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ABSTRACT: Palytoxin (PLT) first isolated from zoanthids is extremely lethal to animals by intraperitoneal or intravenous administration but shows little toxicity by gavage dosing in contradiction to the occurrence of fatal poisoning due to PLT-containing seafood. In order to fully elucidate its potential risks to human we evaluated the toxicological effects via three ways of dosing: gavage, intra-tracheal administration (IT) and sublingual administration. A new analog, 42-hydroxy-3,26-didemethyl-19,44-dideoxypalytoxin isolated from the dinoflagellate Ostreopsis siamensis and named ostreocin-D (OSD), was also used for comparison, additionally conducted by i.p. By gavage dosing, both toxins did not produce death in mice at the maximum dosage of 200 microg/kg of PLT and 300 microg/kg of OSD. Addition of dietary lipid components to PLT solutions for gavage or use of ulcerated mice did not alter the results, indicating no enhancement of PLT absorption. The two toxins were most toxic by the IT route, causing bleeding and alveolar destruction in the lung and resultant death at 2 microg/kg of PLT, and 11 microg/kg of OSD. Both toxins also induced organ injuries after 24h when dosed by sublingual administration at about 200 microg/kg. The injuries became fatal when PLT was dosed 2 or 3 times. The results pointed to the necessity of taking multiple approaches to assess the potential health risks due to PLT and its analogs in food and environments.
Toxicon 05/2009; 54(3):244-51. · 2.51 Impact Factor
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ABSTRACT: In a previous study, it was suggested that β-cyclocitral plays an important role in understanding the lysis of cyanobacteria under natural conditions. The present study was conducted in order to understand how the β-cyclocitral lyses cyanobacterial cells, and other anticyanobacterial agents were also investigated. The preliminary study using a scanning electron microscope (SEM) demonstrated that there were three types of morphological changes in the cyanobacterial cells when they were incubated with anticyanobacterial agents: volatile compounds from cyanobacteria cause shrinking and then wrinkling; terpenoids contact directly and cause stripping; basic amino acids cause swelling and then collapsing. In order to clarify the extreme difference in the damage during the morphological changes between the β-cyclocitral and L-lysine (Lys), the transmission electron microscope (TEM) technique was applied. Although a definite difference in the morphological damage was observed, a plausible mechanism for β-cyclocitral could be not deduced. Throughout the experiments using antibiotics, it was found that the apparent morphological changes after lysis did not always correspond to the mode of action.
Journal of Health Science. 01/2009; 55:578-585.
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ABSTRACT: One of bacteria collected from Lake Sagami, Japan, Brevibacillus sp., was found to have a lytic activity of cyanobacteria, but did not produce active compounds. Instead, the co-culturing of Microcystis with the Brevibacillus sp. enhanced the production of two volatile compounds, beta-cyclocitral and 3-methyl-1-butanol, and the former had a characteristic lytic activity. It was confirmed that these volatile compounds were derived from the cyanobacteria themselves. beta-Ionone, geosmin and 2-methylisoborneol derived from cyanobacteria and similar volatile compounds, terpenoids, produced by plants also had a lytic activity. The minimum inhibitory concentration values of the cyanobacterial metabolites were estimated to be higher than those of compounds from plants except for a few compounds. Among them, beta-cyclocitral only produced a characteristic color change of culture broth from green to blue. This color change is similar to the phenomenon observed when a sudden decline in growth of cyanobacteria begins in a natural environment.
Chemosphere 05/2008; 71(8):1531-8. · 3.21 Impact Factor
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ABSTRACT: Diarrhetic activity of pectenotoxin-6 (PTX6), a shellfish contaminant in Japanese scallops (Patinopecten yessoensis), was studied in vivo. Mice gavaged with 5mg/kg PTX6 did not show diarrhea or fluid secretion, and no prominent pathological changes were observed. There was no synergistic toxicity of PTX6 with okadaic acid (OA) or pectenotoxin-2 (PTX2) when toxins were given to mice by gavage. Synergistic activity of PTX6 with OA was also not confirmed under crude conditional simulation with oil. In contrast to the oral administration to mice, PTX6 at 500 microg/kg by i.p. was the lethal dose with bleeding in the liver, injuries at the gastric organs and the kidney. When rats were gavaged with PTX6 at a dose of 2 mg/kg, PTX6 did not have diarrhetic activity; however, the middle-lower small intestine (jejunum-ileum) was eroded at villi by edema. PTX6 is a potent toxin if administered by intraperitoneal injection to mice, or if administered orally to the rat. However, it is not clear if PTX6 passes through the intestinal barrier if given by the oral route.
