[Ca(2+)]-dependent generation of intracellular reactive oxygen species mediates maitotoxin-induced cellular responses in human umbilical vein endothelial cells. (57/156)

Maitotoxin (MTX) is known as one of the most potent marine toxins involved in Ciguatera poisoning, but intracellular signaling pathways caused by MTX was not fully understood. Thus, we have investigated whether intracellular reactive oxygen species (ROS) are involved in MTX-induced cellular responses in human umbilical vein endothelial cells. MTX induced a dose-dependent increase of intracellular [Ca(2+)]. MTX stimulated the production of intracellular ROS in a dose- and time-dependent manner, which was suppressed by BAPTA-AM, an intracellular Ca(2+) che-lator. Ionomycin also elevated the ROS production in a dose-dependent manner. MTX elevated transamidation activity in a time-dependent manner and the activation was largely inhibited by transfection of tissue transglutaminase siRNA. The activation of tissue transglutaminase and ERK1/2 by MTX was sup-pressed by BAPTA-AM or ROS scavengers. In addition, MTX-induced cell death was significantly de-layed by BAPTA-AM or a ROS scavenger. These results suggest that [Ca(2+)]-dependent generation of in-tracellular ROS, at least in part, play an important role in MTX-stimulated cellular responses, such as activation of tTGase, ERK phosphorylation, and in-duction of cell death, in human umbilical vein endothelial cells.  (+info)

Effects of brevetoxin-B on motor nerve terminals of mouse skeletal muscle. (58/156)

1. The effects of brevetoxin-B, a red tide toxin, on motor nerve terminal activity were assessed on mouse triangularis sterni nerve-muscle preparations. The perineural waveforms were recorded with extracellular electrodes placed in the perineural sheaths of motor nerves. 2. At 0.11 microM, brevetoxin-B increased the components of waveforms associated with sodium and potassium currents while it decreased the calcium activated potassium current and the slow calcium current of the nerve terminal. The fast calcium current and slow potassium current were not affected. 3. At 1.11 microM, brevetoxin-B decreased all of the components of waveforms associated with sodium, potassium and calcium currents. 4. It is concluded that brevetoxin-B affects sodium, potassium as well as calcium currents in the nerve terminal. The effects may contribute to its pharmacological actions on synaptic transmission.  (+info)

Harmful algal bloom toxins alter c-Fos protein expression in the brain of killifish, Fundulus heteroclitus. (59/156)

The immediate early gene c-fos, and its protein product c-Fos, are known to be induced in neurons of mammals and fish as a result of neuronal stimulation. The purpose of this study was to quantitatively examine CNS alterations in killifish, Fundulus heteroclitus, in relation to harmful algal bloom (HAB) toxin exposure. c-Fos expression was visualized using immunocytochemistry in the brains of killifish exposed to the excitatory neurotoxins domoic acid (DA) and brevetoxin (PbTx-2), and a paralytic neurotoxin, saxitoxin (STX), released from HABs. In addition, a simulated transport stress experiment was conducted to investigate effects of physical stress on c-Fos induction. Groups of fish were exposed to the different stress agents, brain sections were processed for c-Fos staining, and expression was quantified by brain region. Fish exposed to DA, STX, and transport stress displayed significant alterations in neuronal c-Fos expression when compared to control fish (p< or = 0.05). DA, PbTx-2, and transport stress increased c-Fos expression in the optic tecta regions of the brain, whereas STX significantly decreased expression. This is the first study to quantify c-Fos protein expression in fish exposed to HAB toxins. General alterations in brain activity, as well as knowledge of specific regions within the brain activated in association with HABs or other stressors, provides valuable insights into the neural control of fish behavior as well as sublethal effects of specific stressors in the CNS.  (+info)

Uptake, tissue distribution, and excretion of brevetoxin-3 administered to mice by intratracheal instillation. (60/156)

