+ signal triggered by T-2 toxin is transduced by the activation of endonuclease and protease. For example. in some layers of the central nervous system moderate pyknosis or karyorrhexis was seen.g.F. T-2 toxin induced apoptosis at 10 ng/ml levels within 2-6 hrs (Ueno et al. However.P. Albarenque et al. an enhancement of caspase-3-activity and cleavage of poly(ADPribose)polymerase compared to controls (Galvano et al.p65 101 fos and perhaps of c-jun mRNAs may be associated with T-2 toxin-induced epidermal cell apoptosis (Albarenque et al. After 72 hrs of treatment. FB 1 (50 and 100 mM) induced DNA damage.. In the same study. 2002). 1996). Surai and J. Effects of exposure of human fibroblasts to FB1 were investigated.. The author suggested that nanomolar 19/12/2004. In particular... FUMONISIN B1 The effects of FB1 on apoptosis in various in vitro and in vivo studies have received substantial attention over the last few years. 2001).. FB 1-treated keratinocytes developed morphological features consistent with apoptosis. The authors also demonstrated that the tumour necrosis factor (TNF) pathway and caspases play an important role in FB 1 -induced apoptosis. (2001) suggested that the elevation of TNF-α mRNA expression may play an important role in T-2 toxin-induced epidermal cell apoptosis. For example. 1996). e. In particular.. apoptotic C6 glioma cells were also observed after FB1 incubation. 2001). 23:24 .. (2000a) demonstrated that rank order of trichothecene-mediated apoptosis is similar to their cytotoxicity. T-2 toxin (2 mg/kg BW) was given orally to pregnant mice at various gestational days and the fetuses were examined 24 hrs later. 1995). The cytotoxicity and genotoxicity of FB1 in rabbit kidney RK13 cells were examined.1 mM FB1 and showed increased DNA strand breaks (Tolleson et al. Dvorska 101 apoptosis were observed. Such activation may signal cell survival or induce apoptosis in various cell types depending on the conditions. It was shown that in human promyelotic cell line HL-60. the embryotoxic effect of T-2 toxin on the mouse fetus is mediated through apoptosis. length of signal. FB 1 induced a significant and dose-related increase of modifications of DNA bases (8-OH-dG) and DNA fragmentation in both C6 glioma and mouse embryonic fibroblasts cells (Mobio et al. Apoptosis in HL-60 cells induced by T-2 toxin was dose dependent when cells were treated with concentrations of 5-100 ng/ ml for more than 2 hrs (Yoshino et al. Since T-2 toxin readily crosses the placenta. recently it has been shown that trichothecene mycotoxins trigger a ribotoxic stress response that activates the stressactivated kinases c-Jun N-terminal kinase and/ or p38 mitogen-activated kinase and induces apoptosis (Shifrin and Anderson. The induction of c- 05-Surai. Exposure to FB1 caused a significant increase in micronucleus frequency in a concentrationand in a time-dependent manner and an increased number of the cells were dying by the process of apoptosis (Rumora et al.

chromatin condensation and DNA fragmentation. In particular. Moreover recent results of Mobio et al. In the same study. FB1.... FB1 has been shown to cause apoptosis in a variety of cell types and tissues. 2002). Treatment of monkey kidney cells (CV-1 cells) with FB1 led to cell cycle arrest and apoptosis (Zhang et al. FB2. 2001). FB 1-induced apoptosis involves the activation of caspase 3. but the apoptotic potential of other fumonisins and fumonisin metabolites could substantially vary. both FB 1 and AFB 1 exposure induced the expression of apoptosis-related heat shock protein 72 in AM (Liu et al.. (2000) showed that cytotoxic concentrations of FB1 induce cellular cycle arrest in phase G(2)/M in rat C6 glioma cells. which subsequently may proceed to secondary necrosis. but not AFB1. Furthermore. increases in tissue concentration of the ceramide synthase substrate sphinganine and the sphinganine:sphingosine ratio were correlated with apoptosis (Voss et al. 2001).. 2002).e. More advanced lesions in both organs were characterised by simultaneous cell loss (apoptosis and necrosis) and proliferation (Voss et al. In general. but only FB1 was able to induce apoptosis. FB 1 induces apoptosis of hepatocytes and of proximal tubule epithelial cells. FB 1 caused an activation of the cytokine network in liver. cells treated with FB 1 showed increased DNA fragmentation and terminal uridine nucleotide end labeling in response to TNF-α treatment (Johnson et al. (2001) demonstrated that FB1 kills LLC-PK(1) kidney cells by inducing apoptosis. For example. For example. 2001). (2003) exposed human proximal tubule-derived cells (IHKE cells) to FB1.. Seefelder et al. hydrolyzed FB1 and N-palmitoyl-hydrolyzed FB 1 and investigated caspase-3 activation. The results demonstrated that all compounds led to increased sphinganine levels in IHKE cells. However. 2003). FB1 toxicity caused induction of cytokine networks in liver with involvement of the TNF-α signaling pathway (Bhandari and Sharma. induced the apoptosis of swine alveolar macrophages (AM) with evidence of DNA laddering and nuclear fragmentation... FB3. This included initial disruption of sphingolipid metabolism and accumulation of sphinganine (or a metabolite). the precise mechanism of apoptosis is not fully understood. in turn. In the short-term studies. FB1 also increased DNA synthesis and resulted in cell cycle arrest in the G2/M phase of the cell cycle. 2002). Induction of apoptosis was suggested to be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by FB1 (Dragan et al. under experimental conditions (9 or 18 mM FB1 in the medium) there was an induced DNA fragmentation and laddering and many apoptotic bodies in glioma cells. induced expression of calmodulin. Kim et al. Although it has been demonstrated that FB1 induces apoptosis in many cell lines. cell shrinkage. 2002).102 Effects of mycotoxins on antioxidant status and immunity concentrations of FB1 induced apoptosis. As mentioned above. FB 1 caused morphological changes (i. which is associated with the repression of protein kinase C and possibly its downstream . For example. which. A dose-dependent increase in TNF-α−induced apoptosis was observed in porcine renal epithelial cells pretreated with FB1. It was suggested that the ability of FB 1 to alter gene expression and signal transduction pathways may be necessary for its carcinogenic and toxic effects. suggesting its involvement in hepatotoxic mechanisms (Bhandari et al.. Similarly. membrane blebbing) and time-dependent increases in DNA fragmentation characteristic for apoptosis. particularly the TNF-α signaling pathway. It seems likely that the elevated endogenous sphinganine acts as a contributing factor to the fumonisin-induced cell death (Yu et al. whereas IL-1Ra induction could contribute to the proliferating effects observed in FB1 toxicity. The authors suggested that increased expression of caspase 8 involved in the TNF-α signaling pathway may contribute to the apoptosis. 2001).

