scholarly journals Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study

2018 ◽  
Vol 49 (2) ◽  
pp. 743-757 ◽  
Author(s):  
Paula Abal ◽  
M. Carmen Louzao ◽  
Toshiyuki Suzuki ◽  
Ryuichi Watanabe ◽  
Natalia Vilariño ◽  
...  
Keyword(s):  
Okadaic Acid ◽  
Lethal Dose ◽  
Maximum Level ◽  
Organ Damage ◽  
Ultrastructural Changes ◽  
Shellfish Poisoning ◽  
Oral Toxicity ◽  
Ultrastructural Studies ◽  
Dsp Toxins

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 µg 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 h. 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 µg kg-1 bw for DTX1, 760 µg kg-1 bw for OA and 2262 µg kg-1 bw for DTX2. Therefore, the oral TEF values are: OA = 1, DTX1 = 1.5 and DTX2 = 0.3. Conclusion: This is the first comparative study of DSP toxins performed with accurate well-characterized standards and based on acute toxicity data. 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.

scholarly journals Effects of the Marine Biotoxins Okadaic Acid and Dinophysistoxins on Fish

2021 ◽  
Vol 9 (3) ◽  
pp. 293
Author(s):  
Mauro Corriere ◽  
Lucía Soliño ◽  
Pedro Reis Costa
Keyword(s):  
Okadaic Acid ◽  
Harmful Algal Blooms ◽  
Algal Blooms ◽  
Current Knowledge ◽  
Global Climate ◽  
Scientific Evidence ◽  
Shellfish Poisoning ◽  
Morphological Alterations ◽  
The Impact ◽  
Dsp Toxins

Natural high proliferations of toxin-producing microorganisms in marine and freshwater environments result in dreadful consequences at the socioeconomically and environmental level due to water and seafood contamination. Monitoring programs and scientific evidence point to harmful algal blooms (HABs) increasing in frequency and intensity as a result of global climate alterations. Among marine toxins, the okadaic acid (OA) and the related dinophysistoxins (DTX) are the most frequently reported in EU waters, mainly in shellfish species. These toxins are responsible for human syndrome diarrhetic shellfish poisoning (DSP). Fish, like other marine species, are also exposed to HABs and their toxins. However, reduced attention has been given to exposure, accumulation, and effects on fish of DSP toxins, such as OA. The present review intends to summarize the current knowledge of the impact of DSP toxins and to identify the main issues needing further research. From data reviewed in this work, it is clear that exposure of fish to DSP toxins causes a range of negative effects, from behavioral and morphological alterations to death. However, there is still much to be investigated about the ecological and food safety risks related to contamination of fish with DSP toxins.

scholarly journals Delving into the Antiurolithiatic Potential of Tribulus terrestris Extract Through –In Vivo Efficacy and Preclinical Safety Investigations in Wistar Rats

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jyoti Kaushik ◽  
Simran Tandon ◽  
Rishi Bhardwaj ◽  
Tanzeer Kaur ◽  
Surinder Kumar Singla ◽  
...  
Keyword(s):  
Body Weight ◽  
Aqueous Extract ◽  
Kidney Stones ◽  
Wistar Rats ◽  
Lethal Dose ◽  
Tribulus Terrestris ◽  
Oral Toxicity ◽  
Preclinical Safety

