9,10-Deepithio-9,10-didehydro-acanthifolicin

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ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

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/The authors/ generated a neuroblastoma (SH-SY5Y) cell system in which cytoskeletal proteins are abnormally phosphorylated resulting in microtubule disruption due to the marked inhibition of protein phosphatase activities by okadaic acid (OA). OA-induced declines in cell viability and mitochondrial metabolic activity were remarkably prevented by melatonin. In addition, the hyperphosphorylation/accumulation of neurofilament-(NF-) H/M subunits and the disruption of microtubules, induced by OA, were significantly inhibited by melatonin.

In awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases.

Okadaic acid (OA) is a marine toxin, a tumor promoter and an inducer of apoptosis. It mainly inhibits protein-phosphatases, protein synthesis and enhances lipid peroxidation. Caco-2 cells were treated exclusively by OA (15 ng/mL) or cadmium (Cd) (0.625 and 5 ug/mL) for 24 hr, protein synthesis was inhibited (by 42 +/- 5%, 18 +/- 13%, and 90 +/- 4% respectively) while /malondialdehyde/ (MDA) production was 2,235 +/- 129, 1710 +/- 20, and 11,496 +/-1,624 pmol/mg protein respectively. In addition, each toxicant induced modified bases in DNA; increases in oxidised bases and methylated dC. The combination of OA and cadmium was more cytotoxic and caused more DNA base modifications; the ratio m(5)dC/(m(5)dC + dC) was increased from 3 +/- 0.15 to 9 +/- 0.15 and the ratio 8-(OH)-dG/10(5) dG also (from 36 +/- 2 to 76 +/- 6). The combination of OA and Cd also increased the level of MDA (1,6874 +/- 2,189 pmole/mg protein). The present results strongly suggest that DNA damage resulting from the oxidative stress induced by these two toxicants may significantly contribute to increasing their carcinogenicity via epigenetic processes.

25 nM okadaic acid promotes DNA fragmentation in B16 melanoma, increasing cell detachment as well as pigmentation, a characteristic of melanocytic cell differentiation. At lower levels, okadaic acid synergizes with UV exposure to increase DNA fragmentation.

For more Interactions (Complete) data for Okadaic acid (20 total), please visit the HSDB record page.

LC50; Species: Tigriopus californicus (Harpacticoid copepod); Conditions: static; Concentration: 51.8 uM for 24 hr (95% confidence interval: 48.5-55.4 uM)

LD50 Mouse oral 760 ug/kg

IDENTIFICATION AND USE: Okadaic acid (OA) is a solid. OA is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and, subsequently, can be consumed by humans causing alimentary intoxications. OA is used as a biochemical tool as tumor promoter and probe of cellular regulation. HUMAN STUDIES: OA is the main representative diarrheic shellfish poisoning (DSP) toxin and its ingestion induces gastrointestinal symptoms, although it is not considered lethal. At the molecular level, OA is a specific inhibitor of several types of serine/threonine protein phosphatases. Induction of DNA adducts by OA was shown in human keratinocytes and human bronchial epithelial cells. ANIMAL STUDIES: In mice after 7 days of oral administration of 1 mg/kg/day OA induced diarrhea, body weight loss, reduced food consumption, and death. OA was a tumor promoter in two-stage experiments on mouse skin. OA can induce disorganization in cytoskeletal architecture and cell-cell contact, cause chromosome loss, apoptosis, DNA damage and inhibit phosphatases, suggesting its potential embryotoxicity. OA is used as a pharmacologically induced model of Alzheimer's disease in different species. In rats intrahippocampal bilateral microinjection of OA led to a spatial memory impairment. A significantly higher frequency of micronuclei was observed in hemocytes from the OA-exposed group of the mussel Perna perna compared to control. Induction of DNA adducts by OA was shown in Baby Hamster Kidney (BHK) cells, also the induction of DNA adducts in zebra fish embryos was demonstrated. ECOTOXICITY STUDIES: The blue mussel, Mytilus edulis and the pacific oyster, Crassostrea gigas were exposed in vivo to OA and impacts on DNA fragmentation were measured. A significant increase in DNA fragmentation was observed in the two cell types from both species relative to the controls. This increase was greater in the pacific oyster at the higher toxin concentration. In mussel Mytilus galloprovincialis mussel gill cells display higher sensitivity to early OA-mediated genotoxicity than hemocytes. In maize cells, OA caused the cell cycle arrest at preprophase, leading to seedling growth inhibition.

