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Dose-Dependent Effects of T-2 Toxin on Performance, Lipid Peroxidation, and Genotoxicity in Broiler Chickens

V. Rezar, T. Franki, M. Narat, A. Levart and J. Salobir¹

Biotechnical Faculty, Department of Animal Science, University of Ljubljana, 1230 Domale, Slovenia

¹ Corresponding author: janez.salobir{at}bfro.uni-lj.si

	ABSTRACT

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The objective of the present study was to evaluate the effects of different concentrations of T-2 toxin in feed on performance, lipid peroxidation, and genotoxicity in vivo. For a 17-d period, T-2 toxin was added to the diet of the chickens. Fifty 22-d-old male broiler chickens were divided into 5 groups that were supplemented with different concentrations of T-2 toxin: control (0.0 mg/kg of feed), T 0.5 (0.5 mg/kg of feed), T 1.5 (1.5 mg/kg of feed), T 4.5 (4.5 mg/kg of feed), and T 13.5 (13.5 mg/kg of feed). Deoxyribonucleic acid fragmentation in spleen leukocytes, malondialdehyde in plasma and liver, total plasma antioxidative status, glutathione peroxidase activity, and total serum Ig (IgA and IgG) were measured. Feed consumption and BW gain decreased when the concentration of T-2 toxin was 4.5 and 13.5 mg/kg of feed. Compared with the control group, the rate of DNA damage increased significantly in the group fed 13.5 mg of T-2 toxin/kg of feed. In contrast to DNA fragmentation, indicators of oxidative stress did not show differences between groups fed T-2 toxin and the control. More serum IgA was detected in the group T 13.5 compared with the control, whereas there were no differences in serum IgG levels. The results of the present study indicate that impaired performance, DNA fragmentation in spleen leukocytes, and elevated serum IgA levels induced by T-2 toxin are dose-dependent. Based on our results, we could not confirm the hypothesis that oxidative stress is among the mechanisms by which T-2 toxin induces DNA fragmentation.

Key Words: mycotoxin • T-2 toxin • deoxyribonucleic acid damage • lipid peroxidation

	INTRODUCTION

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The Fusarium fungi are probably the most prevalent toxin-producing fungi of the northern temperate regions and are commonly found on cereals grown in these regions of America, Europe, and Asia (Creppy, 2002). A mycotoxin produced by several species of the genus Fusarium is T-2 toxin, and it is found as a natural contaminant in cereals, feed, and vegetables (Jelinek et al., 1989). Mycotoxins exhibit a wide array of biological effects, with individual toxins being genotoxic, carcinogenic, embryotoxic, neurotoxic, immunomodulating, and teratogenic agents (Smith et al., 1995). Madhyastha et al. (1994) demonstrated that among the 16 trichothecenes studied, T-2 showed the highest relative toxicity. Toxic effects of T-2 toxin have been reported in humans and various farm and laboratory animal species. The chronic toxicity of trichothecenes is characterized by anorexia, reduced weight gain, diminished nutritional efficiency, neuroendocrine changes, and immunological effects (Larsen et al., 2004). In broiler chickens, T-2 toxin causes reduced feed consumption and BW gain (Wyatt et al., 1973b), severe oral lesions (Hoerr et al., 1982), altered feathering (Wyatt et al., 1975), neural disturbances (Wyatt et al., 1973a), and coagulopathy (Doerr et al., 1981).

Lipid peroxidation may be one of the main manifestations of cellular damage in the toxicity of several mycotoxins. The targets of oxidative damage are usually critical biomolecules such as nucleic acids, proteins, and lipids (Gutteridge and Halliwell, 1990). Through induction of lipid peroxidation, trichothecenes can affect cellular membrane integrity and induce metabolic disturbances in animals (Vila et al., 2002). Nevertheless, Rizzo et al. (1998) suggested that T-2 toxin- and deoxynivalenol-(DON) induced oxidative stress may be only one of the mechanisms causing DNA damage in rat liver cells. Our previous in vivo study showed that T-2 toxin and DON are genotoxic to chicken leukocytes at a concentration of 10 mg/kg of feed. It could not be excluded that oxidative stress may be one of the mechanisms by which Fusarium mycotoxins induce DNA fragmentation (Franki et al., 2006).