Toxicon 04/2008; 51(4):707-16. · 2.51 Impact Factor
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ABSTRACT: The intact Adda was isolated from microcystin-LR by a microbial degradation using an isolated Sphingomonas strain, B-9. The reaction of microcystin-LR with cell extract of this strain proceeded smoothly to give the final degradation product by way of two intermediates, linearized microcystin-LR and a tetrapeptide. The purified Adda that was structurally characterized using various spectral data did not show the toxicity to mice or inhibition to protein phosphatase activity in contrast to the native toxin.
Toxicon 08/2004; 44(1):107-9. · 2.51 Impact Factor
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ABSTRACT: Gambierol was isolated from Gambierdiscus toxicus, which causes ciguatera fish poisoning. The acute toxicological effects induced in mice by synthesized gambierol were studied. The lethal doses were about 80 microg/kg by i.p. and i.v., and 150 microg/kg by p.o. The main injury by this toxin was observed in the lung, and secondary in the heart, resulting in systemic congestion. Another toxic effect was seen in the stomach, inducing hypersecretion and ulceration. With survival from the severe stage during the initial 3 h, recovery was favorable, especially after 4 days. Additional effects were not evident during 1-week post-administration observation.
Toxicon 01/2004; 42(7):733-40. · 2.51 Impact Factor
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ABSTRACT: Two metabolites of microcystin-LR glutathione conjugate and, microcystin-cysteine conjugate, as well as microcystin-RR (MCRR) are less toxic than microcystin-LR (MCLR). In the present study, we investigated why these compounds are weakly toxic in comparison with MCLR, as the reason is still unknown and no systematic study has so far been carried out for a clarification of this issue. Although they showed almost the same inhibitory activity against protein phosphatases 1 and 2A as MCLR in vitro, the apparent toxicity of these three compounds by intratracheal administration to mice decreased to about 1/12 the level of MCLR at 100microg/kg. An immunostaining study showed that these conjugates at a sublethal dose of 200microg/kg were prominently observed in the intestine and kidney, whereas effective accumulation and bleeding were not found in the liver in spite of the larger dosage. As an explanation for these results, there may be two possibilities. First, the transport system to the liver might not function well, and second, transported toxins may be effectively eliminated by an appropriate system such as the GS-X (ATP-dependent glutathione S-conjugate exported) pump. It was concluded that the inhibitory activity against protein phosphatases is not always related to the apparent LD(50) level, and that the appearance of toxicity by microcystins depends on the balance between accumulation and metabolism in the liver.
Toxicon 08/2002; 40(7):1017-25. · 2.51 Impact Factor
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ABSTRACT: Histopathological changes induced in mice by lyngbyatoxin A were studied in connection with the occurrence of the toxin in marine turtles implicated in human intoxication. Lyngbyatoxin A showed an i.p. lethal dose 250 microg/kg in immature mice (3-week old) and most severely damaged capillaries of villi in the small intestine. Immature mice were more sensitive than matured ones and died of bleeding from the small intestines. With sublethal doses were observed erosion in the stomach, small intestine, cecum, and large intestine, as well as inflammation in the lung. Time course changes observed after p.o. administration of sublethal doses indicated severe mucus secretion and injuries to occur within 60 min in the intestine and within 24h in the stomach. Increased inflammatory cells followed these injuries. The injuries in the lung, stomach, and small intestine took a few weeks for recovery. The cause of death and the effective dose levels resembled those of aplysiatoxin poisoning.