caryomegaly.75. For example. 5. 1998). FB1 was investigated in four groups of growing ducks. hepatic and renal GSH concentrations were depressed and proliferation and apoptosis were observed in the outer medulla of the kidney cell (Lim et al.75 mg/kg BW daily for 5 days. Increased hepatocellular apoptosis was also detected in the mice consuming diets containing 72 and 143 mmol/kg FM1 (Howard et al. 2001). Multiple daily doses of FB1 after surgery elevated the number of apoptotic hepatocytes in rats (Li et al. After intravenous injection of male rats with FB1 (1. The authors suggested that FB1-induced alteration of hepatocyte membrane lipid composition is an early key event in the FB1 apoptotic effect. including apoptosis. Electron microscopic analysis revealed margination of nuclear chromatin and swollen mitochondria with amorphous matrical deposit (Moon et al. Mild toxic effects. Surai and J.F.. and early signs of fibrosis were noticed in the liver of rats fed FB1 (25 mg/FB1/kg diet. 2002). 2002)..P. as well as dilation of proximal renal tubules.. 2001). Wistar rats were fed diets containing 0 (control) or 100 ppm FB1 for 12 weeks. 2000). 0. 2002).. Similar observations were described by Sharma et al. FB1 increased apoptotic cells in liver (Bhandari et al. Gelderblom et al. NF-κB and TNF-α (Gopee et al. When a specially designed oxidation system was used. OTA was found to facilitate single-strand 19/12/2004. Nevertheless. proliferation of bile duct epithelial cells. It is interesting that female rats demonstrated more sensitivity than male rats in the induction of hepatocellular apoptosis and mitosis.. 0. 2000). Six hours after administration of FB1. and proliferation of proximal renal tubular cells. No sign of apoptosis was present in the liver or in peripheral blood lymphocytes and only moderate oxidative damage was noted (Bailly et al. a dose-dependent increase in apoptosis in liver and kidney was observed (Tsunoda et al. 23:24 .25 and 6. however molecular mechanisms of this stimulation are not clear at present.p65 103 FB1. renal lesions in FB1-treated calves consisted of vacuolar change. the induction of tubular epithelial cell apoptosis was the primary response of the kidneys to dietary 05-Surai. Dvorska 103 effectors. 2001). The apoptosis-stimulating effect of FB1 has been clearly demonstrated. 2003). Similarly.. Apoptosis was present at all doses (99484 ppm for 28 days) in the kidney of male rats and occurred in females at doses of 153484 ppm FB1 (Tolleson et al. histopathology revealed the occurrence of apoptosis in the liver of rats exposed to FB1 (Pozzi et al.. apoptosis. marked morphologic changes of rat hepatocytes included the appearance of small vacuoles along the margin of the cell membrane. When male mice were injected with FB1 subcutaneously at doses of 0. Necrosis and apoptosis of tubular epithelial cells in the kidney were observed and increased mitotic figures and lymphocytic infiltrate in the small intestine were found (Theumer et al.E. each receiving 0. stimulation of lipid peroxidation by FB1 and decreased antioxidant concentrations including GSH in tissues could lead to changes in redox status of the cell and trigger a cascade of apoptotic changes. 2. 2001). Including FB1 in the diets of rats increased hepatocellular and renal tubule epithelial cell apoptosis (Howard et al.. 1996).. OCHRATOXIN A Lipid peroxidation due to OTA consumption may be implicated in DNA damage. Male mice were injected subcutaneously with vehicle or 2.. which contained cellular debris and protein (Mathur et al. (1997).. FB1 can induce renal injury and organ sphingolipid alterations in cattle.25. Therefore. Probably there is species-specificity in susceptibility to FB1..25 mg/kg).. 2001). 1996).25 mg/kg/day of FB1 for 5 days and sampled 1 day after the last treatment. For example.. 15 or 45 mg/kg FB1 by daily oral administration over 12 days.

the presence of intracellular apoptosis bodies was detected two weeks after toxin treatment.and concentration-dependent direct or indirect caspase-3 activation and subsequently to apoptosis in cultured human proximal tubule cells and in other renal epithelial cell lines of different origins (Schwerdt et al. Marked treatment-specific transcriptional changes were detected for genes involved in DNA damage response and apoptosis (Luhe et al.. cell proliferation. The number of apoptotic bodies was further enhanced at two weeks..104 Effects of mycotoxins on antioxidant status and immunity cleavage of supercoiled plasma DNA through ROS production (Gillman et al. NO synthesis and cell surface markers were largely suppressed by OTA at concentrations between 10 and 1000 ng/ml (Muller et al. 1999). In particular. For example. 2000). 2000). OTA is implicated in DNA-adduct formation (Grosse et al.. Changes in redox status of the cell due to the pro-oxidant action of OTA could trigger cell apoptosis.. In general.. respectively) or a high dose (12. Light microscopic examination demonstrated the presence of eosinophilic globules. Because of OTA consumption.. They were found within the cytoplasm of intact hepatic cells.. cell membrane integrity. at noncytotoxic doses. tissue source and glucocorticoid induction. phagocytic behaviour.. Furthermore.. 2003). resulting in an 8-fold increase in liver over the control values (Atroshi et al. Exposure to low OTA concentrations (530 nmol/L) can lead to time.5 mM and 10 mg/kg. cell differentiation. 1994). 2000). 2002). OTA greatly induced apoptosis in human myc-transfected cell line (Horvath et al. spleen and Peyer’s patch cultures was studied (Pestka et al.5 and 930.2. 1994) it was shown that depending on lymphocyte subset. Exposure of human proximal tubule-derived cells to 30 nmol/L or more OTA led to DNA fragmentation and chromatin condensation (Schwerdt et al. the results indicated that OTA might activate different cellular processes involved in the degradation of DNA in HaK and HeLa cells. OTA. Relatively low OTA concentrations (547. Administration of OTA twice a week for one or two weeks resulted in apoptosis in the liver of mice (Atroshi et al. For example. 2003).. OTA treatment of rats resulted in a 5-fold increase in the expression of the protein haem oxygenase-1 generated during oxidative stress (Gautier et al. 752. Wistar rats were treated with a low dose (5 mM and 1 mg/kg. 2003). 2003). DON could either .. Nanomolar concentrations of OTA promote apoptosis in a cell-type specific fashion.and fibronectin-adherent cells from immobilized substratum causing apoptosis as measured by caspase-3 activation (Scibelli et al. was able to detach collagen.. 1997). 1999). OTHER MYCOTOXINS When the in vitro effect of deoxynivalenol (DON) on apoptosis in specific T. 2001). In human monocyte/macrophage line THP-1 metabolic activity.. Additional evidence was provided indicating that OTA interacts in a cell type-specific way with distinct members of the mitogenactivated protein kinase family providing induction of apoptosis via the c-jun amino terminal kinase pathway (Gekle et al.and B-cell subsets within thymus. OTA at a dose of 20 mg/kg caused nuclear changes characteristic of apoptosis in hamster kidney (HaK) and HeLa cells (Seegers et al. 1999).. It was concluded that exposure to low OTA concentrations can lead to direct or indirect caspase-3 activation and subsequently to apoptosis in cultured human proximal tubule cells and in other renal epithelial cell lines of different origins. respectively) of OTA for 24 or 72 hrs..3 ng OTA/g kidney tissue) have activated apoptotic processes and oxidative damage in kidney cells (Petrik et al. 1999). there was a striking increase in the counts of eosinophils and of apoptotic phagocytes in weaner pigs in a dose-dependent manner (Muller et al.. often containing apoptotic bodies.

ZEA (10. Apoptotic rates in rat liver were significantly reduced when melatonin was co-administered with AFB1 (ElGibaly et al.) concurrently with DON (12.. apoptotic bodies were found in lung cells of rats given AFB1. It seems likely that apoptosis is the principal mechanism contributing to germ cell depletion and testicular atrophy following zearalenone (ZEA) exposure. Surai and J. In particular. 2003). 2003). 19/12/2004. It is interesting that melatonin treatment of rats could enhance hepatic antioxidant/detoxification system.E. In another study. Therefore. GSHPx and GSH-reductase in rat livers treated with AFB1. As demonstrated by DNA fragmentation and flow cytometric analysis. which was confirmed by observations of formation of apoptotic bodies.. 20 and 40 mM) induced concentrationdependent DNA fragmentation in three cell lines (Vero. caspase-3 activity was positively correlated with MDA while negatively correlated with GSH. It seems likely that DON can interact with other inducers of apoptosis to increase apoptotic action. and bone marrow was marked in mice 12 hrs after administering Escherichia coli LPS (0. ZEA induced cell cycle arrest in the three cell lines characterised by an increase in the number of cells in the G2/M phase of the cell cycle (Abid-Essefi et al. In the study.o. Rats were treated with AFB1 (50 mg/kg BW) for 8 weeks.. spleen and Peyer’s patches showed ultrastructural characteristics of apoptosis. (2003) demonstrated that a single dose of ZEA (5 mg/kg) induced testicular germ cell apoptosis in a time-dependent and stage-specific pattern. Caco-2 and DOK) resulting in DNA laddering patterns on agarose gel electrophoresis. Dvorska 105 enhance or inhibit apoptosis. a typical sub-diploid apoptosis peak was demonstrated in lymphocytes treated with DON and AFG1 (Wang et al. 2000). It was suggested that inhibition of protein synthesis and induction of apoptosis are the main mechanisms of DON toxicity in intestinal cells (Maresca et al. Dead lymphocytes in the thymus.. whereas apoptosis in control mice or mice treated with either toxin alone was minimal (Islam et al.p65 105 which was correlated with micronuclei induction. 2001). 1999).. 2003). DON and aflatoxin G 1 (AFG 1 ) could induce and accelerate apoptosis in human peripheral blood lymphocytes... This stimulation could be associated with the stimulation of the phosphatidylinositol (PI) cycle and activation of PI kinase by AFB1 (Pasupathy et al.. Combined treatment of mice with DON and lipopolysaccharide significantly increased the amount of apoptotic thymic and splenic tissue (Zhou et al.p. 23:24 . 2001a). Clearly. which consequently reduced the apoptotic rate and the necrobiotic changes in the liver.P. a significant dose response effect and time effect correlation was found between apoptosis rates and mycotoxin concentrations and the treated time. lipopolysaccharide can interact with DON in mice to induce the glucocorticoid-driven apoptotic loss of immature thymocytes and cytotoxic T-lymphocytes in thymus. apoptosis in thymus. 2002). In particular. It is interesting that vitamin E (25 mM) added simultaneously with ZEA partially reduced DNA fragmentation and apoptotic body formation after 24 hrs incubation.F. This observation was consistent with apoptosis. and pro/preB-lymphocytes and mature B-lymphocytes in bone marrow in mice (Islam et al. Peyer’s patches. Dose-dependent induction of micronuclei in bone marrow and lung cells was observed. 2002).. matureB-lymphocytes in Peyer’s patch. or intratracheally at 2-8 mg/ kg BW and animals were killed after 26 hrs (Raj et al. Furthermore. Kim et al. For example. The levels of caspase-3 activity in the AFB1 group were significantly higher than in controls and the apoptosis was associated with degenerative and necrotic changes in the hepatocytes (Meki et al. AFB1 induced micronuclei and apoptosis in lung and bone marrow cells.). In an experiment with male rats.5 mg/ kg BW p.p.1 mg/ kg BW i. Furthermore. 1999).. AFB1 was administered i. 05-Surai.