The immune system is the primary target for trichothecenes (Bondy and Pestka, 2000), yet only limited information is available on the immunomodulatory effects of T-2 toxin in chickens. Different farm animal lymphoid organs have been shown to be extremely sensitive to T-2 toxin. It seems that the effect of T-2 toxin on cell-mediated immunity is dose-dependent. Effects such as B and T lymphocyte mitogen proliferation (Berek et al. 2001); production of IL-1, IL-2, B and T cell blastogenic response (Pestka and Bondy, 1994); phagocytosis; and lymphocyte proliferation (Müller et al., 1999) were enhanced or suppressed in a T-2 toxin dose-dependent manner. The most commonly reported effect of T-2 toxin on humoral immunity is a reduction in circulating IgG and IgM levels (Islam et al., 1998).

To our knowledge, there are no studies demonstrating the concentration at which T-2 toxin starts causing DNA damage in chicken spleen leukocytes in vivo. Therefore, the aim of the present study was to evaluate the effects of different concentrations of T-2 toxin in feed on DNA damage, lipid peroxidation, and performance of broiler chickens.

	MATERIALS AND METHODS

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Birds and Dietary Treatments

Day-old male broiler chickens (Ross 308) were raised in floor pens and fed commercial starter (d 1 to 18) and grower (d 18 to 21) diets. On d 22, the birds were moved to individual cages and subjected to a temperature of 27°C and constant light. Water and feed were provided for ad libitum consumption. On d 22, chickens were randomly assigned to 5 experimental groups (10 animals/group) with different concentrations of T-2 toxin (dietary treatments): the control (0.0 mg of T-2), T 0.5 (0.5 mg of T-2/kg of feed), T 1.5 (1.5 mg of T-2/kg of feed), T 4.5 (4.5 mg of T-2/kg of feed), and T 13.5 (13.5 mg of T-2/kg of feed). At the expense of corn, T-2 toxin fungal culture material was added. Feed consumption and live weight gain were recorded weekly and just before slaughter. After 17 d of treatment, chickens were killed by cervical dislocation and exsanguination (licence of Slovenian Veterinary Administration number 323-02-579/2003/3). Whole blood was taken for glutathione peroxidase (GPx) analysis; half of the blood was allowed to coagulate, and other half was taken in a centrifuge tube containing EDTA K₃ or heparin as an anticoagulant. After centrifugation, the serum or plasma was collected and stored at –70°C for further analysis. Spleen was used immediately; liver, abdominal fat, and brain samples were collected and stored at –70°C for further analysis. Relative organ weights of liver, spleen, brain, kidney, heart, gizzard, testis, small intestine, large intestine, and bursa of Fabricius were also determined.

Diets and T-2 Toxin

Diets composed of 61% corn, 6% gluten, 24% soybean meal, 5% sunflower and canola oil, 1.2% limestone, 0.36% salt, and 0.5% mineral-vitamin supplement (complete feed mixtures) were formulated to meet nutrient requirements for broilers from 3 to 6 wk of age (NRC, 1994). The T-2 toxin was purchased from Biopure Referenzsubstanzen GmbH, Tulln, Austria, as fungal culture material [0.49% (wt/wt)] and added to the feed in previously defined amounts (Table 1).