Marine food sources such as oysters, clams, mussels, and scallops may be contaminated by dinoflagellate or cyanobacteria toxins. Consumption of these toxins can cause poisoning with neurologic and gastrointestinal symptoms. The action sites include ion channels, kainate receptors, and protein phosphatases, and disruption of these nerve and muscle functions causes the symptoms observed in patients with shellfish toxicity. Shellfish poisoning may be classified into four clinical syndromes, depending on the specific etiology and clinical presentation: paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), amnesic shellfish poisoning (ASP), and diarrheic shellfish poisoning (DSP). PSP is associated with saxitoxins. NSP is produced by brevetoxin. ASP is due to domoic acid ingestion. DSP is caused by okadaic acid. These toxins and their associated illnesses are related to harmful algal blooms.

/AQUATIC SPECIES/ Two bivalve species of global economic importance: the blue mussel, Mytilus edulis and the pacific oyster, Crassostrea gigas were exposed in vivo, to the diarrhoetic shellfish toxin okadaic acid (OA), and impacts on DNA fragmentation were measured. Shellfish were exposed using two different regimes, the first was a single (24 hr) exposure of 2.5 nM OA (~0.1 ug/shellfish) and algal feed at the beginning of the trial (T0), after which shellfish were only fed algae. The second was daily exposure of shellfish to two different concentrations of OA mixed with the algal feed over 7 days; 1.2 nM OA (~0.05 ug OA/shellfish/day) and 50 nM OA (~2 ug OA/shellfish/day). Hemolymph and hepatopancreas cells were extracted following 1, 3 and 7 days exposure. Cell viability was measured using the trypan blue exclusion assay and remained above 85% for both cell types. DNA fragmentation was examined using the single-cell gel electrophoresis (comet) assay. A significant increase in DNA fragmentation was observed in the two cell types from both species relative to the controls. This increase was greater in the pacific oyster at the higher toxin concentration. However, there was no difference in the proportion of damage measured between the two cell types, and a classic dose response was not observed, increasing toxin concentration did not correspond to increased DNA fragmentation.

/AQUATIC SPECIES/ Okadaic acid (OA) is the predominant biotoxin responsible for diarrhetic shellfish poisoning (DSP) syndrome in humans. While its harmful effects have been extensively studied in mammalian cell lines, the impact on marine organisms routinely exposed to OA is still not fully known. Few investigations available on bivalve molluscs suggest less genotoxic and cytotoxic effects of OA at high concentrations during long exposure times. In contrast, no apparent information is available on how sublethal concentrations of OA affect these organisms over short exposure times. In order to fill this gap, this study addressed for the first time in vitro analysis of early genotoxic and cytotoxic effects attributed to OA in two cell types of the mussel Mytilus galloprovincialis. Accordingly, hemocytes and gill cells were exposed to low OA concentrations (10, 50, 100, 200, or 500 nM) for short periods of time (1 or 2 hr). The resulting DNA damage, as apoptosis and necrosis, was subsequently quantified using the comet assay and flow cytometry, respectively. Data demonstrated that (1) mussel hemocytes seem to display a resistance mechanism against early genotoxic and cytotoxic OA-induced effects, (2) mussel gill cells display higher sensitivity to early OA-mediated genotoxicity than hemocytes, and (3) mussel gill cells constitute more suitable systems to evaluate the genotoxic effect of low OA concentrations in short exposure studies. Taken together, this investigation provides evidence supporting the more reliable suitability of mussel gill cells compared to hemocytes to evaluate the genotoxic effect of low short-duration exposure to OA.