skin. . RNS. which are responsible for immunosuppression and increased susceptibility to various diseases and consequently decreased productive and reproductive performance of farm animals. In that sense. an increase in the production of reactive oxygen species (ROS). which is an important determinant of animal health and well being. specific molecules such as agglutinins. However. There are two major types of immune function: natural and acquired immunity (Figure 2). secretion of prostaglandins and cytokines. As a result of stimulation (for example by microbes) monocytes differentiate into macrophages that are more powerful in mediating host defence (Klasing. called the innate immune system. 1998). phagocytosis is the major mechanism by which microbes are removed from the body and is especially important for defence against extracellular microbes. fungi. Macrophage activation and phagocytosis of foreign particles are regularly accompanied by a respiratory burst. Complement Acute phase proteins Humoral Cell-mediated B-lymphocytes T-lymphocytes Immunoglobulins (antibodies) Direct contact with target cells Pathogen removal and resistance to pathogens (immunologic memory) Inflammatory response Figure 2. specific) Natural (innate) Physical barriers Specific molecule Phagocytes NK cells Macrophages ROS. In this respect mycotoxins are one of the most immunosupressive factors in animal diets. General overview of the immune system. Small peptides Kill pathogen Mast cells Dendritic cells Neutrophils Elcosanoids Cytokines.g.106 Effects of mycotoxins on antioxidant status and immunity Mycotoxins and the immune system All animals protect themselves from invasion by microorganisms. Therefore macrophages as well as Immunity Aquired (adaptive. exerted by the enzyme complex NADPH oxidase. Natural immunity. In fact. Macrophages perform a range of functions. acute phase proteins and lysozyme. mucus layer of the gastrointestinal tract). including phagocytosis of foreign particles. Commercial animal production is based on balanced feed. viruses and any foreign molecules. and as a result regulating activity of lymphocytes and other macrophages (Qureshi. This protective capacity requires an effective immune system. parasites. includes physical barriers (e. providing nutrient requirements and optimised environmental conditions. precipitins. and lysing activity by lymphocytes called natural killer (NK) cells. destruction of bacterial or tumor cells. phagocytic destruction of pathogens by macrophages and neutrophils. the remarkable ability of the immune system to distinguish between self and non-self is a great achievement of evolution. it is very difficult to avoid various nutritional or environmental stresses. 1998a).

. Cell-mediated immunity is based on specific antigen recognition by thymusderived T-lymphocytes. Humoral immunity is mediated by antibodies that are released by B-cells into the bloodstream. They also produce cytokine inhibitors. It takes only 15 minutes for chicken macrophages to kill more than 80% of the internalized Salmonella (Qureshi et al. Due to this immunity cells infected with a foreign agent. are destroyed via direct contact between an activated T-cell and the target (infected) cell (Qureshi et al. macrophages also synthesize and secrete a great number of cellular communication molecules such as cytokines. monocytes and eosinophils) can synthesize toxic oxygen metabolites such as superoxide anion (O 2-). In 19/12/2004. macrophages bind. which penetrates the bacterium with production of hydroxyl radical. They are responsible for recognition and elimination of specific antigens: they bind and remove from the host invading organisms/ substances. This immunity is based on the production of immunoglobulins. RNS and eicosanoids mentioned above. a bacterium coming into contact with the plasma membrane is enclosed in a plasma membrane vesicle containing NADPH oxidase.. 1998). Interactions between T.p65 107 immunity (initiating and directing the immune and inflammatory responses) and many other related physiological responses. bacteria) quite quickly. singlet oxygen ( 1 O 2 ).and B-cells. 1998a). hydrogen peroxide (H 2O 2).. In addition to ROS.g.F. 1998). B-cells and T-cells. are specific for distinct macromolecules and increase in magnitude with each successive exposure to a particular macromolecule (Miles and Calder. and degrade foreign antigens (e. hydroxyl radical (OH • ). foreign graft rejections. the production of ROS and reactive nitrogen species (RNS) is a characteristic of both mammalian and avian macrophages (Qureshi et al. nitric oxide (NO) and peroxinitrite (ONOO-) during the respiratory burst (Zhao et al. In general. 1998). The bursa of Fabricius is the site of B-lymphocyte development and differentiation in birds. There are two major types of lymphocytes. Surai and J. 1998a). In general ROS.P. are responsible for the development of specific immunity. Macrophages contain various substances (including enzymes producing free radicals and small peptides with antibiotic activity) involved in microbial killing. Because of this powerful weapon. They also have receptors for chemoattractive factors released from microbes. neutrophils. Therefore natural immunity works rapidly. which is ultimately deadly to biological molecules. RNS and eicosanoids (e. In birds.g. Superoxide radical can dismutate to H2O2. hormones and neurotransmitters (Klasing. as well as antigen presenting cells. both by cytokine production and by serving to present parasite derived peptides to T-cells. 1995). Cell-mediated immunity is responsible for delayed-type hypersensitivity (DTH) reactions. resistance to many pathogenic microorganisms and tumor immunosurveillance (Wu and Maydani.E. leukotrienes and prostaglandins) have recently received substantial attention as major metabolites produced by macrophages (Dietert and Golemboski. 1998). Therefore macrophages are important amplifiers of the immune response. Dvorska 107 other phagocytic leukocytes (e. The defence mechanisms of specific immunity are induced or stimulated by exposure to foreign substances. and TNF-α.. and exposed to an intensive flow of superoxide radical (Giller and Sigler.g. interleukin 6 (IL-6). including the pro-inflammatory cytokines interleukin 1 (IL-1). 23:24 . 1998). 1998a). Acquired or specific immunity consists of humoral and cell-mediated immunity. 1998). internalize. both T-cell and B-cell precursors originate in the bone marrow. for example virus.. Actual development of T-cells takes place in the thymus and B-cells develop in the bursa of Fabricius in birds and in bone marrow of mammals (Lahtala. For example. and gives rise to the acute inflammatory response. which regulate specific 05-Surai.

