Trichothecene Mycotoxins Depress the Mononuclear-Phagocytic System of Young Turkeys
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AbstractMacrophage cells isolated from the abdominal cavity of 21-day-old turkeys after a single injection of Sephadex suspension were used to quantitate the effects of direct in vitro exposure to deoxynivalenol (DON), 3-acetyldeoxynivalenol (3ac-DON), scirpentriol (STO), or 15-acetylscirpenol (15-MAS). Macrophage monolayers were established on glass surfaces and cells were exposed to graded levels of individual mycotoxins for 1 hour: DON, 20 -640 μ9/μ1 of culture; 3ac-DON, STO, 15-MAS, 20 -1280 μg/μ1 of culture. All four mycotoxins caused dose-related effects. A concentration of 50 μg/ml DON caused a significant decrease in macrophage adherence, phagocytosis of opsonized SRBC, and number of opsonized SRBC per macrophage; at 200 μg/ml, phagocytosis of unopsonized SRBC was decreased. There were also increasing percentages of damaged macrophages with increasing DON doses as indicated by morphological alterations. Linear decreases in macrophage viability on exposure to 3-acDON and STO were observed. Moreover, STO and 15-MAS decreased macrophage adherence to glass and 3-acDON, STO, and 15-MAS induced macrophage morphological alterations. This study suggests that trichothecene mycotoxins may be immunosuppressive by affecting viability, adherence and phagocytic potential of mononuclear phagocytic cells of young turkeys.Antibody opsonization
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The influence of serum on phagocytosis related to the complement system was examined by means of a kinetic phagocytosis method using IgG-coated particles, isolated polymorphonuclear neutrophil leucocytes (PMNs), fresh serum, in vitro activated sera and in vivo activated sera. The previously described opsonic properties of C3b and C4b were confirmed by the enhancement of phagocytic rate by the opsonization of IgG particles with C3 and C4. An anti-opsonic effect of serum was revealed by the initial inhibition of PMN phagocytosis of IgG-coated particles in the presence of fresh serum. In vitro activated norma fresh serum and in vivo activated SLE sera mediated a prolonged or even irreversible inhibition of phagocytosis dependent on the degree of complement activation. Investigation of this anti-opsonic effect of serum, which was heat-labile, suggested that it was caused by an inhibition of the interaction between the Fc receptor and IgG mediated by the C1q component of the C1 complex.
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Plasma fibronectin enhances phagocytosis of opsonized particles by human peripheral blood monocytes.
We have investigated the effect of plasma fibronectin (Fn) on binding and phagocytosis of sheep erythrocytes (E) by human peripheral blood monocytes. Unopsonized E were not phagocytosed in the absence or presence of Fn, but Fn enhanced the phagocytosis of E bearing IgG. Sheep erythrocytes sensitized with IgM and C3b were ingested only when monocytes were exposed to Fn. The Fn enhancement of phagocytosis occurred for both fluid-phase and glass-adherent monocytes. Experiments in which Fn was washed out before mixing monocytes with opsonized E demonstrated that the Fn effect occurred because of interaction with the monocytes and not the opsonized particles. Chromatography of the Fn on Biogel A 1.5m showed that the phagocytosis-enhancing activity exactly co-chromatographed with the Fn protein. Fn did not increase the number of monocyte membrane receptors for the Fc fragment of monomeric IgG. We conclude that Fn enhances monocyte phagocytosis, not by binding to particles as a conventional opsonin, but by stimulating monocytes to ingest already opsonized particles more avidly.
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Trichothecenes, such as deoxynevalenol (DON), nivalenol (NIV) and T-2 toxin are typical immunotoxic mycotoxins. Contamination of trichothecene mycotoxins in wheat is a serious world-wide problem affecting human health. In Japan, in particular, it has been reported that relatively high levels of DON and NIV are frequently found in domestic wheat. I have extensively conducted studies on the toxicity and control of trichothecene mycotoxins in order to assess their risk, and this paper is the summary of those findings.
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This study demonstrates the detection and dynamics of macrocyclic trichothecene mycotoxin (MTM) tissue loading using a commercially available assay in a goat model. The detection of MTMs has been difficult and complex due to the uncertainty of what tissues to examine and when to sample. Twelve goats (two groups of each) were instilled with Stachybotrys chartarum conidial suspension via the trachea. The first group was challenged repeatedly with fungal conidia containing 1 mg/kg of MTM per instillation whereas the second group was exposed once, to spores with a calculated concentration of 5 microg/kg of mycotoxin. These toxin estimates were generated by the QuantiTox(TM) Kit assay; a conidium of S. chartarum possessed 8.5 pg of MTM. After repeated exposure of 3 days, MTM was detected in one of six animals. This animal and two others from the same group had mycotoxin detected in their serum 24 hours after challenge at a comparable level (1.69 ng/mL) to the six animals challenged with a single dose (2.02 ng/mL) at the same time post-instillation. Results showed that MTMs are detectable in experimental animals soon after challenge and contribute to the understanding of the role of these mycotoxins in the disease process following mold exposure.