Deoxyribonucleic acid fragmentation was examined in leukocytes isolated from chicken spleen. Immediately after the birds were killed, and each spleen was placed in RPMI 1640 medium (Sigma R-8758, Sigma-Aldrich, St. Louis, MO) at 4°C and macerated through a nylon mesh (pore size 80 x 48 µm) with approximately 5 mL of RPMI 1640 medium. This suspension was transferred to a 1.5-mL microcentrifuge tube and centrifuged at 3,000 x g for 5 min. The pellet of leukocytes was mixed with 0.5 mL of solution of phosphate buffer (PBS, pH 7.2 to 7.4). Single-cell gel electrophoresis (comet assay) was performed according to Singh et al. (1988) with slight modifications as described by Rezar et al. (2003). An Olympus CH 50 epifluorescent microscope (Olympus, Center Valley, PA) with attached Orca 1 CCD camera (Hamamatsu, Japan) was used to examine the leukocyte nuclei. Images were analyzed by Comet 5 computer software (Kinetic Imaging Ltd, Nottingham, UK). Deoxyribonucleic acid damage was evaluated as percentage of DNA in the tail of the comet and Olive tail moment (Olive et al., 1992).

Malondialdehyde Determination

The methodology of Wong et al. (1987) modified by Chirico (1994) and Fukunaga et al. (1995) was used to measure the concentrations of malondialdehyde (MDA) in blood plasma by HPLC. The MDA in liver was determined following the method of Vila et al. (2002) with minor modifications as described in Franki et al. (2006). A Waters Alliance HPLC (Waters, Milford, MA) equipped with a Waters 474 scanning fluorescence detector was used to determine MDA-TBA adducts. The mobile phase consisted of 50 mmol/L of KH₂PO₄ buffer (pH 6.8) and CH₃OH in a gradient mode. A 10-µL aliquot was injected on to a reversed-phase C₁₈ HPLC chromatographic column [HyperClone 5u ODS (C₁₈) 120A, 4.6 x 150 mm; Phenomenex Inc., Torrance, CA]. The flow rate of the mobile phase was 1 mL/min, and column temperature was set at 30°C. The chromatographic data were evaluated by the Millenium32 Chromatography Manager program (Waters).

GPx, Total Antioxidant Status

The methodology of Paglia and Valentine (1967) was used for measurements of GPx, and the methodology of Miller and Rice Evans (1996) was used for measurements of total plasma antioxidant status (TAS). Samples were assayed with commercially available GPx and TAS kits (Randox, Crumlin, UK) following the instructions of the kit manufacturer.

Serum Ig Quantification

Total serum IgG and IgA were measured using ELISA according to the method of Banotai et al. (1999) with some modifications. Briefly, serum samples from each bird were diluted with 0.05% PBS-Tween to dilutions of 1:10 to 1:50 for IgA and 1:50 to 1:800 for IgG. Additionally, 96-well microtiter plates (MaxiSorp 442404, Nunc, Roskilde, Denmark) were coated with 70 µL of sera dilutions (each in triplicate) and incubated overnight at 4°C. Coated plates were washed 5 times with 0.05% PBS-Tween and then incubated for 60 min at 37°C with 300 µL of 0.5% BSA in PBS to prevent nonspecific binding. After washing 5 times with 0.05% PBS-Tween, 70 µL of horseradish peroxidase conjugated mouse antichicken IgG (Sigma-Aldrich) or goat antichicken IgA (Serotec, Oxford, UK) was added to each well (diluted 1:10000 and 1:3000, respectively). After 45 min of incubation at 37°C, plates were washed 5 times, and o-phenylenediamine dichlorhydrate (OPD-FAST, Sigma-Aldrich) was added as a substrate. Absorbance was measured 30 min later at the wavelength of 450 nm with an ELISA reader (EL 808 Bio-Tek Instruments, Winooski, VT).

Statistical Analysis

The data were analyzed by the GLM procedures of the SAS/STAT module (SAS Inc., Cary, NC). Differences among groups were determined using Tukey’s multiple comparison tests. Significance was considered established at P < 0.05.

	RESULTS

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BW Gain, Feed Efficiency, and Relative Organ Weights

At the end of the experiment, 0.5 and 1.5 mg of T-2 toxin/kg of feed had no adverse effects on the measured production parameters (Table 2). However, at the concentration of 4.5 mg/kg of T-2 toxin, a significant decrease in feed intake and daily weight gain was observed. Chickens fed 13.5 mg of T-2 toxin/kg of feed had significantly lower body daily weight gain and feed:gain ratio than those of other groups (Table 2).