Therefore. bursa-derived B-lymphocytes and thymusderived T-lymphocytes with various other types of cells. 1997). Various mitogens are used in such assays. which regulate cell activation. 1996). differentiation. isolated lymphocytes are incubated with mitogens. This shows the number of antibody-producing cells. the animal immune system requires the co-operation of macrophages.. Cytokine production. Decreased proliferation may indicate impaired cell-mediated immunity. inflammation and immunity. lipopolysaccharide (LPS. Molecular immunology is developing very quickly. enhanced protein synthesis (including immunoglobulin synthesis by B-lymphocytes and acute phase protein synthesis in the liver) and inflammatory mediator production. These two parts of the immune system work together through direct cell contact and through interactions involving such chemical mediators as cytokines and chemokines. This assay identifies cells with different surface markers. which are often sheep red blood cells (SRBC). and mechanisms and factors affecting avian immunocompetence have recently received substantial attention (McCorkle. Flow cytometric analysis. In this assay. Plaque-forming cell (PFC) test. The results can be used for understanding the cellular basis of immune response. This assay provides information about cell-mediated immune response and consists of measuring the number of cells in culture • • • • with or without addition of a stimulatory agent (mitogen). For example. anorexia and loss of tissue components (Grimble. Physiological changes resulting from stimulation of the immune system include fever. The banning of feed grade antibiotics in Europe has made immunocompetence the major factor determining efficiency of poultry production. immunisation with appropriate antigens (viral or bacterial) can elicit serum antibodies. This assay provides information about humoral immunity (B-cell responsiveness) and its association with cellmediated immunity (T-cell co-operation). but is highly specific for antigens and has memory. T-cells produce a range of protein mediators called cytokines. The immune response involves cellular proliferation (T-lymphocytes). a T-cell mitogen). Saif and Swayne. in vivo methods of immune function assessment are based on two main approaches: antibody response to vaccine or delayed-type hypersensitivity (DTH) reactions. a T-cell mitogen). specific immunity takes longer to develop. In vitro indices of immune function include (Wu and Meydani. 1998): • Lymphocyte proliferation assay. The second (DTH) method is used to assess cellmediated immune function. 1998) is a frontline for future research. phytohemagglutin (PHA. It must be emphasised that cellular integrity is very important for receiving and . The haemagglutination (HA) assay measures serum antibody concentration (titre) against antigens. T. a Bcell mitogen) and pokeweed mitogen (PWM.and B-cell mitogen) (Hayek et al. which activate division of either T-or Blymphocytes. 1998) and nutritional modulation of resistance to infectious diseases in poultry (Klasing. 1998. The impact of the avian immune system in modern production cannot be overestimated.108 Effects of mycotoxins on antioxidant status and immunity comparison to natural immunity. This assay assesses activity of cytotoxic T-lymphocytes (a group of T-cells that kill other cells by recognising their cell-surface antigens) and NK cells (a group of non-T and non-B lymphocytes that kill virus-infected and tumour cells). growth. but most often they include concanavalin A (con A. In the first method. Cytotoxicity assay. When analysing data related to immunomodulation careful attention must be paid to methods used to assess immunological functions.

. 2000). 2002).E. rats and mice. ß-zearalenol and NIV on T.. Therefore.. In particular. 1992). Bondy and Pestka. Therefore. Therefore.F.. depressed complement and interferon production could also result from AFB1 exposure. and in such cases the signs of disease observed are those of the infectious process rather than those of the aflatoxin that predisposed the animal to infection.or B-lymphocyte activity. The immunomodulatory effects of ochratoxins have also been considered for many years and a summary is shown in Table 6. pigs and lambs) and also in laboratory animals (mice and rats) and in various in vitro systems. For example. anti-Brucella abortus antibody production was compromised and ROS production by macrophages from AFB1 progeny decreased (Qureshi et al. Furthermore. T-2 toxin. IL production was also compromised.2-1800 ng/ml). NO production stimulated by LPS significantly decreased (Moon et al. T-2 toxin. Furthermore. α−zearalenol. Long-term immune depression of macrophagemediated functions can occur following embryonic exposure to AFB1 (Neldon-Ortiz and Qureshi. most data were obtained with laboratory animals. they also inhibited NK cell activity (Berek et al.p65 109 on cell-mediated immunity and phagocytic cell function. Effects of DON. 1998). OTA has been shown to affect mainly humoral immune function at the level of antibody synthesis in chickens. fusarenon-X. turkeys. lethality. poultry and laboratory animals and range from acute mortality to decreased performance and immunosuppression. ZEA. AFB 1 decreased proinflammatory and increased antiinflammatory cytokine mRNA expression in weanling piglets (Marin et al. 1991). AFB1 can be transferred from chicken to the egg and further to the developing embryo. acquired immunity from vaccination programs may be substantially suppressed. mycotoxin-induced immunosuppression was related to depressed T. 3-acetyldeoxynivalenol. 2001). chickens. However. fusarenon-X. In some instances. 1992). NIV and DON showed the highest immunosuppressing effects in vitro. the antioxidant/pro-oxidant balance of the host is a critical consideration in optimal immune system function. The mycotoxin concentrations used in the experiments were comparable to those found in normal human peripheral blood (0. Therefore.g. As can be seem from Table 5. suppresses immune function and decrease resistance to infectious disease (Corrier.P. In fact. Among the mycotoxins tested. farm animals and cells derived from livestock species have been employed to evaluate the immunotoxicity of mycotoxins (Sharma. For example. AFB 1 mainly decreases lymphocyte activity and may affect macrophages assisting lymphocyte function. The effects of several mycotoxins on immune responses have been investigated (Tables 5-9). 1998). consumption of certain mycotoxins. Dvorska 109 responding to the messages needed to coordinate an immune response (Latshaw. 1993. Mixtures of aflatoxin with other mycotoxins can result in greatly augmented biological responses in terms of weight gain depression. 2001). Aflatoxin is an immunomodulating agent that acts primarily 05-Surai. in macrophages exposed to AFB 1.. immunosuppression caused by AFB1 has been demonstrated in various livestock species (e. 1992). and immune reactivity (Pier. Surai and J. however..and B-cells were studied using a proliferation assay and antibody-dependent cellular cytotoxic NK cell activity on human peripheral blood mononuclear cells (Berek et al. The clinical toxicologic syndromes caused by ingestion of mycotoxins have been characterized in domestic animals. It has been demonstrated that exposure of purified 19/12/2004. 23:24 . Immunosupressive potency of various mycotoxins differs substantially. number and phagocytic activity of macrophages were also decresed in growing gilts receiving OTA for 35 days (Harvey et al. Furthermore. at levels that do not cause overt clinical mycotoxicosis. 1991).. the progeny of hens consuming an AFB 1 -contaminated diet may be increasingly susceptible to disease owing to suppression of humoral and cellular immunity.

. 1985a +AFB2 for 5 weeks measured by DTH skin test ↓.. Effects of aflatoxin B1 on immunity.0 µg AFB1 Broiler chicks Broiler chicks 1 mg/kg.5 mg/kg diet for 21 days .. Humoral immunity unchanged.5 µg/g diet from Cell-mediated immunity (graftGiambrone et al... 1985 for 42 days Chickens 2. 1998 hens 10 mg/kg titres ↓. 1. 2003 Peripheral T-lymphocyte counts ↓... Acquired immunity to ND or fowl cholera vaccination unchanged 4-month-old 100-400 µg/kg Lymphoblast transformation ↓ Quist et al.p. 2000 wild turkeys feed for 2 wk Chick embryo 1. 1985b turkeys and test) ↓. Phagocytosis of SRBC and ROS production by macrophages ↓ in 5 mg AFB1/kg Broiler chicks 5 mg/kg Secondary antibodies Okotie-Eboh et al. Humoral immunity unchanged.09-17. Sister chromatid exchanges in T-lymphocytes ↑ 6-day chick 0. 2000 activity ↓. 5 or In progeny.1. Substrate adherence potential of peritoneal exudate cells ↓ at 1 µg AFB1. and 1 Macrophages recruited in the Neldon-Ortiz and Qureshi.5 µg/g of feed Total complement activity ↓ Stewart et al. embryos µg/per embryo peritoneal cavity after i. embryo at day 18 index T-cells unchanged. anti-Brucella abortus Qureshi et al.. IgM unchanged Chickens 0. 2000 Splenic plasma cell counts ↓ Broiler chicks Percentage/mean phagocytic Ibrahim et al. Immune response measured by HI test ↓ Broiler breeder 0. 1988 0 to 6 weeks (DTH reaction ) suppressed at 30. Mitotic Potchinsky and Bloom. Sister 1993 of incubation chromatid exchanges in Blymphocytes ↑. host reaction) ↓. DTH weeks of age reactions to tuberculin ↓. 1992 Sephadex elicitation ↓.2.5. Humoral immunity (to rabbit RBC) unchanged. 0.4 µg/g Mitotic index B-cells ↓. Serum IgG and IgA↓..5 mg/kg diet for 21 days 2.5-1.110 Effects of mycotoxins on antioxidant status and immunity Table 5..3 mg/kg from Cell mediated immune response Kadian et al. 1997 against IBD↑ Broiler chicks 400 µg/kg AFB1 Cell-mediated immunity Giambrone et al. 7-49 days 2.. Species Dose Effects on immune system Reference Titres to NK ↓ Shivachandra et al. Celik et al. 1978 hatching to 4 vs. Macrophage phagocytic potential ↓ at 0. 45 and 60 days of age 14-day-old 200 µg/kg Cell-mediated immunity (DTH skin Giambrone et al. Acquired immunity to ND or fowl cholera vaccination unchanged Broiler chickens 2.

