IDENTIFICATION AND USE: Domoic acid forms colorless crystal needles. Domoic acid is an excitatory amino acid containing the structure of glutamic acid and resembling kainic acid. Seaweed Chondria armata may contain domoic acid and extracts of the plant have been used in Japan as an ascaricidal medication at a dose of 20 mg/person without adverse effects. Its insecticidal properties were also known since flies die soon after landing on the seaweeds. HUMAN EXPOSURE AND TOXICITY: Amnesic shellfish poisoning (ASP) occurs after ingestion of bivalve molluscs or possibly fish contaminated with domoic acid. Until now, only bivalve molluscs harvested in Prince Edward Island, Canada, have produced poisonings in humans. However, domoic acid has been found in algae or dinoflagellates in Japan, the Mediterranean region, the East Coast of North and South America, and the West Coast of North America. After a delay of a few hours to one-day post ingestion of molluscs contaminated with domoic acid, gastrointestinal symptoms appear. They may include nausea, vomiting, abdominal cramps, diarrhea, hemorrhagic gastritis and anorexia. The neurological symptoms may occur after a delay of a few hours or up to three days according to the outbreak observed in 1987. These consist of a wide variety of symptoms varied among patients: severe headaches, loss of balance or dizziness, vision disturbances, memory loss. In more severe cases (old age and renal insufficiency being the two main risk factors): symptoms included confusion, disorientation, mutism for up to two weeks; autonomic nervous system dysfunction for a few days to a few weeks (cardiac arrhythmias, unstable blood pressure, hiccoughs, bronchial hypersecretion which may require endo-tracheal intubation); involuntary chewing, grimacing, myoclonia, convulsions; coma. Death occurred in 4 of the 107 confirmed cases. Permanent sequelae included memory loss and peripheral polyneuropathy. Domoic acid has mutagenic potential as revealed in Caco-2 cells by induction of micronucleus formation. ANIMAL STUDIES: The toxin acts as a glutamate agonist and is excitotoxic in the vertebrate central nervous system and other glutamate receptor-rich organs. Experimental studies with adult nonhuman primates have established that domoic acid is a dose-dependent emetic that produces clinical and neuropathological changes consistent with excitotoxicity. Behavioral evaluations of treated rodents have shown that hyperactivity and stereotypical scratching are the first functional markers of toxicity. Mid-dose treatment is associated with memory impairment and behavioral hyperreactivity, suggesting changes in arousal and/or emotionality. At higher doses, domoic acid treatment results in frank neurotoxicity that is characterized by seizures, status epilepticus and death in treated animals. The route of domoic acid exposure is important and influences the severity of effects; intraperitoneal and intravenous treatments produce classic signs of poisoning at significantly lower doses than oral exposure. While developmental studies are few, domoic acid readily crosses the placenta and enters the fetal brain. Domoic acid is not associated with congenital dysmorphia but is linked to persistent changes in motor behavior and cognition in exposed offspring. Comparative research suggests that functional losses associated with domoic acid can be persistent and injuries to the CNS can be progressive. Domoic acid was genotoxic in a fish Oreochromis niloticus, producing significant increases in the frequencies of micronuclei, nuclear abnormalities as well as DNA strand breaks. ECOTOXICITY STUDIES: It was shown in a large sample of wild sea lions, that spatial memory deficits are predicted by the extent of right dorsal hippocampal lesions related to natural exposure to DA and that exposure also disrupts hippocampal-thalamic brain networks. Because sea lions are dynamic foragers that rely on flexible navigation, impaired spatial memory may affect survival in the wild. Monitoring California sea lion (Zalophus californianus) health indicated that changes in the symptomatology and epidemiology of domoic acid toxicosis in this species are associated with the increase in toxigenic blooms. Two separate clinical syndromes exist: acute domoic acid toxicosis, and a second neurological syndrome characterized by epilepsy associated with chronic consequences of previous sub-lethal exposure to the toxin.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
神经毒素 - 其他中枢神经系统神经毒素
Neurotoxin - Other CNS neurotoxin
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Fetal poisoning of California sea lions (CSLs; Zalophus californianus) has been associated with exposure to the algal toxin domoic acid. These same sea lions accumulate a mixture of persistent environmental contaminants including pesticides and industrial products such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Developmental exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and its stable metabolite 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p -DDE) has been shown to enhance domoic acid-induced seizures in zebrafish; however, the contribution of other co-occurring contaminants is unknown. We formulated a mixture of contaminants to include PCBs, PBDEs, hexachlorocyclohexane (HCH), and chlordane at levels matching those reported for fetal CSL blubber to determine the impact of co-occurring persistent contaminants with p,p -DDE on chemically induced seizures in zebrafish as a model for the CSLs. Embryos were exposed (6-30 hr postfertilization) to p,p -DDE in the presence or absence of a defined contaminant mixture prior to neurodevelopment via either bath exposure or embryo yolk sac microinjection. After brain maturation (7 days postfertilization), fish were exposed to a chemical convulsant, either pentylenetetrazole or domoic acid; resulting seizure behavior was then monitored and analyzed for changes, using cameras and behavioral tracking software. Induced seizure behavior did not differ significantly between subjects with embryonic exposure to a contaminant mixture and those exposed to p,p -DDE only. These studies demonstrate that p,p -DDE--in the absence of PCBs, HCH, chlordane, and PBDEs that co-occur in fetal sea lions--accounts for the synergistic activity that leads to greater sensitivity to domoic acid seizures.
Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses >/= 0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses >/= 0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.
... DA potentiated the KCl-induced increase in [Ca(2+)](i) in quiescent cardiomyocytes and augmented the nicardipine-sensitive Ca(2+) transients in electrically stimulated cardiomyocytes.
When administered orally doses of between 35 and 70 mg domoic acid/kg body weight were required to produce toxicity in mice and rats. This reduced toxicity is consistent with a lack of absorption from the gastro-intestinal tract: fecal excretion accounted for 102 +/- 17% and 98 +/- 12% (mean +/- SE) of the domoic acid administered to mice and rats, respectively. Since human intoxication occurred at an estimated 1-5 mg domoic acid/kg body weight, susceptible individuals appear to be more sensitive than rodents to the oral toxicity of domoic acid.
Domoic acid (DA) is a potent neurotoxin that has both marine wildlife and human health impacts, including developmental effects during prenatal exposure in rodent models. However, little is known regarding DA toxicokinetics in the fetal unit during maternal-fetal transfer. Tissue distribution and toxicokinetics of DA were investigated in pregnant rats and their pups just prior to birth at gestational day 20. Pregnant Sprague Dawley rats were given an intravenous dose of 1.0 mg DA/kg and samples of maternal plasma, fetal plasma, placenta, amniotic fluid and fetal brain were taken at intervals over 24 hr. Toxicokinetic parameters were determined using WinNonLin software analysis. Maternal plasma DA log concentration-time curves fit a two compartment pharmacokinetic profile, with alpha and beta half-lives of elimination of 26.9 and 297 min, respectively. Placenta had a C(max) of 752 ng/mL and a terminal half-life of 577 min. Maternal-fetal transfer between the plasma compartments was 31% with a fetal plasma C(max) of 86 ng/mL at 60 min and terminal half-life of 553 min. Amniotic fluid and fetal brain had overall averages of 27 +/- 12 ng/mL and 8.12 ng/g, respectively, and did not show evidence of elimination over 24 hr. The longer fetal retention of DA, particularly in amniotic fluid, indicates that the fetus may be continually re-exposed during gestation, which could potentially lead to a disease state even at small exposure dose. This has implications for the California sea lions (Zalophus californianus), which exhibit an epilepsy-like disease that arises months after DA producing blooms.
In northern Chile, domoic acid (DA) has been detected in several bivalve species. In Mesodesma donacium, one of the most important commercial species for local fishermen, no information is available on depuration, or on the anatomical distribution of this toxin and its potential use as a palliative measure to minimize the consequences of ASP outbreaks. Deputation of DA is very fast in M. donacium, and can be adequately described by means of a two-compartment model. The estimated rates for the first and second compartments were 1.27 d(-1) and 0.24 d(-1), respectively, with a transfer rate between compartments of 0.75. Having high depuration rates protects this species from being affected by Pseudo-nitzschia blooms for an extended period of time. Taking this into account, the time in which the bivalves are unsafe for consumers is very short, and therefore the economic losses that could result by the DA outbreaks in local fisheries should be moderate. In relation to anatomical distribution, at least during the uptake phase, the toxin was evenly distributed within the soft tissues, with a total toxin burden corresponding to 27%, 32% and 41% for Digestive Gland (DG), Foot (FT) and Other Body Fractions (OBF), respectively. Since the contribution of each organ to the toxin concentration is a function of both weight contribution and toxin burden, the pattern of toxin distribution showed the following trend: "all other body fractions" (OBF) > Foot (FT) > Digestive Gland (DG). Thus, the highest concentration of DA, with a contribution close to 72%, corresponds to the edible tissues (OBF + FT), while the DG (non-edible tissue) only contributes the remaining 28%. Consequently, in view of the anatomical distribution of domoic acid in M. donacium, the elimination of the digestive gland does not substantially reduce the toxicity of the final product and therefore selective evisceration would not improve their quality for human consumption.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在大鼠和小鼠中关于尿液和粪便排泄的研究表明，几乎100%的给药剂量在36小时内通过粪便排出。
Studies in rats and mice on urinary and fecal excretion have shown that almost 100% of the administered dose is eliminated in the stools within a delay of 36 hours.
软骨藻酸（分子式：C15H21NO6，分子量：311.3）是由水中藻类产生的生物毒素。其结构与红藻氨酸和谷氨酸相似，作为红藻氨酸受体的兴奋剂发挥作用。目前已知能够产生该毒素的硅藻类有Pseudonitzschia australis、P. pungens f. multiseries 和 P. pseudodelicatissima 等。检测