Toxicon 06/2002; 40(5):551-6. · 2.51 Impact Factor
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ABSTRACT: Toxicological effects of orally administered azaspiracid (AZA), a new toxin isolated from mussels, were investigated. First, a total of 25 mice were administered AZA twice at 300-450 microg/kg doses and observed for recovery processes from severe injuries. Slow recoveries from injuries were revealed: erosion and shortened villi persisted in the stomach and small intestine for more than 3 months: edema, bleeding, and infiltration of cells in the alveolar wall of the lung for 56 days; fatty changes in the liver for 20 days; and necrosis of lymphocytes in the thymus and spleen for 10 days. Secondly, low doses of AZA (50, 20, 5 and 1 microg/kg) were administered twice a week up to 40 times to four groups of mice. Many mice, nine out of ten at 50 microg/kg and three out of ten at 20 microg/kg, became so weak that they were sacrificed before completion of 40 injections. All these mice showed interstitial pneumonia and shortened small intestinal villi. Most importantly, lung tumor were observed in four mice, one out of ten (10%) at 50 microg/kg and three out of ten (30%) at 20 microg/kg. Tumors were not observed in 11 mice treated at lower doses and in 19 control mice. Hyperplasia of epithelial cells was also observed in the stomach of six mice out of ten administered at 20 microg/kg.
Toxicon 03/2002; 40(2):193-203. · 2.51 Impact Factor
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ABSTRACT: This paper describes the distribution and excretion of okadaic acid (OA) administered orally to mice and examined by immunostaining method. Five min after administration, OA was systemically distributed, being detected in the lung, liver, heart, kidney, and small and large intestine. The swollen small intestinal villi contained OA, causing the separation of epithelial cells from villi and erosion, which developed within 1h. Bleeding and edema in the lung were also found, and the distribution of OA coincided with these injuries. Although a considerable amount of OA was accumulated in the liver, no symptoms, such as bleeding, were observed. The detection of OA continued for 2 weeks in the liver and blood vessels. Excretion from kidney, cecum and large intestine began even after 5 min of the administration, and the excretion from intestine continued for 4 weeks.
Toxicon 03/2002; 40(2):159-65. · 2.51 Impact Factor
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ABSTRACT: The hepatic metabolism of microcystins (MCs), potent cyclic peptide hepatotoxins produced by cyanobacteria, was studied by ip injection in mice and rats. An immunoaffinity purification method using an anti-MC-LR monoclonal antibody showed a remarkable effect on the removal of contaminants in the hepatic cytosol and enabled us to analyze MCs and their metabolites by HPLC and Frit-FAB LC/MS. At 3, 6, and 24 h post-injection of MC-RR, a small percent of the applied dose was detected in all of the mouse livers together with several metabolites. Among them, GSH and Cys conjugates of MC-RR were identified at 3 and 24 h, respectively, by comparison with the chemically prepared standards, indicating that the thiols of GSH and Cys nucleophilically bound to the Mdha moiety of MCs. Another metabolite was presumed to be formed by both epoxidation followed by hydrolysis and sulfate conjugation in the Adda moiety and GSH conjugation in the Mdha moiety. In rat livers, MC-LR showed almost the same behavior as that of MC-RR in mouse livers. These results suggest that the conjugation of GSH with MCs may play a role in the metabolic pathway leading to detoxification of MCs.
11/1996;
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ABSTRACT: An exotoxin (HS-6) produced by Nocardia otitidiscaviarum isolated from certain lesions of cutaneous nocardiosis of a male 82-year-old patient induced severe injuries in the pancreas, liver, stomach, small intestine, heart, thymus and kidney of male ICR mice. Mice given Nocardia-free preparation of HS-6 at a dose of 1 mg/kg of body weight developed several autophagic vacuoles in the pancreas and liver within 20 min after the i.p. injection. Thereafter, the autophagic vacuoles increased in number and size with time. About 24 hr after the administration of HS-6, the liver showed marked accumulation of fat droplets in the cytoplasm of the hepatocytes. Although they contained abundant autophagic vacuoles in the regions of RER, there were no lipomatoses in the acinar cells of the pancreas, those of the chief cells and smooth muscle cells of the stomach, Paneth cells, goblet cells, smooth muscle cells of the small intestine, and plasma cells in the digestive tract. Biochemical examinations revealed that HS-6 had no significant effect on the protein synthesis of reticulocytes. Inoculation of the Nocardia into the mouse peritoneal cavities caused marked granulomatoses in the pancreas, liver and regional lymph nodes, but did not develop autophagic vacuoles in RER regions of these organs.