Brevetoxins are a family of potent lipid-soluble neurotoxins produced by the dinoflagellate Karenia brevis, the organism responsible for Florida red tide. Brevetoxins aerosolized by surf and wind produce irritation of the eyes, nose, and throat in people on or near red tide-affected beaches. The effects of chronic exposures to brevetoxins on healthy and health-compromised individuals are not known. The purpose of this study was to investigate the pulmonary uptake, tissue distribution, and excretion of polyether brevetoxin-3 in mice, a rodent model for investigating the potential systemic adverse health effects associated with repeated brevetoxin inhalation. Male CBA/CaJ mice were administered [3H]brevetoxin-3 by intratracheal instillation. Groups of 3 mice were sacrificed immediately after instillation and at 0.5, 3, 6, 12, 24, 48, and 96 h postinstillation. Four additional mice were placed into metabolism cages for excreta collection up to 168 h postinstillation. Brevetoxin-3 distributed rapidly to all tissues, with the highest initial doses in the liver and gastrointestinal tract. Elimination half-times ranged from approximately 28 h for fat, heart, intestines, kidneys, liver, and muscle to approximately 90 h for brain and testes. The total dose to tissue ranged from 39 ng brevetoxin equivalents-h/g for testes to 406 ng brevetoxin equivalents-h/g for liver. Approximately 90% of excretion had occurred within 96 h, with 11 and 64% of the initial brevetoxin dose excreted in urine and feces, respectively. These results are consistent with earlier reports of rapid absorption and widespread tissue distribution of brevetoxins in rats.  (+info)

Neurological disease in wild loggerhead sea turtles Caretta caretta. (61/156)

Beginning in October 2000, subadult loggerhead sea turtles Caretta caretta showing clinical signs of a neurological disorder were found in waters off south Florida, USA. Histopathology indicated generalized and neurologic spirorchiidiasis. In loggerhead sea turtles (LST) with neurospirorchiidiasis, adult trematodes were found in the meninges of the brain and spinal cord of 7 and 3 affected turtles respectively, and multiple encephalic intravascular or perivascular eggs were associated with granulomatous or mixed leukocytic inflammation, vasculitis, edema, axonal degeneration and occasional necrosis. Adult spirorchiids were dissected from meningeal vessels of 2 of 11 LST brains and 1 of 10 spinal cords and were identified as Neospirorchis sp. Affected LST were evaluated for brevetoxins, ciguatoxins, saxitoxins, domoic acid and palytoxin. While tissues from 7 of 20 LST tested positive for brevetoxins, the levels were not considered to be in a range causing acute toxicosis. No known natural (algal blooms) or anthropogenic (pollutant spills) stressors co-occurred with the turtle mortality. While heavy metal toxicosis and organophosphate toxicosis were also investigated as possible causes, there was no evidence for their involvement. We speculate that the clinical signs and pathologic changes seen in the affected LST resulted from combined heavy spirorchiid parasitism and possible chronic exposure to a novel toxin present in the diet of LST.  (+info)

Placental transport of brevetoxin-3 in CD-1 mice. (62/156)

The purpose of this study was to examine the distribution of brevetoxin-3 administered to pregnant dams and to determine the extent of placental transport to fetuses. Twenty-nine pregnant CD-1 mice were administered (3)H-brevetoxin-3 ( approximately 1.3 microCi/animal; approximately 2.8 microg compound/kg) by intratracheal instillation on one of gestational days 15-18. Groups of four or five dams were killed at selected times through 48 h post-dosing. Four pregnant dams were administered (3)H-brevetoxin-3 on gestational day 15 or 16 via osmotic minipump to provide continuous delivery of compound ( approximately 0.13 microCi, 7.5 ng compound/day) over a 72-h period. Then the dams and fetuses were killed. Brevetoxin-associated radioactivity was detected in placentas and fetuses within 0.5h of intratracheal administration. Concentrations of brevetoxin equivalents in fetuses were approximately 0.3 ng/g throughout the 48-h post-dosing, resulting in a calculated dose to fetuses of 19 ng/gh. Following brevetoxin infusion, concentration of brevetoxin equivalents in fetuses was 0.1 ng/g, lower than that present in most maternal tissues. Results demonstrated placental transport of brevetoxin or its metabolites following maternal acute exposure and repeated low-dose exposure. The consequences of these findings for pregnant women exposed to brevetoxins by inhalation or ingestion remain to be determined.  (+info)