Very recently, several toxic components have been isolated from shellfish .... Five of the toxic components have been structurally elucidated as okadaic acid and derivatives, and polyether lactones. ... Several species of dinoflagellates have been identified as organisms that produce okadaic acid and are also associated with disease outbreaks. ... okadaic acid, has been confirmed in a benthic dinoflagellate, Prorocentrum lima, though involvement of this species in /Diarrhoeic Shellfish Poisoning/ has never been known(1). /Diarrhoeic Shellfish Poisons/

Okadaic acid is isolated from marine sponges Halichondria okadai or H. melanodocia. It is a tumor-associated cytotoxin associated with diarrhetic seafood poisoning(1).

/SIGNS AND SYMPTOMS/ Diarrhetic Shellfish Poisoning; Symptoms: Exculusively gastrointestinal with nausea, vomiting, cramping abdominal pain, severe diarrhea (>20 stools/day), no CNS symptoms... Prognosis: Self-limited, symptoms resolve within 3 days, no fatalities.

/CASE REPORTS/ A new outbreak of human diarrheic poisonings (DSP) with esters of okadaic acid (OA) was confirmed after ingestion of razor clams (Solen marginatus) harvested at Aveiro lagoon (NW Portugal) in the summer of 2001. Accumulation of marine toxins in second order consumers was investigated in the edible parts of a shellfish predator abundant at Aveiro lagoon, the green crab Carcinus maenas. Okadaic acid was found, also in a predominant esterified form. Levels in edible parts (comprising mainly viscera) surpassed 16 ug/100 g. ... One patient may have developed profuse diarrhea after ingestion of a large number of green crabs contaminated with okadaic acid esters. At least 32 ug OA/100 g were found in a remaining sample of its meal. Domoic acid was also found but under the allowable level in force in USA of 30 ug/g crab viscera. In cooked crabs, significant losses of domoic acid were found and it is not suspected to have contributed to the poisoning event, although being a vector for this toxin. The low percentage of free okadaic acid found is in accordance with a predation predominantly on benthonic shellfish (razor clams, clams and common cockle) rather than on rock mussels.

/EPIDEMIOLOGY STUDIES/ OBJECTIVES: This investigation was undertaken in response to an outbreak of suspected shellfish poisoning in Zhejiang Province, China. The objectives of this project were to confirm the outbreak and to identify the etiology, source and mode of transmission. METHODS: A probable case was defined as an individual with diarrhea (=3 times/day) plus at least one of the following symptoms: fever (=37.5 °C), vomiting, or abdominal pain after consuming seafood between May 23(rd) and May 28(th), 2011. Using a case-control study design, we compared exposures to suspected seafood items and cooking methods between 61 probable cases and 61 controls. RESULTS: Over 220 suspected or probable cases of diarrhetic shellfish poisoning (DSP) were identified (incidence of 18 cases per 100,000). The case control study revealed that 100% of cases and 18% of controls had eaten mussels during the exposure period (OR=infinity, Chi(2)=84.72,P=0.000). The number of mussels consumed was related to DSP risk (P=0.004, Chi2 test for trend). Consumption of other seafood items was not associated with disease. The frequency of diarrhea and vomiting were positively correlated with the number of mussels consumed (r=0.424 and r=0.562, respectively). The frequency of vomiting and the incubation period were significantly correlated with the total time the mussels were boiled (r=0.594 and r=-0.336, respectively). Mussels from 3 food markets and one family contained Okadaic acid (OA) and Dinophysistoxin-1 (DTX-1). CONCLUSIONS: This outbreak was attributed to the consumption of mussels contaminated by DSP-toxins (OA and DTX-1) which are produced by different species of dinoflagellates (toxic microalgae) from the genus Dinophysis or Prorocentrum. Suspension of mussel sales and early public announcements were highly effective in controlling the outbreak, although oversight of seafood quality should be a priority to prevent future contamination and outbreaks.