Indicators of Oxidative Stress: DNA Damage, MDA Concentration, TAS, and GPx

Single-cell gel electrophoresis (comet assay) was performed to monitor toxin-induced DNA fragmentation in leukocytes isolated from chicken spleen. The highest concentration of T-2 toxin (13.5 mg/kg) significantly increased the rate of DNA damage, which was presented as the percentage of DNA in the tail of the comet and as Olive tail moment (Olive et al., 1992; Table 2).

In contrast to the comet assay, determination of MDA in plasma (Table 2) and liver (data not shown) did not show differences between groups fed different concentrations of T-2 toxin and the control (P > 0.3). Different concentrations of T-2 toxin in the feed also did not significantly alter the concentrations of plasma TAS and GPx in erythrocytes (Table 2).

Serum Ig

Compared with other groups, the highest level of total serum IgA was detected in the group T 13.5 (Table 2). There were no differences among groups in total serum IgG levels.

	DISCUSSION

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Nonmacrocyclic type A trichothecenes are important mycotoxins to poultry, because they occur naturally in cereals and are highly toxic (Bergsjo et al., 1993). The oral 50% lethal dose for T-2 toxin has been determined at approximately 5 mg/kg of BW (Dänicke et al., 2002).

Effects of T-2 toxin in poultry include reduced feed intake, BW gain, and feed efficiency (Eriksen and Pettersson, 2004). In our study we noticed significantly reduced feed consumption in groups fed 4.5 and 13.5 mg/kg of T-2 toxin. Impaired growth in these 2 groups was concomitant with a reduced feed intake. These results are in agreement with some other studies in which feed intake and BW gain were also lowered when purified T-2 toxin was fed at levels of 2 to 6 mg/kg of feed. No such reduction in feed intake was observed in chickens given 1 mg of T-2 toxin/kg of feed (Wyatt et al., 1973a; Kubena et al., 1994; Raju and Devegowda, 2000). A severe reduction in feed intake and weight gain was also observed when chickens were fed 10 mg of T-2 toxin/kg of feed (Franki et al., 2006).

In the present study T-2 toxin had no effect on the relative weights of spleen and bursa of Fabricius. This was in contrast to the report of Vila et al. (2002), who observed altered relative organ weights in mice fed T-2 toxin. However, in the group with the highest concentration of T-2 toxin (13.5 mg/kg), relative weights of kidney, gizzard, brain, and large intestine were significantly higher compared with the control. The relative weights of heart either increased or did not change when T-2 toxin was used in the experiments of Dänicke et al. (2003). Our study supports the statement that the dose of trichothecenes must be rather high to change relative organ weights (Kubena et al., 1997).

In addition to reduction in feed intake, BW gain, and relative organ weights, Hoehler and Marquardt (1998) demonstrated that T-2 toxin stimulates lipid peroxidation in biological systems due to an increased generation of hydroxyl radicals. The prooxidant properties of T-2 toxin were confirmed with rat, mice, chicken, duck, and goose liver samples (Rizzo et al., 1994; Atroshi et al., 1997; Vila et al., 2002). Lipid peroxidation caused by T-2 toxin in the liver has also been identified as an important underlying mechanism of T-2 toxin-induced cell injury and DNA damage (Surai, 2002). The results of our study are not in full accordance with previous findings concerning lipid peroxidation, because T-2 toxin did not alter plasma and liver concentration of MDA (lipid peroxidation indicator). Similar to our investigation, Schuster et al. (1987) concluded that T-2 toxin does not influence the formation of thiobarbituric reactive substances in rat liver. Our results showed that increased concentrations of T-2 toxin did not decrease plasma TAS and did not significantly change erythrocyte GPx activity. It is not clear 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. Some studies have suggested that the toxicity of mycotoxins is induced by various mechanisms of action (Surai and Dvorska, 2005).