Brevetoxin-induced neural insult in the retrosplenial cortex of mouse brain. (63/156)

Brevetoxins (polyether breve toxins; PbTx) are polyether neurotoxins produced by the marine dinoflagellate Karenia brevis, an organism associated with red tide blooms in the Gulf of Mexico and along the Atlantic coast from Florida to North Carolina. Brevetoxin-3 (PbTx-3) is a major component of the array of brevetoxins found in marine aerosols measured along red tide affected beaches. Humans exposed to aerosolized brevetoxins for short periods of time often suffer a variety of adverse health effects. It was consequently of interest to assess the potential for aerosolized brevetoxin to produce a neurotoxic response. Female BALB/c mice were exposed nose-only for 2 consecutive days to PbTx-3 aerosol, with a 2-h exposure on the first day and a 4-h exposure on the second day. The average PbTx-3 exposure concentrations on days 1 and 2 were 312 +/- 113 mug brevetoxin 3/m3 and 278 +/- 24 mug brevetoxin 3/m3, respectively. The brevetoxin-containing aerosol had a mass median aerodynamic diameter of 0.92 mum with a geometric standard deviation of 1.38. Coronal sections of mouse brains were evaluated for neuronal damage using both silver and Fluoro-Jade B staining to identify degenerating neuronal elements. PbTx-3 inhalation exposure produced neuronal degeneration in the posterior cingulate/retrosplenial cortex of mice as evidenced by silver-positive degenerating neurons in this region. No staining was found in other regions of the PBTx-3-exposed mouse brains or in brains of control, sham-exposed mice. The existence of a neurotoxic insult in PbTx-3-exposed mice was confirmed using Fluoro-Jade B to label degenerating neurons. Fluro-Jade-positive neurons were observed in the retrosplenial cortex of PBTx-3 exposed, but not control, mice. These results suggest that subacute exposure to PbTx-3 for 2 days is sufficient to induce neuronal degeneration in a discrete region of the mouse cerebral cortex.  (+info)

Azaspiracid-1 alters the E-cadherin pool in epithelial cells. (64/156)

Azaspiracids cause severe damages in the epithelium of several organs. In this study we have investigated the effects of azaspiracid-1 (AZA-1) on two epithelial cell lines. Nanomolar concentrations of AZA-1 reduced MCF-7 cell proliferation and impaired cell-cell adhesion. AZA-1 altered the cellular pool of the adhesion molecule E-cadherin by inducing a dose- and time-dependent accumulation of an E-cadherin fragment (E-cadherin-related antigen [ECRA(100)]), with a concentration inducing the half-maximal effect (EC(50)) of 0.47nM. The immunological characterization of ECRA(100) revealed that it consists of an E-cadherin molecule lacking the intracellular domain, and these data showed that the effect induced by AZA-1 in MCF-7 cells is undistinguishable from that induced by yessotoxin (YTX) in the same experimental system. A comparison of toxin effects in MCF-7 and Caco 2 cells confirmed that the effects induced by AZA-1 and YTX are undistinguishable in these cells. Treatment of fibroblasts with AZA-1 did not affect the cellular pool of N-cadherin showing that the toxin effect is cadherin-specific. A comparison of the effects induced by AZA-1, YTX, and okadaic acid on F-actin and E-cadherin in MCF-7 and Caco 2 cells showed that 1nM AZA-1 did not cause significant changes in F-actin and that accumulation of ECRA(100) did not correlate with decreased levels of F-actin under our experimental conditions. Matching our results with those available in literature, we notice that, when molecular effects induced by AZA-1 and YTX have been studied in the same in vitro systems, experimental data show that they are undistinguishable in terms of sensitive cellular parameters, effective doses, and kinetics of responses in several cell lines. The possibility that azaspiracids and YTXs might share their molecular mechanism(s) of action in defined biological settings should be considered.  (+info)