p65 0.03. and protein Human 0... Synthesis every other day for of DNA in mixed lymphocyte ↓. AFB1 decreased proinflammatory Marin et al. 300 and Cell mediated immunity. Complement titers↓. 1990 700 µg/kgBW capacity of macrophages ↓ Rats and mice Aerosol inhalation Alveolar macrophage Jakab et al. Raisuddin et al.F. mRNA..8 mg/kg for 8 Lymphocyte proliferation and Quist et al. 1997 deer wks DTH reactions unchanged Weanling rats 60. DTH reaction to hemocyanin ↓ Murine 10 or 50 mM NO production stimulated Moon et al. 1995 cells in vitro killing of Candida albicans ↓. Intrinsic antiviral activity or superoxide production unchanged Rat Kupffer 0. 1986 of feed to Erysipelothrix rhusiopathiae..01 pg/ml Phagocytosis ↓. intracellular Cusumano et al.8 µg/kg instillation to AFB1 with the effect persisting for ~2 weeks Mice 0.. or 280 µg/kg. Cell-mediated immunity (graft vs host and cutaneous basophil hypersensitivity reactions) ↓ Weanling 140-280 µg/kg. Surai and J. 1996 monocytes activity ↓. Skin thickness (PHA test) ↓ van Heugten et al.. TNF-α) and increased anti-inflammatory (IL-10) cytokine mRNA expression Weaned pigs 140. 1994 or intratracheal phagocytosis ↓ at 16. intrinsic anti-Herpes virus activity ↓ 6-day chick embryos 05-Surai. Proliferative responses to mitogens unchanged. Serum IgG and M values↑ Female lambs 2 mg/kg for 37 d Response to intradermal Fernandez et al. 1998 peritoneal by LPS ↓. Dvorska 111 Table 5. 1987 0..1 µg 111 19/12/2004..P. ↓ at the 300 and 600 µg dose levels Weanling rats 350 and Population and phagocytic Raisuddin et al.1-1 pg/ml Phagocytosis and microbicidal Cusumano et al... 1993 600 µg/kg BW measured by DTH response assay. mediated by the macrophages reduction of iNOS activity.. 1994 for 3 wks linearly with ↑ dietary AFB1 Pigs 300 or 500 mg/kg Humoral immune response Panangala et al.145 or [3H]thymidine uptake in Reddy et al. 23:24 . 0. 2002 piglets 4 wks (IL-1ß. 2000 injection of PHA↓ White-tailed 0.. measured by ELISA unchanged. 1985 exchanges in blood cells ↑ (5-fold).70 mg/kg orally lymphocyte cultures↓. Continued.E. Species Dose Effects on immune system Reference Incidence of sister chromatid Dietert et al. 2 weeks Primary antibody production by splenic cells from animals challenged with SRBC..

Species Dose Effects on immune system Reference Broiler chicks 2 mg/kg Santin et al. IgG ↓ at BW for 4 wks 0..34-1.. 1996a OTA (500 µg/kg lymphocytes in the offspring BW) on day 10 when stimulated with B. 1994 challenged blastogenesis ↓. 2002 130. 1992 for 35 days sensitivity response to PHA ↓. percentages of mature CD4+ cells ↓ and percentages of immature..34 or membrane and reduction in 1.07. Total Ig levels ↓ at 2-4 ppm Broiler chickens 0. 2001 0. Stimulation index for lymphoblastogenesis ↓. Humoral immune response ↓ HI titers to ND vaccination ↓ Stoev et al. Proliferation of day 11 of lactation thymocytes in response to ConA ↑ in pups from dams exposed to 50 µg OTA/kg BW Mice Dams... 0. 50 or from dams given 10 or 50 µg 250 mg/kg BW) on OTA/kg BW. Il-2 production when lymphocytes were stimulated with ConA ↓. 1984 20 days from hatch lymphoid organs ↓... 1996 200 µg/kg before postpartum percentages of splenic and during gestation CD4+ and CD8+ cells ↓ Mice Dam’s exposure to Proliferation of splenic and Thuvander et al. Mitotic cells in the bursa ↓ Weight of lymphoid organs ↓.. Effect of Ochratoxin A on immunity.68 mg/kg OTA Rat Dam’s exposure to The proliferative response of Thuvander et al. 1979 day-old to 3 weeks Monocytes ↓ at 2.112 Effects of mycotoxins on antioxidant status and immunity Table 6. S. 305 and Stoev et al. Chang et al.or T-cell postpartum mitogens 3 days after exposure ↑ Broiler chicks .5 mg/kg of feed Cutaneous basophil hyperHarvey et al. DTH to tuberculin ↓.5-8 µg/g from Total circulating lymphocytes ↓.0 mg/kg PHA.68 mg OTA/kg splenic T-cell fraction.0 µg/g. 2000 790 mg/kg Broiler chicks Up to 4 mg/kg for Ig-containing cells in Dwivedi and Burns. Thickening of the basement Dortant et al. typhimurium broiler chicks alone had no effect on the variables measured Growing gilts 2. 10. 1996b a single dose of splenocytes to ConA ↑ in pups OTA (0. Number and phagocytic activity of macrophages ↓ Rats Gavage with 0. 1996a OTA (500 µg/kg BW) thymic lymphocytes in response on day 16 of to mitogens in pups at 15 gestation days of age ↓.and ConA-stimulated Elissalde et al. doublepositive (CD4/CD8+) cells in the exposed pups ↑ Mice Dam’s exposure to Proliferative responsiveness of Thuvander et al.. 2002 Chicks 5 mg/kg Vaccination titres to NK ↓. In offspring on days 14 and 28 Thuvander et al. of age Circulating heterophils unchanged Salmonella3... OTA.

1989). lymphopenia. In particular. In fact. The results strongly suggest that the toxin caused immunosuppression through interference with essential processes in cell metabolism (Lea et al. Dvorska 113 Table 6. 2000).005 µg/kg BW Immune response to SRBC ↓ Haubeck et al.. neutrophilia and eosinophilia. and apparently inducing an antigenic response to FB1. short-term exposure of suckling pups to OTA via the milk stimulated the proliferative responses of lymphocytes to polyclonal activation. while Salmonella alone had no effect on these parameters (Elissalde et al. Immunized animals also showed a lower survival rate after experimental infection with Pasteurella multocida as well as an increase in oxygen radicals in blood cells (Muller et al.F.. antibodyproducing cells. 1999). Surai and J. 1989). There was also a substantial increase in the counts of eosinophils and of apoptotic phagocytes. prenatal exposure to relatively low doses of OTA may induce immunosuppression in the progeny.E. Furthermore. 1996a). and fumonisininduced immunotoxicity is an area of active research (Bondy and Pestka. in Salmonella-challenged broiler chicks PHA. Species Dose Mice 250 or 2600 mg/kg After 28 days. It is important to note that subchronic oral exposure to OTA affects certain immune functions in mice at exposure levels that may be found in contaminated food products (Thuvander et al. In weaner pigs subtoxic amounts of OTA produced immunomodulation in a dosedependent mode (Muller et al.. Continued. 2000). 1995). in IgG and macrophage phagocytic activity (Qureshi 19/12/2004. OTA appears to suppress NK cell activity by inhibiting production of basal interferon. It has been shown that the decrease in proliferation and antibody production in young animals resulted from prenatal modulation of the immune system. Reduced phagocytosis and reduced expression of a swine-specific surface marker on lymphocytes were also observed. 23:24 .. 1995 diet.. both IL-2 production and IL-2 receptor expression of activated T-lymphocytes were severely impaired. Recent studies have examined immune function in the offspring of rats and mice exposed to OTA pre. After 90 days.. in chickens FB1 caused a decrease in total immunoglobulins. They include weight depression. In contrast. 28 days and plaque-forming cells ↓. causing both stimulation and suppression of responses to foreign antigens.. In the mouse model OTA had a non-selective suppressive effect on various immune reactions. FB 1 has diverse effects on the immune system. 1981 Mice Effects on immune system human lymphocyte populations and subpopulations to the toxin will abrogate the cell’s ability to respond to activating stimuli in vitro (Lea et al. Thus. (Luster et al. In particular. 1995).. AB production Thuvander et al. proportion of mature CD4+ or CD8+ cells ↓ 0. Fumonisin toxicity has been characterized relatively recently in comparison to aflatoxin and ochratoxin (Table 7). For example. antibody titres in blood serum and phagocytosis of E.and perinatally (Bondy and Pestka. Decrease in thymocyte cell counts ↓ in the 250-µg/kg group. It 05-Surai. 1987). 1994). coli by blood phagocytes become suppressed..and ConA-stimulated blastogenesis was depressed as a result of OTA consumption. Similarly. It is interesting that the time of exposure significantly influences the immunotoxic effects of OTA on the developing immune system in rodents (Thuvander et al..p65 113 Reference included increased counts of total leukocytes and neutrophils in the blood and reduced lymphocyte levels.P.