Okadaic acid equivalents reported in shellfish and phytoplankton collected around the Firth of Clyde, Scotland, between May and December, 2015. Okadaic acid was detected in mussels from Lake Ewe every week from May-October, 2002; concentrations ranged from 0-150 ug/kg, with the highest concentration being reported during week 33 of 52(1).[Table#6845]

Okadaic acid (OA), Dinophysistoxins (DTX1 and DTX2) and their acyl-derivatives (DTX3) are marine toxins responsible for the human diarrhetic shellfish poisoning. To date the amount of toxins ingested from consumption of shellfish has been considered equal to the amount of toxins available for uptake by the human body. The aim of this study is to assess the OA, DTX2 and DTX3 fractions released from raw and steamed mussels and cockles into the digestive fluids (bioaccessibility) using a static in vitro digestion model. Higher bioaccessibility was found in mussels (86%) than in cockles (59%). A significant reduction of ester derivatives of OA and an increase of OA were observed in the bioaccessible fraction of mussel samples, suggesting that DTX3 undergo conversion into their more toxic parent compounds during human digestion. However, similar increase of DTX2 and reduction of the respective acyl derivatives was not observed. Steaming lead to significant reduction of OA and analogues bioaccessibility in both species even though increased concentrations of toxins are obtained after this treatment. Risk assessment based solely on DSP toxins occurrence in seafood can conduct to an overestimation of the exposure and lead to more conservative regulatory measures.

The occurrence of okadaic acid (OA) group toxins in bivalve mollusk collected from Vietnamese coastal areas was investigated from April 2016 to April 2017. OA group toxins were detected in mollusk by UPLC-MS/MS with the highest level of 11.3 ng/g and detection frequency of 11.8%. Toxins were detected more frequently in dry season (14.4% of analyzed samples) than in wet season (7.9%). Toxins were also detected more frequently at sampling locations in the northern parts (>/= 10.4%) than in the southern part (>/= 8.3%) of Vietnamese coastline. Results of this study were similar to those obtained in long-term studies in regions geographically close to Vietnam, confirming decisive influence of geographic location on the accumulation of toxins in mollusks. Within the scope of the study, toxin levels in all contaminated samples were below the regulation limit (160 ng/g), but the presence of OA group toxins in bivalve mollusk suggests the need of a more stringent control of toxins in bivalve mollusk in Vietnam.

The occurrence and seasonal variations of marine algal toxins in phytoplankton and oyster samples in Daya Bay (DYB), South China Sea were investigated. Two Dinophysis species, namely, D. caudata and D. acuminata complex, were identified as Okadaic acid (OA)/pectenotoxin (PTX) related species. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis demonstrated that 2.04-14.47 pg PTX2 per cell was the predominant toxin in single-cell isolates of D. caudata. D. acuminata was not subjected to toxin analysis. The occurrence of OAs in phytoplankton concentrates of net-haul sample coincided with the presence of D. accuminata complex, suggesting that this species is most likely an OA producer in this sea area. OA, dinophysistoxins-1 (DTX1), PTX2, PTX2sa, gymnodimine (GYM), homoyessotoxin (homoYTX), and domoic acid (DA) demonstrated positive results in net haul samples. To our best knowledge, this paper is the first to report the detection of GYM, DA, and homoYTX in phytoplankton samples in Chinese coastal waters. Among the algal toxins, GYM demonstrated the highest frequency of positive detections in phytoplankton concentrates (13/17). Five compounds of algal toxins, including OA, DTX1, PTX2, PTX2sa, and GYM, were detected in oyster samples. DA and homoYTX were not detected in oysters despite of positive detections for both in the phytoplankton concentrates. However, neither the presence nor absence of DA in oysters can be determined because extraction conditions with 100% methanol used to isolate toxins from oysters (recommended by the EU-Harmonised Standard Operating Procedure, 2015) would likely be unsuitable for this water-soluble toxin. In addition, transformation of DA during the digestion process of oysters may also be involved in the negative detections of this toxin. GYM exhibited the highest frequency of positive results in oysters (14/17). OAs were only detected in the hydrolyzed oyster samples. The detection rates of PTX and PTX2sa in oysters were lower than those in the net haul samples.