Mycopathologia 07/1992; 119(2):115-125. · 1.65 Impact Factor
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ABSTRACT: The basis for resistance of yeast form of Histoplasma capsulatum to antifungal activity of human neutrophils was studied. In limiting dilution assays and short term coculture assays human neutrophils were ineffective in killing H. capsulatum whereas Candida albicans was readily killed. By contrast, in a cell free hydrogen peroxide-peroxidase-halide system H. capsulatum was as sensitive to killing as C. albicans. Moreover, lysate of human neutrophils effectively substituted for horse-radish peroxidase in a cell free system for killing H. capsulatum. H. capsulatum elicited significant products of the oxidative burst in human neutrophils as detected by luminol-enhanced chemiluminescence. However, the response was two-fold less (pC. albicans. Transmission electron microscopy studies showed that phagosome-lysosome fusion took place when neutrophils phagocytosed C. albicans or H. capsulatum. Taken together, these findings indicate that, even though H. capsulatum elicits an oxidative burst and phagosome-lysosome fusion within the phagosome, it is capable of evading damage in short term assays.
Mycopathologia 08/1991; 115(3):207-213. · 1.65 Impact Factor
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ABSTRACT: K. Terao, E. Ito, T. Yanagi and T. Yasumoto. Histopathological studies on experimental marine toxin poisoning. I. Ultrastructural changes in the small intestine and liver of suckling mice induced by dinophysistoxin-1 and pectenotoxin-1. Toxicon24, 1141 – 1151, 1986 — Sequential ultrastructural changes were studied in mouse digestive organs after i.p. injections of dinophysistoxin-1 and pectenotoxin-1, causative agents of diarrhetic shellfish poisoning. Dinophysistoxin-1, a diarrheagenic substance, produced severe mucosal injuries in the small intestine within 1 hr after the administration of the toxin. The injuries were divided into 3 consecutive stages: extravasation of villi vessels, degeneration of absorptive epithelium and desquamation of the degenerated epithelium from the lamina propria. In contrast to dinophysistoxin-1, pectenotoxin-1, a non-diarrheagenic toxin from diarrhetic shellfish poisoning causative mussels, resulted in no abnormalities in the small intestine, but did cause characteristic liver injuries. Within 1 hr after the injection of pectenotoxin-1 numerous non-fatty vacuoles appeared in the hepatocytes around the periportal regions of the hepatic lobules. Electron microscopic observations with colloidal iron demonstrated that these vacuoles originated from invaginated plasma membranes of the hepatocytes.
Toxicon.
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ABSTRACT: Microcystin-LR (MCLR) was injected into mice intratracheally, absorption from the lungs was easy and it was confirmed that both the cause of death and lethality dose level were the same as by intraperitoneal injection treatment. An immunostaining method revealed that there was a time lag of about 60 min before accumulation of MCLR, and that it caused bleeding in the liver. Clearance from internal organs took about 2 weeks; during the initial stage (the first 2 days), the small intestine, kidney, cecum and large intestine were already involved. However, even after 2 weeks, small amounts of MCLR were still present in epithelial cells in the gastrointestinal mucosa.
Toxicon.
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ABSTRACT: Maitotoxin (MTX), a Ca2+ channel-activating marine toxin, caused shape change followed by aggregation in rabbit platelets, like U46619, a thromboxane A2 analogue. Although both drugs failed to cause aggregation in the absence of external Ca2+, U46619, but not maitotoxin, elicited shape change in the absence of external Ca2+. The observations of platelets with a scanning electron microscope showed that both drugs caused contraction of platelets and extension of pseudopodia (shape change) followed by aggregation with a clot in the presence of Ca2+. It is noteworthy that long term exposure to MTX caused the lysis of platelets in the presence of Ca2+. While U46619 transiently increased the internal Ca2+ concentration ([Ca2+]i), maitotoxin slowly but irreversibly increased [Ca2+]i in an external Ca2+-dependent manner. MTX-induced phosphoinositide hydrolysis was totally dependent on the presence of external Ca2+, but U46619-induced phosphoinositide hydrolysis was still observed in the absence of external Ca2+. MTX-induced phosphoinositide hydrolysis was partly inhibited by SK&F96365, a voltage-independent Ca2+ channel antagonist, or by genistein, a tyrosine kinase inhibitor. MTX caused phosphorylation of tyrosine residues of several proteins, like U46619. Thus, MTX is similar to U46619 in functions of Ca2+ mobilization, phosphoinositide hydrolysis and tyrosine phosphorylation, but MTX-induced actions are strictly dependent on the presence of external Ca2+.