The results of our study showed that a concentration of 13.5 mg/kg of T-2 toxin induces DNA fragmentation in chicken leukocytes as measured by comet assay and presented as percentage of DNA in the tail of the comet. Olive tail moment, a parameter also frequently used for presentation of DNA fragmentation, also showed a significant increase in DNA damage in the group T 13.5. The comet assay in our conditions detects only DNA fragmentation but does not clarify the exact mechanisms responsible for the formation of DNA damage. Deoxyribonucleic acid damage detected can be a reflection of early stages of apoptosis. If so, the results obtained by the comet assay overestimate the genotoxic potential of T-2 toxin. Moreover, some DNA damage could be the consequence of excision and repair of methylated or oxidised bases or nucleotides (Collins, 2004). The possibility that single- or double-strand DNA breaks are a result of direct interaction of T-2 toxin with DNA has, to our knowledge, never been explored. The results of our comet assay can be supported by the study of Atroshi et al. (1997), who reported an increase in DNA damage in livers of mice fed T-2 toxin (2.8 mg/kg of BW), and of Rizzo et al. (1998), who tested the genotoxic effect of T-2 toxin (2.8 mg/kg of BW) on rat liver cells. Another study by Franki et al. (2006) showed that T-2 toxin caused DNA fragmentation to chicken leukocytes at a concentration of 10 mg/kg of feed.

It appears that trichothecenes are potent immunosuppressive agents that can directly affect immune cells or modify immune responses because of tissue damage elsewhere; however, the degree of sensitivity is apparently species-specific. It has been observed that T-2 toxin (up to 1 mg/kg of feed) in the diet does not affect antibody production when poultry are stimulated with various antigens (Sklan et al., 2003). Studies indicate that the immune system of the chicken may be depressed when the concentration of T-2 toxin reaches 4 mg of T-2 toxin/kg of feed or higher (Eriksen and Pettersson, 2004). Our results show that total serum IgA was significantly higher in the group T 13.5 but not in the group fed 4.5 mg/kg of feed. There were no differences in IgG levels among the groups. Similar results were obtained by Jia and Pestka (2005), who studied the effect of type B trichothecene DON on IgA nephropathy. They observed an elevation in serum IgA levels in mice fed 10 mg of DON/kg of feed. Deoxynivalenol-mediated accumulation of IgA in the serum, which is influenced by upregulation of IL-6, is considered to be an etiological factor of kidney mesangial IgA deposition and thus the incidence of IgA nephropathy. It is possible that T-2 toxin, which is closely related to DON, acts through a similar mechanism. Whether the level of IgA detected in our study was high enough to cause kidney damage, as reported by Jia and Pestka (2005), is not known. It is also unknown if these high IgA levels have any protective effects against other immunomodulating substances. It could also be hypothetically possible that high levels of IgA in serum occur due to a damaged mucosal layer in the intestine and thus an increase in permeability. Furthermore, T-2 toxin may induce intestinal damage, which could promote IgA production by exposing gastrointestinal lymphoid tissue to more feed antigens.

This study showed that the effects of T-2 toxin are dose-dependent. The concentration of 4.5 mg of T-2 toxin/kg of feed or higher decreased feed consumption and consecutively weight gain of the animals. The results indicate that low concentrations (up to 1.5 mg of T-2 toxin/kg of feed) do not provoke DNA fragmentation in spleen leukocytes. The significant elevation of DNA damage in leukocytes was observed only at a concentration of 13.5 mg/kg of T-2 toxin. Based on our results, we cannot confirm the theory that oxidative stress is among the mechanisms by which T-2 toxin induces DNA fragmentation. Further studies focused on identification of exact mechanisms by which T-2 toxin induces DNA damage are needed.

	ACKNOWLEDGMENTS

 
This work was supported by a grant from the Ministry of Higher Education, Science and Technology of the Republic of Slovenia.

Received for publication October 26, 2006. Accepted for publication February 19, 2007.

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