/LABORATORY ANIMALS: Acute Exposure/ Recently it was shown that the phosphatase 1/2A inhibitor okadaic acid induced Mallory body formation, suggesting that the mechanism of formation involves hyperphosphorylation or oxidative stress-induced NF kappa B activation. To test this hypothesis drug-primed mice /were exposed/ to okadaic acid and phosphorylation of Mallory proteins /was measured/. Beginning 15 min after okadaic acid injection, complex changes were progressively seen in the liver cells focally including aggregation of cytokeratins 8 and 18 in hepatocytes. Immunoblots showed a progressive increase in positive staining of the Mallory body band with the antibody to phosphothreonine. NF kappa B activation was progressive up to 2 hr after okadaic acid treatment but was downregulated 7 days later. /The authors/ conclude that hyperphosphorylation and NF kappa B activation may play a role in the early phases of Mallory body formation.

/LABORATORY ANIMALS: Acute Exposure/ A short-term toxicity study after 7 days oral daily administration of the main diarrhetic shellfish toxin okadaic acid (OA; 1 mg/kg/day) was carried out in mice. ... OA induced diarrhea, body weight loss, reduced food consumption, and the death of 2/5 mice after 5 days. Necroscopy and/or light microscopy analysis revealed toxic effects mainly at forestomach (ulceration and hyperplasia), liver and, indirectly to body weight loss of mice, atrophic signs in the lymphoid organs and exocrine pancreas. Electron microscopy of heart tissue showed alterations of mitochondria and fibers in myocardiocytes, although no apoptotic change was recorded.

/LABORATORY ANIMALS: Acute Exposure/ BACKGROUND/AIMS: Okadaic acid (OA) and the structurally related compounds dinophysistoxin-1 (DTX1) and dinophysistoxin-2 (DTX2) are marine phycotoxins that cause diarrheic shellfish poisoning (DSP) in humans due to ingestion of contaminated shellfish. In order to guarantee consumer protection, the regulatory authorities have defined the maximum level of DSP toxins as 160 ug OA equivalent kg-1 shellfish meat. For risk assessment and overall toxicity determination, knowledge of the relative toxicities of each analogue is required. In absence of enough information from human intoxications, oral toxicity in mice is the most reliable data for establishing Toxicity Equivalence Factors (TEFs). METHODS: Toxins were administered to mice by gavage, after that the symptomatology and mice mortality was registered over a period of 24 hr. Organ damage data were collected at necropsy and transmission electron microscopy (TEM) was used for ultrastructural studies. Toxins in urine, feces and blood were analyzed by HPLC-MS/MS. The evaluation of in vitro potencies of OA, DTX1 and DTX2 was performed by the protein phosphatase 2A (PP2A) inhibition assay. RESULTS: Mice that received DSP toxins by gavage showed diarrhea as the main symptom. Those toxins caused similar gastrointestinal alterations as well as intestine ultrastructural changes. However, DSP toxins did not modify tight junctions to trigger diarrhea. They had different toxicokinetics and toxic potency. The lethal dose 50 (LD50) was 487 ug/kg bw for DTX1, 760 ug/kg bw for OA and 2262 ug kg-1 bw for DTX2. Therefore, the oral TEF values are: OA = 1, DTX1 = 1.5 and DTX2 = 0.3. CONCLUSION: ... Results confirmed that DTX1 is more toxic than OA by oral route while DTX2 is less toxic. Hence, the current TEFs based on intraperitoneal toxicity should be modified. Also, the generally accepted toxic mode of action of this group of toxins needs to be reevaluated.