p daily.25 mg/kg/d FB1 weights in M. Effects of Fumonisins on immunity. ConA-induced Dombrink-Kurtzman et al.. 10.1-10 µM White Leghorn 6.. 200 µg/kg SRBC ↑ (combination of FB1 and feed. Dresden et al. Number of plaque-forming cells Martinova et al. in turkey poults a combination of FB1 and AFB1 was responsible for increased primary immune response to SRBC (Weibking et al. at 1 to 4 to 12-fold increase in the Martinova et al. injections of weights in F ↓.. 1995).. with SRBC. 1994).. and chicks 42.. 1995 at 5-100 µg produced against SRBC ↓ I. 2002 peroxidative damage ↑ 1-100 µM LPS-induced production of NO Meli et al. 10.5 or Thymus weight ↓. .c. and liver Qureshi et al. PHA response unchanged 1 to 21 1-100 mg/animal/d Titres unchanged. Membrane Ferrante et al. 1995 50 µg number of of plaque-forming cells after SRBC injection 1-10 µM Membrane fluidity ↑. from day AFB1).. 1994 AB1. Relative spleen and thymus Johnson and Sharma. PHA-induced T-lymphocyte and LPS-induced B-lymphocyte proliferation in F ↓. Lymphocyte Tornyos et al. 1995 weights ↓. Circulating phagocytic for 4 days cell numbers ↑ 50 (LD).114 Effects of mycotoxins on antioxidant status and immunity Table 7. No effect on organ 2001 2. 2003). cruzi. 2000 and PGE2↑ at 0. However. Serum Bondy et al. NK cell activity unchanged 75 mg/kg feed and Primary immune response to Weibking et al. Species Dose Effects on immune system Reference Splenic.5. Bursa of Fabricius unchanged.1.. thymic. 6 weeks NO production by MG↑ after 14 days Five daily s.. 2002 FM2. Effects of FB1 on immunocompetence of laboratory animals also vary substantially (Table 7). Total Ig and IgG. ConA. and 100 µM LPS-induced NO production ↑ Rotter and Oh.. 2003 stimulation by PHA. Splenic cellularity and the basal rate of lymphocyte proliferation in F ↓..p. LPS unchanged Injected at 7. 1996 macrophage cell Rat splenic 1-100 µg/ml NO production ↑. FM1+ After challenge with T. Expression of IL-2 mRNA in splenocytes in F ↓ I. 1995 10 mg/kg BW/day IgM ↑.7 mg/kg from day 7 to 42 Turkey poults Weaned pigs Rat Mice Mice Mice Mice Macrophage cell line Murine macrophage cell line Murine 1. FB1 (up to 100 mg/animal/day) did not affect immunity (Tornyos et al. Macrophage phagocytic activity ↓. macrophages proliferation of splenic cells in 2000 and lymphocytes the presence of NO synthase inhibitor ↑ et al. In weaned pigs...

which is consistent with the sharp decrease in the ceramide content in this organ (Martynova et al. immunostimulation can be a result of interference with various cellular regulatory mechanisms (Rotter et al. including altered parameters of humoral immunity. For example. virulence of both E.P. or to potential immune cell targets.F. Futhermore. 1993). subchronic T-2 toxin treatment of timedpregnant B6C3F1 mice resulted in significant and selective depletion of fetal liver cells expressing low levels of surface CD44 and CD45 antigens. It appears that trichothecenes are potent immunosuppressive agents that directly affect immune cells and modify immune responses because of tissue damage elsewhere. represent highly sensitive targets of T-2 toxin exposure. Surai and J. typhimurium and then treated with T-2 toxin every other day for 10 days had markedly larger and more bacteria-related lesions in the spleen. antioxidant/pro-oxidant balance and interactions with other factors. 2003). responsible for thymic atrophy (Holladay et al. The authors showed that the precursors of B-cells might represent highly sensitive targets of T-2 toxin exposure. The evidence is quickly accumulating to show that DON can be immunosuppressive or immunostimulatory. Although these effects have been largely characterised in the mouse. Most of the research on T-2 toxin effects on immunity was perfomed with laboratory animals and there are only a few publications addressing immunomodulating properties of T-2 toxin in farm animals. the trichothecenes can both suppress and stimulate immune function (Table 8). 1993). Apparently there are species-specific features in sensitivity to trichothecenes. limited information is presently available regarding the contribution of such a mechanism to immunosuppression in vivo. 1996). In great contrast.p65 115 agent (Holladay et al. exposure of experimental animals and humans to T-2 toxin has been shown to have a variety of immunosuppressive effects. 1990). While immunosuppression is probably related to the inhibition of translation. In fact. coli and S. 1990).. in contrast to thymocytes. sheep and calves treated with Fusarium T-2 toxin develop leukopenia and decreased function of peripheral lymphocytes (Sharma.E. 23:24 . It is well established that T-2 toxin is cytotoxic to lymphocytic cells in vitro. 2000).. Impaired resistance to pathogenic microorganisms occurs after exposure to the trichothecenes T-2 toxin and DON. This may predispose food animals to infectious disease and could result in decreased productivity as well as increased animal-to-human transmission of pathogens such as Salmonella and Listeria (Pestka and Bondy. typhimurium alone (Tai and Pestka. Characteristic effects of DON also include superinduction of cytokine production by T-helper cells (in vitro) and activation of macrophages and T-cells to produce proinflammatory cytokines.. Similar to FB1. 1995). however. For example. For example. For example. Dvorska 115 Immunomodulatory properties of FB 1 probably depend on its effect on lipid metabolism. auerus decreased. several investigations with DON suggest that immunotoxic effects are 19/12/2004.. kidney. in mice exposed to T-2 toxin at 3 mg/kg BW by gavage. the molecular basis of immune modulation by mycotoxins remains mostly unknown and continues to be an active area of research (Bondy and Pestka. For example. in vivo DON suppresses normal immune response to pathogens and simultaneously induces autoimmune-like effects. and liver than animals challenged with S.. suggestive of possible lymphoid progenitor cell sensitivity to this 05-Surai. mice challenged with S. depending upon the dose and duration of exposure. 1995). For example. recently it has been shown that T-2 toxin (up to 1 ppm) in the poult diet did not affect antibody production stimulated by various antigens (Sklan et al. Immunomodulating properties of DON have been studied mainly with rodents (Table 9). It seems likely that lymphocyte progenitors. FB 1 decreased CD3 receptor expression on the surface of thymus cells in vitro and in vivo.

typhimurium alone Immune response to sheep RBC ↓ Pang et al. 1982 Jagadeesan et al. T-cell number ↓.0 or 3.5 or 3.0. the cortex was atrophic while the medulla was proliferative.and T-cells were impaired and responsiveness to PHA and LPS decreased Virulence of both E... coli and S. 1990 Tai and Pestka.6 mg/kg per day for 43 days Gastric intubation at 100 µg/kg BW/ day for 4-5 wk Rats 2 mg/kg Mice 3 mg/kg BW by gavage 1 mg/kg every other day for 10 d Mice challenged with S. 2. Proportion of T-lymphocytes ↓.116 Effects of mycotoxins on antioxidant status and immunity Table 8. Blastogenic transformation of lymphocytes ↓ Lymphocyte count ↓. kidney. 1988 Pang et al. 390 µg/L 9-10-weekold pigs 15 mg/kg Calves 0.. 1982 Mann et al. ConA. 2003 Leukocyte count ↓.0 ppm in the diet for 16 months 4. Antibody formation ↓. Mortality ↑ Corrier and Ziprin. PHA and PWM ↓ at early (3 to 5 days) and late (20 to 28 days) postdosing intervals. aureus ↓ Markedly larger and more bacteria-related lesions in the spleen. 1995 Leucocyte counts↓ at the end of wk 4. In the spleen. 1..5. Lymphocyte transformation ↓. T-lymphocyte-dependent humoral immunity unaffected Schiefer et al. HA titer to SRBC unchanged Lymphocyte responses to mitogens ↓.6 mg/kg/day Calves Monkeys 0.. Effects of T-2 toxin on immunity. Chemotaxic migration of neutrophils ↓ IgM and IgA ↓. 1986 . 1987 Buening et al. Species Dose Young poults Up to 1 mg/kg for 32 days 7-week-old pigs 0. B-cell number ↓.. 1990 Cooray and Jonsson.0 mg/kg diet for 3 weeks 9-10-weekold pigs Aerosol.. Neutrophil count ↑.0 mg/ kg of BW Effects on immune system Reference Antibody titres unchanged Sklan et al. 1987 Growth of Listeria ↑. 1982 Lafarge-Frayssinet et al. typhimurium Mice 1988 Mice Mice exposed to Listeria 20 ng 1. and PWM blastogenic responses and H1 titers to SRBC↓ Blastogenic responses to ConA.. Bactericidal activity of neutrophils ↓. IgG and IgM levels ↓ In progeny. and liver than animals challenged with S. 1990 Holt and DeLoach. both B. IgG→ Rafai et al.. PHA.

