Inhalational Toxicity, Immunotoxicity of Trichothecenes, Probiotics, etc.

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Toxicology. 2008 Jun 3;248(1):39-44. Epub 2008 Mar 14.

Tissue distribution and proinflammatory cytokine induction by the

trichothecene deoxynivalenol in the mouse: comparison of nasal vs.

oral exposure.

Amuzie CJ, Harkema JR, Pestka JJ.

Comparative Medicine and Integrative Biology Program, Michigan

State University, East Lansing, MI, USA.

Oral exposure to the trichothecene deoxynivalenol (DON), a common

cereal grain contaminant, adversely affects growth and immune function

in experimental animals. Besides foodborne exposure, the potential

exists for DON to become airborne during the harvest and handling of

grains and therefore pose a risk to agricultural workers. The purpose

of this study was to compare the effects of oral and intranasal

exposure to DON (5mg/kg bw) on tissue distribution and proinflammatory

cytokine induction in the adult female mouse. Competitive direct ELISA

revealed that, regardless of exposure route, DON concentrations in

plasma, spleen, liver, lung and kidney were maximal within 15-30 min

and declined by 75-90% after 120 min. However, plasma and tissue DON

concentrations were 1.5-3 times higher following intranasal exposure

as compared to oral exposure. The functional significance of elevated

DON tissue concentrations was assessed by measuring IL-1beta, IL-6,

and TNF-alpha mRNA responses in spleen, liver and lung. Oral exposure

to DON-induced robust proinflammatory cytokine gene expression after

60 and 120 min. In contrast, inductions of IL-1beta, IL-6 and

TNF-alpha mRNAs in nasally exposed mice were 2-10, 2-5 and 2-4 times

greater, respectively, than those in the tissues of orally exposed

mice. Taken together, these data suggest that DON was more toxic to

the mouse when nasally exposed than when orally exposed, and that this

might relate to greater tissue burden of the toxin.

Publication Types:

* Comparative Study

* Research Support, N.I.H., Extramural

* Research Support, U.S. Gov't, Non-P.H.S.

PMID: 18433975 [PubMed - indexed for MEDLINE]

Toxicology. 2008 May 2;247(1):46-54. Epub 2008 Feb 15.

Subclinical doses of T-2 toxin impair acquired immune response and

liver cytochrome P450 in pigs.

Meissonnier GM, Laffitte J, I, Benoit E, Cossalter AM,

Pinton P, Bertin G, Oswald IP, Galtier P.

Laboratoire de Pharmacologie-Toxicologie UR66, INRA, F-31931

Toulouse, France.

This study was designed to investigate the effect of subclinical

doses of T-2 toxin on liver drug-metabolizing enzymes and the immune

response. Pigs were offered over a 28-day period either a control diet

or diets contaminated with 540, 1324 or 2102 micrograms of pure T-2

toxin/kg feed. Pigs were immunized with ovalbumin and subsequent

humoral and cellular immune responses measured. Monooxygenase and

transferase enzyme activities and protein expression were investigated

in liver tissue samples. Pigs fed 1324 or 2102micrograms T-2 toxin/kg

feed exhibited reduced anti-ovalbumin antibody production without

significant alteration to specific lymphocyte proliferation. The

livers of pigs exposed to T-2 toxin presented normal cytochrome P450

content, UGT 1A and P450 2B, 2C or 3A protein expression, and

glutathione- and UDP glucuronosyl-transferase activities. However,

P450 1A related activities (ethoxyresorufin O-deethylation and

benzo-(a)-pyrene hydroxylation) were reduced for all pigs given T-2

toxin, with P450 1A protein expression decreased in pigs fed the

highest dose. In addition T-2 toxin exposure reduced certain

N-demethylase activities. The results of this study confirm the

immunotoxic properties of T-2 toxin, in particular toward the humoral

immune response. The reduction of monooxygenase activities, even

though the liver presented no tissue lesion or lipid peroxidation,

suggests possible deleterious interactions of T-2 toxin with these

enzymes.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 18355953 [PubMed - indexed for MEDLINE]

Toxicol Lett. 2008 Apr 1;177(3):215-22. Epub 2008 Feb 2.

Ingestion of deoxynivalenol (DON) contaminated feed alters the pig

vaccinal immune responses.

Pinton P, Accensi F, Beauchamp E, Cossalter AM, Callu P, Grosjean

F, Oswald IP.

INRA, Unité de Pharmacologie-Toxicologie, 180 chemin de

Tournefeuille, 31931 Toulouse cedex 9, France.

Deoxynivalenol (DON), a mycotoxin produced by some Fusarium

species, is a frequent contaminant of cereals. This toxin is known to

modulate the immune function but only few studies have investigated

the effect of DON on the vaccinal immune response. In the present

experiment, 24 pigs received for 9 weeks either control feed or feed

naturally contaminated with 2.2-2.5 mgDON/kg feed. At days 4 and 15 of

the experiment, the animals were subcutaneously immunized with

ovalbumin. Consumption of DON-contaminated diet does not have a major

effect on the hematological and biochemical blood parameters. By

contrast, ingestion of DON significantly affects the global and the

specific immune response of the pigs. In the serum, DON increases the

concentration of total IgA and, in vaccinated animals, DON also

increases the concentration of ovalbumin-specific IgA and IgG. DON

does not modulate lymphocytes proliferation after mitogenic

stimulation but the toxin had a biphasic effect on lymphocyte

proliferation after antigenic stimulation (up-regulation at day 21 and

down-regulation at day 35-49). Because cytokines play a key role in

immunity, the expression levels of TGF-beta, IFN-gamma, IL-4 and IL-6

were measured, by RT-PCR in the spleen, the ileum and the mesenteric

lymph node of the animals at the end of the experiment. In the

mesenteric lymph node, a significantly lower expression of both

TGF-beta and IFN-gamma mRNA expression levels is observed in animals

feed with DON when compared with control piglets. Taken together, our

data indicate that DON alters the vaccinal immune response. These

results may have implications for humans and animals consuming

DON-contaminated food or feed as breakdown in vaccinal immunity may

lead to the occurrence of disease even in properly vaccinated

populations.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 18329193 [PubMed - indexed for MEDLINE]

J Vet Sci. 2008 Mar;9(1):39-44.