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We examined the mechanism of surface phagocytosis of Staphylococcus aureus by human polymorphonuclear leucocytes (PMN). Surface phagocytosis of unopsonized bacteria occurred, but was significantly enhanced by the presence of serum. The serum requirement was low, and a maximal effect occurred with serum concentrations of 0.25-0.5%. The opsonic effect of serum was not removed by heat inactivation of complement but was adsorbed, at low serum concentrations, by protein A, indicating that opsonin-dependent surface phagocytosis requires IgG but not C3. The requirement of opsonin-dependent surface phagocytosis for IgG was demonstrated further with purified IgG preparations as the sole opsonin. Activation of PMN by N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA) increased opsonin-independent surface phagocytosis by 47% and 66%, respectively, but had no effect on opsonin-dependent surface phagocytosis. Blockade of the PMN iC3b receptor (CR3), which has lectin-like properties, by a panel of monoclonal antibodies against the alpha- and beta-chains of CR3 did not inhibit the surface phagocytosis of opsonized or unopsonized S. aureus, and one antibody (NIMP-R10) enhanced opsonin-independent surface phagocytosis. These results indicate that the mechanism of surface phagocytosis is quite different to that observed in suspension assays. Opsonin-independent surface phagocytosis occurs and is enhanced by PMN activation, opsonin-dependent surface phagocytosis is dependent on IgG and not complement, and neither opsonin-independent nor -dependent surface phagocytosis proceeds through CR3.
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The ubiquitous filamentous fungus Fusarium graminearum causes the important disease Fusarium head blight on various species of cereals, leading to contamination of grains with mycotoxins. In a survey of F. graminearum (sensu stricto) on wheat in North America several novel strains were isolated, which produced none of the known trichothecene mycotoxins despite causing normal disease symptoms. In rice cultures, a new trichothecene mycotoxin (named NX-2) was characterized by liquid chromatography-tandem mass spectrometry. Nuclear magnetic resonance measurements identified NX-2 as 3α-acetoxy-7α,15-dihydroxy-12,13-epoxytrichothec-9-ene. Compared with the well-known 3-acetyl-deoxynivalenol (3-ADON), it lacks the keto group at C-8 and hence is a type A trichothecene. Wheat ears inoculated with the isolated strains revealed a 10-fold higher contamination with its deacetylated form, named NX-3, (up to 540 mg kg(-1) ) compared with NX-2. The toxicities of the novel mycotoxins were evaluated utilizing two in vitro translation assays and the alga Chlamydomonas reinhardtii. NX-3 inhibits protein biosynthesis to almost the same extent as the prominent mycotoxin deoxynivalenol, while NX-2 is far less toxic, similar to 3-ADON. Genetic analysis revealed a different TRI1 allele in the N-isolates, which was verified to be responsible for the difference in hydroxylation at C-8.
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Deoxynivalenol(DON), 3a,7a,15-trihydroxy-12,13-epoxytrichothec-9-en-8-one, is a toxic metabolite such Fusarium spp. as F.graminearuml) and F. culmorum.2)It is commonly found together with nivalenol in wheat and barley grains in Japan,3) and is also one of the most important trichothecene mycotoxins occurring naturally in several cereals and animal feed in other countries.4)As a result of the consumption of these contaminated agricultural products, animals, even man, are suffering from sublethal toxicoses including emesis, diarrhea and feed refusal.5*However, the metabolic fate of the toxin is still unknown.In this paper, we describe the elimination of DONin rats and the structural elucidation of a novel metabolite found in the excreta.DONwas dissolved in 10% aqueous ethanol and intubated to Wistar male rats weighing 240~245g at a single dose of 6mg/kg.Urine and feces samples were collected every 12hr
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The role of immunoconglutinin (IK) in phagocytosis was investigated using an in vitro opsonic test system. Phagocytosis of Gram-negative bacteria was increased when pre-treated with rabbit serum containing immunoconglutinin. The enhanced phagocytosis was reflected by an increase in the number of macrophages engaged in phagocytosis as well as an increase in the opsonic index. Heat inactivation of the sera completely destroyed this opsonic activity. The data indicate that immunoconglutinin potentiates the opsonic activity of serum by increasing the amount of complement fixed to the bacteria. IK may also influence the rate of phagocytosis by providing immune aggregates of suitable size, thus facilitating ingestion of immune complexes.
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