005-100 ng/ml Human lymphocytes Murine macrophage cell line 216 ng/ml 05-Surai.0 mg/kg over 8 wks Weanling mice 0. 1992 Miller and Atkinson. 23:24 .6. the T-helper 1 cytokines IFN-γ and IL-2. 1997 Young pigs 0.p65 25-100 ng/ml 117 Rotter et al.PMN neutrophils ↑. IgA ↑ Serum IgM to SRBC ↓. 1986 Meky et al. Continued.E. Microbiocidal activity ↓. 1.7 mg/kg Overnes et al.F.. Dvorska 117 Table 8. Species Dose Effects on immune system Reference Growing pigs 0.. NO production ↓ at 25-250 ng/ml Ayral et al.. and TNF-α. 1984 forming cell numbers ↓ Phagocytosis ↓. Superoxide anion production ↓ at 1 ng/ml. 1997 Dong and Pestka. 1993 Rasooly ands Pestka. 1986 cells ↓. 2001 Table 9..5 ng DON/ml.5 mg/kg BW by gavage Murine 0.3. Effects of DON on immune system. IL-6. but ↓ at 250 ng/m.005.. and the T helper 2 cytokines IL-4 and IL-10 ↑ Serum IgA and microhematuria index ↑ after 4 to 8 wks and continued to increase with further exposure Total IgA ↑. at 50-100 ng/ml lymphocyte proliferation ↓ 50% inhibition in cell proliferation Production of H2O2 after LPS stumulation ↑. 1994 Zhou et al.8 and 4..75.00 mg/kg diet for 28 days 5 or 25 mg/kg BW Secondary antibody response to tetanus toxoid ↓ dosedependently α-globulin levels. antibodies ↓... 1983 Human lymphocytes Meky et al.75.4 weeks 1 -5 ng/ml Spleen proliferative responses to ConA ↓. Phagosome-lysozome fusion ↓ at 100 ng/nl PHA-induced lymphocyte proliferation ↑ at 0. Stimulation of B1988 and T-cells by mitogens ↓ Total circulating white blood Forsell et al. 2.5 or 7.0. PlaqueTryphonas et al. 1998 19/12/2004.1 ng/ml-1 µg/ml peritoneal macrophages Lymphocytes in vitro 0. 1992 Serum levels of anti-SRBC Robbana-Barnat et al. 50% inhibition in cell proliferation Friend et al.. 2001 Ji et al.P.5. Surai and J. Species Dose Effects on immune system Reference Mice 20 ppm for 1. and antibody titers to SRBC↓ mRNAs for IL-1ß.25. Total IgG and IgM ↓ Mice Mice 25 mg/kg for 8 or 24 ws Mice 25 ppm for 4 and 8 wks 10-100 mg/kg in the diet Mice Weanling mice 0... Serum IgM ↓.

oxidative stress caused by mycotoxin consumption could be responsible for breaking effective communication between immune cells. 2002). 1991). Protective effect of antioxidants against mycotoxicoses The wide range of mycotoxins that can contaminate animal feed and their differing chemical compositions makes protection against mycotoxin-related toxicity a difficult task. irradiation. Elevated cytokine expression may play an important role in the pathophysiological effects of DON and other trichothecenes (Zhou et al. For example. nutritional manipulation has been actively used to . modern agronomic technology cannot eliminate pre-harvest infection of susceptible crops by fungi (Wood.. Therefore. this strategy can be only partially effective. stimulation of lipid peroxidation and apoptosis and damage to immune cell receptors appear to be involved in the immunomodulation properties of mycotoxins. which ultimately would misregulate the immune system and result in immunosuppression. threshold dose. Although the molecular basis for many of the specific immunosuppressive effects of mycotoxins is presently unclear. In recent years. a single DON exposure rapidly induces gene expression in vivo for a wide range of cytokines with apparently complete recovery occurring after 24 hrs. It is interesting that experimental dysregulation of IgA production and IgA nephropathy persisted up to four months after a discrete period of dietary DON exposure (Dong and Pestka. 1993). There are various approaches to control or combat mycotoxin problems.or B-lymphocyte activity depressed NK cell activity suppressed immunoglobulin and antibody production reduced complement or interferon activity impaired macrophage functions The sensitivity of the immune system to mycotoxin-induced immunosuppression arises from the vulnerability of the continually proliferating and differentiating cells that participate in immunomediated activities and regulate the complex communication network between cellular and humoral components (Corrier. this strategy can be quite costly. Mycotoxin-induced immunosuppression is related to both natural and adaptive immunity: • • • • • depressed T. 1997). 2001a). 1994). As mentioned above. ammoniation and ozone degradation have not been developed to an industrial level because they are either timeconsuming or comparatively expensive (Dawson. inhibition of DNA. RNA and protein synthesis via a variety of different mechanisms appears to be directly or indirectly responsible for the immunosuppressive action of many mycotoxins (Corrier. Males appeared more susceptible than female mice to DON-induced IgA dysregulation and IgA nephropathy in terms of latency.. 1991). The simplest strategy is based on the prevention of mycotoxin formation in feeds by special management programmes including storage at low moisture levels and prevention of grain damage during processing (Dawson. high levels of polyunsaturated fatty acids in the immune cells and presence of sensitive receptors on cell surfaces make them an important target for free radical attack (Surai. 1996). However. Other strategies based on microbial or thermal inactivation of toxins. In fact. detrimental effects on antioxidant defences. physical separation of contaminated feedstuffs. Therefore. 2001). Furthermore. DON can selectively and concurrently upregulate or downregulate critical functions associated with activated macrophages. and in countries with warm and humid conditions. and severity (Greene et al. Consequences of oxidative stress for immunocompetence are shown in Figure 3.118 Effects of mycotoxins on antioxidant status and immunity also likely in domestic animals (Rotter et al.. 1992).

2001). 1997) or in an in vitro system using cell lines (Shokri et al. Verma and Nair.. Dvorska 119 Phagocyte function compromised Apoptosis of immune cells Damage to lymphocyte receptors and disruption of communication among immune cells.. Vitamin E was also effective in protection against fumonisin B1 (Abel and Gelderblom. improve animal defence against mycotoxins or to decrease the detrimental consequences of mycotoxin consumption. Ghedira-Chekir et al. 1998).. 1994). 1986). hepatic metabolism of AFB1 in turkey poults was examined at various dietary Se concentrations (0. 1999) or ZEA (Grosse et al. 2000).. vitamin E supplementation ameliorated the prooxidative effects of OTA in the chicken (Hoehler and Maraquardt. Burguera et al. 2002). Therefore dietary supplements such as Se are considered effective in the reduction of aflatoxicosis in poultry (Dalvi. T-2 toxicosis in mice in vivo (Atroshi et al. Protective effects of vitamin E were also obvious in aflatoxicosis (Shen et al. Similar protective effects of Se against aflatoxicosis have been shown with mammalian species. DON or T-2 toxicoses (Segal et al..5 mg Se/kg were protected from the toxic effects of AFB1 (Davila et al.. Tsuchida et al.. 23:24 . 2001). Other antioxidant compounds also have protective effects against various mycotoxins. Since lipid peroxidation plays an important role in mycotoxin toxicity. 1996) and mouse (Grosse et al. 1999.2. prevented the genotoxic effects of OTA in E.. Oxidative stress and the immune system (Adapted from Surai.F.. Choi et al. a protective effect of antioxidants is expected (Galvano et al. The experimental results provided clear evidence of Se-induced enhancement of aflatoxin detoxification (Gregory and Edds. 1984. 2000).. Souza et al. 1995.. To investigate the biochemical mechanism of the protective effect of dietary Se during aflatoxin exposure. 1983). The effects were measured by alteration of clinical responses and hematologic (prothrombin times). For example..0 or 4. Indeed.0 ppm). 1994) in rats.. coli (Malavielle et al.. 1997).. in several experiments with various animal species. compromised recognition of target cells Imbalance in eicosanoid production by phagocytes and inflammation OXIDATIVE STRESS Compromised antioxidant system Decre ased act ivi ty of NK cells Damage to healthy tissues by free radicals produced by phagocytes Compromised anti body production by B-lymphocytes Figure 3. It also decreased the cytotoxic effect of T-2 toxin in cell culture (Shokri et al. 1983.E. 1997. 1999).. Rizzo et al.P.p65 119 induced by FB1 (Mobio et al. a water-soluble form of vitamin E. Trolox C. 2.. 1998. 2000). protective effects of antioxidants against the toxic effects of mycotoxins were observed. Surai and J. Atroshi et al. (1983) indicated that selenium (Se) has a protective effect against AFB1 toxicity in turkey poults. 1994. electrophoretic and clinical chemistry 19/12/2004. Recently the protective antioxidant effect of organic Se in combination with vitamin E has been shown in chicks exposed to cold stress and aflatoxincontaminated feed (Stanley. 1984). Pre-incubation of the glioma cells with vitamin E (25 mM) for 24 hrs before FB1 (18 mM) significantly reduced DNA fragmentation and apoptotic bodies 05-Surai. 1998. It was suggested that the protective action of Se was not mediated by an increase in glutathione availability for aflatoxin conjugation or by effects on the activities of these enzymes as measured in vitro. Pigs fed a diet containing 2.