Abstract Modern treatment interventions for kidney stones are wrought with side-effects, hence the need for alternative therapies such as plant-based medicines. We have previously documented through in vitro studies that statistically optimized aqueous extract of Tribulus terrestris (Zygophyllaceae family) possesses antiurolithic and antioxidant potential. This provides strong scientific foundation to conduct in vivo efficacy and preclinical safety studies to corroborate and lend further proof to its ability to prevent and cure kidney stones. The preventive and curative urolithiatic efficacy in experimentally induced nephrolithiatic Wistar rats, along with preclinical toxicity was evaluated following oral administration of statistically optimized aqueous extract of T. terrestris. Treatment showed augmented renal function, restoration of normal renal architecture and increase in body weight. Microscopic analysis of urine revealed excretion of small sized urinary crystals, demonstrating that treatment potentially modulated the morphology of renal stones. Tissue enzymatic estimation affirmed the antioxidant efficacy of treatment with reduced free radical generation. Significant upregulation of p38MAPK at both the gene and protein level was noted in hyperoxaluric group and interestingly treatment reversed it. Acute oral toxicity study established the Median Lethal Dose (LD50) to be greater than 2000 mg/kg body weight (b.wt.) No observed adverse effect level (NOAEL) by repeated oral toxicity for 28 days at 750 mg/kg b.wt. was noted. This study lends scientific evidence to the safe, preventive and curative potential of statistically optimized aqueous extract of T. terrestris at a dose of 750 mg/kg b.wt. and suggests that the extract shows promise as a therapeutic antiurolithic agent.

scholarly journals The diarrhetic shellfish-poisoning toxin, okadaic acid, provokes gastropathy, dysbiosis and susceptibility to bacterial infection in a non-rodent bioassay, Galleria mellonella

2021 ◽  
Author(s):  
Helena Emery ◽  
William Traves ◽  
Andrew F. Rowley ◽  
Christopher J. Coates
Keyword(s):  
Bacterial Infection ◽  
Okadaic Acid ◽  
Galleria Mellonella ◽  
Lethal Dose ◽  
Larval Survival ◽  
Shellfish Poisoning ◽  
Diarrhetic Shellfish Poisoning ◽  
Insect Larvae ◽  
Mechanisms Of Toxicity ◽  
Microbiome Composition

AbstractDiarrhetic shellfish-poisoning (DSP) toxins such as okadaic acid and dinophysistoxins harm the human gastrointestinal tract, and therefore, their levels are regulated to an upper limit of 160 μg per kg tissue to protect consumers. Rodents are used routinely for risk assessment and studies concerning mechanisms of toxicity, but there is a general move toward reducing and replacing vertebrates for these bioassays. We have adopted insect larvae of the wax moth Galleria mellonella as a surrogate toxicology model. We treated larvae with environmentally relevant doses of okadaic acid (80–400 μg/kg) via intrahaemocoelic injection or gavage to determine marine toxin-related health decline: (1) whether pre-exposure to a sub-lethal dose of toxin (80 μg/kg) enhances susceptibility to bacterial infection, or (2) alters tissue pathology and bacterial community (microbiome) composition of the midgut. A sub-lethal dose of okadaic acid (80 μg/kg) followed 24 h later by bacterial inoculation (2 × 105Escherichia coli) reduced larval survival levels to 47%, when compared to toxin (90%) or microbial challenge (73%) alone. Histological analysis of the midgut depicted varying levels of tissue disruption, including nuclear aberrations associated with cell death (karyorrhexis, pyknosis), loss of organ architecture, and gross epithelial displacement into the lumen. Moreover, okadaic acid presence in the midgut coincided with a shift in the resident bacterial population over time in that substantial reductions in diversity (Shannon) and richness (Chao-1) indices were observed at 240 μg toxin per kg. Okadaic acid-induced deterioration of the insect alimentary canal resembles those changes reported for rodent bioassays.

scholarly journals Risk Assessment of Pectenotoxins in New Zealand Bivalve Molluscan Shellfish, 2009–2019

Toxins ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 776
Author(s):  
Michael J. Boundy ◽  
D Tim Harwood ◽  
Andreas Kiermeier ◽  
Cath McLeod ◽  
Jeane Nicolas ◽  
...  
Keyword(s):  
New Zealand ◽  
Okadaic Acid ◽  
Acid Group ◽  
Fundamental Principle ◽  
Toxicity Data ◽  
Shellfish Poisoning ◽  
Oral Toxicity ◽  
Regulatory Policies ◽  
Safe Limit ◽  
The Impact