Toxicon.
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ABSTRACT: K. Terao, E. Ito, Y. Sakamaki, K. Igarashi, A. Yokoyama and T. Yasumoto. Histopathological studies of experimental marine toxin poisoning. II. The acute effects of maitotoxin on the stomach, heart and lymphoid tissues in mice and rats. Toxicon26, 395 – 402, 1988. — Maitotoxin, one of the causative agents of ciguatera isolated from marine dinoflagellate, Gambierdiscus toxicus, induced severe pathomorphological changes in the stomach, heart and lymphoid tissues in mice and rats. Multiple erosions were observed in gastric mucosa accompanied by a marked increase in total calcium content 24 hr after i.p. injection of 200 or 400 ng/kg of maitotoxin. In contrast, there was no close temporal association between the accumulation of calcium and the morphological appearance of dead cells in the heart and thymus. Within 30 min of administration of 200 or 400 ng/kg of maitotoxin, a marked swelling was seen in the endothelial lining cells of blood capillaries between cardiac muscle fibers, followed by the cell death of the fibers. Injection of maitotoxin at a dose of 200 ng/kg or higher also resulted in necrosis of lymphocytes in the cortex of the thymus at 4 hr and in the medulla at 8 hr.
Toxicon.
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ABSTRACT: Neoplastic nodules were observed in mice liver treated with microcystin-LR (MCLR) by the intraperitoneal (i.p.) route over 28 weeks. After 100 i.p. injections of a sublethal dose (20 μg/kg) of MCLR, neoplastic nodules were observed without the use of an initiator. Multiple neoplastic nodules up to 5 mm in diameter were observed in the liver of mice in both groups, i.e. those injected 100 times i.p. and those injected 100 times with a 2 month withdrawal. The cysteine conjugate of MCLR was detected mainly in the affected livers. In contrast, when 80 μg/kg was orally administered 100 times, characteristic chronic injuries such as fibrous changes and nodule formation were not observed.
Toxicon.
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ABSTRACT: Aged mice (32 weeks) were orally administered microcystin-LR at 500 μg/kg, and injuries of the liver were estimated by microscopy 2 hr after treatment. Sixty-two per cent of aged mice proved to be sensitive to microcystin-LR, whereas such changes in the liver were not found in young mice (5 weeks). Uptake of the toxin into the liver was confirmed by high-performance liquid chromatography and frit-fast atom bombardment liquid chromatography/mass spectrometry after clean-up with an immunoaffinity column. To verify the difference in sensitivity to microcystin-LR between aged and young mice, non-treated mice were examined, and among them aged mice were confirmed to have a rough surface of the stomach and small intestinal mucosa. These results suggested that the hepatotoxicity by oral administration of microcystin-LR is deeply related to aging, and particularly to conditions in the small intestine such as the permeability of capillaries in the villi.
Toxicon.
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ABSTRACT: Repeated injections of 45 ng/kg of maitotoxin into the peritoneal cavities of male ICR mice resulted in marked atrophy of lymphoid tissues, a reduction of lymphocytes in the circulating blood, reduced immunoglobulin M in serum, and an increase of calcium content in the adrenal glands. A single injection of 200 ng/kg of maitotoxin induced a marked increase in total calcium content of the adrenal glands as well as in plasma cortisol concentration (about seven times control) within 1 hr. In contrast, mice pretreated with CoCl2, a calcium channel inhibitor, and/or adrenalectomized mice, showed no discernible changes in the lymphoid tissues after repeated injections of maitotoxin. It is thus suggested that maitotoxin first stimulates calcium influx in the adrenal glands, which then causes the release of cortisol into the blood. The excess amount of cortisol in serum produces acute involution of the thymus and other lymphoid tissues.
Toxicon.