but is obvious with T-2 toxin as well. The acute lethal toxicity of T-2 toxin was reduced by administration of sodium selenite (Yazdanpanah et al.. 1994.. 1997). Additional experiments were conducted to verify the effect of Se on the mutagenic activity of AFB1. the same authors reported that Se could effectively inhibit AFB 1 -induced DNA damage (Shi et al.. 2002). Tutelyan et al. 1995) and to prevent DON toxicosis (Rizzo et al.. 1986).0 mg/kg) were studied in 24 dairy calves. Shi et al. 1990) or 3-5-fold (Tutelyan et al... as can be seen from data presented in Tables 1-4. (1990) concluded that Se had an inhibitory effect on the initiation and promotion stages of AFB 1 -induced preneoplastic foci and nodules. breaks and gaps was observed throughout the investigation. Indeed. ascorbic acid.. 1995). but Se can neither prevent the enlargement nor accelerate the regression of the foci already developed after administration of carcinogens (Wang.. Selenium also prevented progression of these nodules to hepatocellular carcinoma even after cessation of AFB 1 administration.5 and 2. antioxidant enzymes as well as synthetic antioxidants and various plant extracts (Surai. Effects of a single intramuscular injection of Se-vitamin E (5 mg of Se + 68 IU of α−tocopherol/60 kg of BW) as a pretreatment 14 days before an oral dose of AFB1 (1. 1990). 1988).. A synthetic seleno-organic compound (ebselen) showed a potent protective effect against AFB 1induced cytotoxicity (Yang et al. typhimurium tests (Francis et al. 1990) lower compared to the unsupplemented group. Se is shown to have protective effects against T-2 toxicity (Rizzo et al. Shi et al. Moreover.. 1994. Shokri et al. 1995. 1990.. After 14 days of Se administration to Chinese hamsters. (1985) showed that Se is able to protect against the hepatocarcinogenic effects of AFB 1 in the rat. inhibitory activity of Se on mutagenesis induced by AFB1 in the presence of a rat liver microsomal activation system has been shown in S. Conclusions Recent results show that in many cases membrane-active properties of various mycotoxins determine their toxicity.. A significant decrease in the frequency of aberrant cells. causing . Kravchenko et al. incorporation of mycotoxins into membrane structures causes various detrimental changes. 1990. Therefore Lei et al. 1994. 1990). Indeed..5 mg/kg) for six weeks.. 1994)... 2000. 1994. In summary. It has been revealed that Se can inhibit the formation of hyperplastic foci and enzymealtered foci as well as hepatocarcinogenesis induced by AFB1.. Yazdanpanah et al. Atroshi et al. Se was found to interact significantly with AFB 1 for feed intake. Although aflatoxin exposure caused a significant decrease in body weight and feed intake. The results of another experiment showed that Se could effectively protect cells from AFB1 cytotoxicity in cultured cells but had no effect on AFB 1 -DNA adduct formation or mutagenesis (Shi et al. In a different study. 1997). the incidence of chromosomal aberrations in bone marrow cells due to a single administration of AFB1 (5 mg /kg BW) was significantly reduced (Petr et al.. These changes are associated with alteration of fatty acid composition of the membrane structures and with peroxidation of long chain PUFAs inside membranes. 2000)... When male Wistar rats were fed diets supplemented with Se (0. 1997).120 Effects of mycotoxins on antioxidant status and immunity values. This ultimately damages membrane receptors. protective effects against lipid peroxidation caused by mycotoxins were attributed to various antioxidant compounds including vitamins A and E. to decrease damaging effects of AFB1 (Shen et al. CoQ10. signs of intoxication from T-2 toxin were less distinct and mortality caused by T-2 toxin was 2-fold (Kravchenko et al. A protective effect of Se is not restricted to aflatoxins. Milks et al. selenium. Choi et al. causing an improvement in this parameter (Brucato et al.

• Mycotoxins and their active metabolites are absorbed from the intestine and accumulate in target tissues. Mobio. Exp.M. 2003. A. Creppy. Consequently. H. we can suggest a hypothetical scheme of mycotoxinantioxidant interactions. and carotenoids in tissues. 23:24 .T. Z. Free Rad. Albarenque.p65 121 downregulation of communicating molecule (cytokines. Biese. W. However.F. Mobio. N. Nakayama and K. 1999. Nuclear lipid peroxidation induced in rat liver by T-2 mycotoxin. S. Considering data reviewed. oxidative stress. Vero and Caco-2 cells: prevention by vitamin E. Bio. proteins and DNA. Mycotoxins promote free radical formation (O2. Ahmed. T2 toxin and AFB1) cause malabsorption in the intestine. I. 24:947-949. Suzuki. K. which further leads to apoptosis and other cytotoxic effects of mycotoxins. and G. Shier. which in turn decreases concentrations of vitamin E. 1986. causing lipid peroxidation and damage to other biological molecules including lipids.A. Veijalainen. • Immunosupressive action of mycotoxins could be associated with downregulation of communications among various cells due to damage to receptors as well as 05-Surai. A. W. P. • A combination of natural antioxidants with mycotoxin adsorbents could be a next step in combating mycotoxicoses in poultry production. DNA fragmentation.Creppy and H. • Mycotoxins in tissues can generate free radicals. 72:233-236. Doi. this causes alterations in membrane permeability. decreasing further antioxidant protection. Baudrimont.P. This could lead to antioxidant/pro-oxidant imbalance causing oxidative stress. eicosanoids. Gene expression and the thiol redox state. Ram. Toxicol. Anane. Finally.C. F. References Abel. Atroshi. Toxicol. apoptosis and cell cycle arrest induced by zearalenone in cultured DOK. Toxicol. plasma and tissue membranes. C.. including gastrointestinal tract. reproduction etc. Rizzo. molecular mechanisms of mycotoxin-antioxidant interactions in vivo await investigation. Arrigo. 1998. 19/12/2004. Badria and E. Kinetics of cytokine mRNA expression in the dorsal skin of WBN/ILA-Ht rats following topical application of T-2 toxin. flexibility and other important characteristics determining membrane function. R. Bacha. I. development.E. Ennamany.P. Surai and J. Abado-Becognee. 1998. K. T. Pathol. etc. 131:121-131. functional alterations in many biochemical pathways and changes in physiological functions including growth. which cause antioxidant depletion. 192:237-248. R. Hassen. F..E. S. and W. Archives of Toxicol. then to inactivation of a range of membrane-binding enzymes responsible for regulation of important pathways.A. S. Toxicon. Gelderblom..and OH • ) in the intestine. T. Ouanes. Oxidative damage and fumonisin B 1induced toxicity in primary rat hepatocytes and rat liver in vivo. Cytotoxicity of fumonisin B1: implication of lipid peroxidation and inhibition of protein and DNA synthesis.) production by macrophages. E. • Mycotoxins in the feed (at least OTA.C. Abid-Essefi. 53:271-274. • Increased antioxidant supplementation protects against toxic actions of mycotoxins by interfering with one or several steps described above.. Med. Fleurat-Lessard. Dvorska 121 alterations in second messenger systems.E. An importance of lipid peroxidation in all these processes is confirmed by the protective effects of natural antioxidants against mycotoxin toxicity. 27:936-944. F. 2001. occur. enterocyte apoptosis and contribute to the development of malabsorption and decreased antioxidant absorption and accumulation.

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