Pectenotoxins (PTXs) are produced by Dinophysis spp., along with okadaic acid, dinophysistoxin 1, and dinophysistoxin 2. The okadaic acid group toxins cause diarrhetic shellfish poisoning (DSP), so are therefore regulated. New Zealand currently includes pectenotoxins within the DSP regulations. To determine the impact of this decision, shellfish biotoxin data collected between 2009 and 2019 were examined. They showed that 85 samples exceeded the DSP regulatory limit (0.45%) and that excluding pectenotoxins would have reduced this by 10% to 76 samples. The incidence (1.3%) and maximum concentrations of pectenotoxins (0.079 mg/kg) were also found to be low, well below the current European Food Safety Authority (EFSA) safe limit of 0.12 mg/kg. Inclusion within the DSP regulations is scientifically flawed, as pectenotoxins and okadaic acid have a different mechanism of action, meaning that their toxicities are not additive, which is the fundamental principle of grouping toxins. Furthermore, evaluation of the available toxicity data suggests that pectenotoxins have very low oral toxicity, with recent studies showing no oral toxicity in mice dosed with the PTX analogue PTX2 at 5000 µg/kg. No known human illnesses have been reported due to exposure to pectenotoxins in shellfish, a fact which combined with the toxicity data indicates that they pose negligible risk to humans. Regulatory policies should be commensurate with the level of risk, thus deregulation of PTXs ought to be considered, a stance already adopted by some countries.

Sulfated diesters of okadaic acid and DTX-1: Self-protective precursors of diarrhetic shellfish poisoning (DSP) toxins

Harmful Algae ◽  
2017 ◽  
Vol 63 ◽  
pp. 85-93 ◽  
Author(s):  
Tingmo Hu ◽  
Patricia LeBlanc ◽  
Ian W. Burton ◽  
John A. Walter ◽  
Pearse McCarron ◽  
...  
Keyword(s):  
Okadaic Acid ◽  
Shellfish Poisoning ◽  
Diarrhetic Shellfish Poisoning ◽  
Dsp Toxins

scholarly journals Specification of the Okadaic Acid Equivalent for Okadaic Acid, Dinophysistoxin-1, and Dinophysistoxin-2 Based on Protein Phosphatase 2A Inhibition and Cytotoxicity Assays Using Neuro 2A Cell Line

2021 ◽  
Vol 9 (10) ◽  
pp. 1140
Author(s):  
Tsuyoshi Ikehara ◽  
Kazuya Chikanishi ◽  
Naomasa Oshiro
Keyword(s):  
Okadaic Acid ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Shellfish Poisoning ◽  
Diarrhetic Shellfish Poisoning ◽  
Oral Toxicity ◽  
Cytotoxicity Assays ◽  
The Core ◽  
Phosphatase 2A ◽  
Core Activity

Diarrhetic shellfish poisoning (DSP) is a globally occurring disease threatening public health and trade. The causative toxins, okadaic acid (OA), dinophysistoxin-1 (DTX1), and dinophysistoxin-2 (DTX2) are collectively called OAs, and are quantified using the LC-MS/MS method. The hazardous effect of total OAs is expressed as the sum of OA equivalents defined for respective OAs based on mouse lethality, produced by either intraperitoneal (OAip) or oral administration (OAor). OAs are potent inhibitors of protein phosphatase 2A (PP2A) and are cytotoxic, necessitating expansion of the concept of OA equivalents to all relevant bioactivities. In this study, we determined OA equivalents for respective OA members in PP2A inhibition and cytotoxicity assays. To secure result credibility, we used certified OAs, reference materials, and PP2A produced using genetic engineering. The relative ratio of the OA equivalents determined by PP2A inhibition assays for OA, DTX1, and DTX2 were 1.0:1.6:0.3, while the ratio determined using the cytotoxicity assays indicated 1.0:1.5:0.5. OA equivalents showed a similar tendency in the PP2A inhibition and cytotoxicity assays, and matched better with oral toxicity data than intraperitoneal toxicity in mice. The PP2A inhibition assay, which measures the core activity of the OAs, suggested a higher OA equivalent for DTX1 than that currently used.