The combination of deoxynivalenol and zearalenone at permitted

feed concentrations causes serious physiological effects in young

pigs.

Chen F, Ma Y, Xue C, Ma J, Xie Q, Wang G, Bi Y, Cao Y.

College of Animal Science, South China Agricultural University,

Guangzhou 510642, PR China.

This study was to investigate the effects of the combination of

deoxynivalenol (DON) and zearalenone (ZON) on pigs. Twenty-four

weaning piglets were divided into a control group fed a diet free of

mycotoxins and a toxin group fed a diet containing 1 mg/kg DON and 250

microg/kg ZON. The results showed that supplementation of DON and ZON

in diets had extensive effects on pigs. More specifically, DON and ZON

caused levels of total protein, albumin, and globulin in sera to

decrease (p < 0.05) by 14.5%, 6.5% and 11.3%, respectively, and at the

same time increased (p < 0.05) the serum enzyme activities of

gamma-glutamyltransferase, aspartate aminotransferase and alanine

aminotransferase by 72.0%, 32.6% and 36.6%, respectively. In addition,

DON and ZON decreased (p < 0.05) the level of anticlassical swine

fever antibody titers by 14.8%. Real-time PCR showed that DON and ZON

caused the mRNA expression levels of IFN-gamma, TNF-alpha, IL-2, to

decrease (p < 0.05) by 36.0%, 29.0% and 35.4%, respectively.

Histopathological studies demonstrated that DON and ZON caused

abnormalities in the liver, spleen, lymph nodes, uterus, and kidney.

The concentrations of DON and ZON used in this study are in line with

the published critical values permitted by BML. Our study clearly put

the standard and adequacy of safety measures for these toxins into

question. The authors suggest that with the increasing availability of

cellular and molecular technologies, it is time to revisit the safety

standards for toxins in feeds so as to make feeds safer, providing

consumers with safer products.

Publication Types:

* Controlled Clinical Trial

* Research Support, Non-U.S. Gov't

PMID: 18296887 [PubMed - indexed for MEDLINE]

Food Chem Toxicol. 2008 Jan;46(1):125-35. Epub 2007 Jul 18.

A 90-day subchronic toxicity study of nivalenol, a trichothecene

mycotoxin, in F344 rats.

Takahashi M, Shibutani M, Sugita-Konishi Y, Aihara M, Inoue K, Woo

GH, Fujimoto H, Hirose M.

Division of Pathology, National Institute of Health Sciences,

1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.

A subchronic toxicity study of nivalenol (NIV), a trichothecene

mycotoxin, was conducted in male and female F344 rats fed diet

containing 0, 6.25, 25 or 100 ppm concentration for 90 days. Decrease

of body weight and loose stools were observed at 100 ppm in both sexes

from the start of the experiment, and body weight reduction was also

observed at 25 ppm in males from week 6. At necropsy, many organs

demonstrated reduced absolute weights at 100 ppm in both sexes, mostly

due to the reduction in the body growth, with reduction of relative

thymus weight also being evident in females. Hematologically, decrease

of the white blood cell count was found at 100 ppm in males and from

6.25 ppm in females. In addition, decreased platelet counts in both

sexes, red blood cell counts in males, and the hemoglobin

concentration in females were detected at 100 ppm.

Histopathologically, treatment-related changes were predominantly

observed in the hematopoietic and immune organs and the anterior

pituitary in both sexes and female reproductive organs at 100 ppm,

such as thymic atrophy, hypocellularity in the bone marrow, diffuse

hypertrophy of basophilic cells with increase of castration cells in

the anterior pituitary, and increase of ovarian atretic follicles.

Based on the hematological data, the no-observed-adverse-effect level

of NIV was determined to be less than 6.25 ppm (0.4 mg/kg body

weight/day for both males and females).

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 17765382 [PubMed - indexed for MEDLINE]

Mikrobiol Z. 2008 Jan-Feb;70(1):52-8.

[Effect of probiotic preparation based on Bacillus subtilis

(BPS-44) in experimental mycotoxicoses of chickens]

[Article in Ukrainian]

Trufanov OV, Kotyk AM, Bozhok LV.

When Road-Island breed chickens were given fodder which included

toxin in concentration of 16 mg/kg or T-2 toxin in concentration of 10

Mg/kg, that resulted in the decrease of the live weight, increase in

the relative weight of the liver, kidneys, pancreas and heart, as well

as the decrease of concentration of Bacillus genus bacteria in the

caecum and rectum content compared with the control group chickens. No

distinctions were observed in activity of alanine aminotransferase and

concentration of total protein in the blood plasm. The drinking of

probiotic preparation BPS-44 when feeding with forage contaminated by

HT-2 or T-2 toxin resulted in the increase of the live weight,

normalization of relative weights of viscera, increase in

concentration of Bacillus genus bacteria in the intestine compared

with chickens which received only mycotoxins.

Publication Types:

* English Abstract

PMID: 18416155 [PubMed - indexed for MEDLINE]