SEAWATER: For the first time, the composition, concentration and distribution characteristics of typical lipophilic marine algal toxins (LMATs) are investigated in surface seawater, suspended particulate matter (SPM) and sediments from the Yellow Sea and the Bohai Sea, China. Pectenotoxin-2 (PTX2) and okadaic acid (OA) were detected in offshore surface seawater samples (n = 67) of the Yellow and Bohai Seas, and PTX2 was found in higher concentrations than OA. The concentrations of PTX2 were between 0.49 and 14.14 ng/L. OA, dinophysistoxin-1(DTX1), PTX2 and gymnodimine (GYM) were detected in the nearshore surface seawater samples (n = 20) of the Haizhou Bay of the Yellow Sea. OA concentrations were between 11.47 and 55.85ng/L. There was a large degree of variation in the concentrations of DTX1, from <limit of quantification (LOQ) up to 143.14 ng/L. The nearshore surface seawater samples (n = 13) obtained from the Longdao area of the Bohai Sea mainly contain OA (5.00-24.14 ng/L) and DTX1 (1.52-49.39 ng/L), with PTX2 concentrations being less than the LOQ. Several LMATs were also detected both in the SPM and sediment samples of each study area. In summary, the LMAT composition and concentration levels in the surface seawater found in nearshore samples were substantially different from those of samples from the distant shore, which indicated the obvious regional characteristics of LMATs according to their spatial distribution in the Yellow Sea and the Bohai Sea.

In recent years, our group and several others have been describing the presence of new, not previously reported, toxins of high toxicity in vectors that may reach the human food chain. These include tetrodotoxin in gastropods in the South of Europe, ciguatoxin in fish in the South of Spain, palytoxin in mussels in the Mediterranean Sea, pinnatoxin all over Europe, and okadaic acid in the south of the U.S. There seem to be new marine toxins appearing in areas that are heavy producers of seafood, and this is a cause of concern as most of these new toxins are not included in current legislation and monitoring programs. Along with the new toxins, new chemical analogues are being reported. The same phenomenom is being recorded in freshwater toxins, such as the wide appearance of cylindrospermopsin and the large worldwide increase of microcystin. The problem that this phenomenon, which may be linked to climate warming, poses for toxicologists is very important not only because there is a lack of chronic studies and an incomplete comprehension of the mechanism driving the production of these toxins but also because the lack of a legal framework for them allows many of these toxins to reach the market. In some cases, it is very difficult to control these toxins because there are not enough standards available, they are not always certified, and there is an insufficient understanding of the toxic equivalency factors of the different analogues in each group. All of these factors have been revealed and grouped through the massive increase in the use of LC-MS as a monitoring tool, legally demanded, creating more toxicological problems.

Biochemical tool as tumor promoter and probe of cellular regulation.

OA /okadaic acid/ is a highly selective inhibitor of protein phosphatases type 1 (PP1) and 2A (PP2A), ... /and/ it causes dramatic increases in phosphorylation of numerous proteins as well as being a potent tumour promoter. For that reason, OA is an extremely useful tool for studying the cellular processes that are regulated by reversible phosphorylation of proteins as signal transduction, cell division and memory.

Okadaic acid is found in mollusks. Okadaic acid is found in the marine sponges Halichondria okadai and Halichondria melanodocia and shellfish. It is a diarrhetic shellfish toxin. Okadaic acid is a toxin that accumulates in bivalves and causes diarrhetic shellfish poisoning. Okadaic acid was named from the marine sponge Halichondria okadai, from which okadaic acid was isolated for the first time. It has also been isolated from another marine sponge, H. malanodocia, as a cytotoxin.