Detection of Ciguatera and Diarrheic Shellfish Toxins in Finfish and Shellfish With Ciguatect Kit

1995 ◽  
Vol 78 (2) ◽  
pp. 533-537 ◽  
Author(s):  
Douglas L Park
Keyword(s):  
Okadaic Acid ◽  
Solid Phase ◽  
Rapid Screening ◽  
Enzyme Linked Immunosorbent Assay ◽  
Shellfish Poisoning ◽  
Fish Flesh ◽  
Test Kit ◽  
User Friendly ◽  
Fish And Shellfish ◽  
Dsp Toxins

Abstract The Ciguatect test kit for the detection of ciguatoxin, okadaic acid, and related polyether compounds, based on solid-phase immunobead assay technology, was developed for rapid screening of toxic fish and shellfish in harvesting areas and the marketplace. Earlier formats, based on radioimmunoassay and enzyme-linked immunosorbent assay (ELISA) technology, were used successfully to identify and separate ciguatoxic fish harvested from Hawaiian waters. The new format utilizes a membrane attached to a plastic strip, immunobead solution, and a user-friendly readout. Multiple formats of the test kit, including a rapid extraction method (REM) and ELISA, were demonstrated to be more sensitive than the mouse assay for detection of ciguatera-related compounds. Depending on the format used, the level of detection can be as low as 50 pg okadaic acid per gram of tissue. The test kit has been used to map ciguatoxic and nontoxic fishing areas around the islands of Hawaii through the use of a biomarker and the monitoring of toxic fish obtained from Pacific and Caribbean regions. Ciguatera-related toxins can be detected directly on fish flesh or after extraction by traditional procedures or the newly developed REM. Initial applications of the test kit to monitor diarrheic shellfish poisoning (DSP)-related toxins in mussels before, during, and after Dinophysis sp. blooms and during depuration operations were successful. The Ciguatect methodology can be used to monitor reef fishing areas for ciguatera potential, shellfish beds for DSP toxins, and shellfish depuration operations for elimination of DSP toxins and to screen for toxic fish and shellfish in the marketplace.

scholarly journals Antibacterial Activity and Pharmacokinetic Profile of a Promising Antibacterial Agent: 22-(2-Amino-phenylsulfanyl)-22-Deoxypleuromutilin

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 878 ◽  
Author(s):  
Xiangyi Zuo ◽  
Xi Fang ◽  
Zhaosheng Zhang ◽  
Zhen Jin ◽  
Gaolei Xi ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antibacterial Agent ◽  
Lethal Dose ◽  
Intraperitoneal Administration ◽  
Serum Levels ◽  
Pharmacokinetic Profile ◽  
Oral Route ◽  
Oral Toxicity

A new pleuromutilin derivative, 22-(2-amino-phenylsulfanyl)-22-deoxypleuromutilin (amphenmulin), has been synthesized and proved excellent in vitro and in vivo efficacy than that of tiamulin against methicillin-resistant Staphylococcus aureus (MRSA), suggesting this compound may lead to a promising antibacterial agent to treat MRSA infections. In this study, the effectiveness and safety of amphenmulin were further investigated. Amphenmulin showed excellent antibacterial activity against MRSA (minimal inhibitory concentration = 0.0156~8 µg/mL) and performed time-dependent growth inhibition and a concentration-dependent postantibiotic effect (PAE). Acute oral toxicity test in mice showed that amphenmulin was a practical non-toxic drug and possessed high security as a new drug with the 50% lethal dose (LD50) above 5000 mg/kg. The pharmacokinetic properties of amphenmulin were then measured. After intravenous administration, the elimination half-life (T1/2), total body clearance (Clβ), and area under curve to infinite time (AUC0→∞) were 1.92 ± 0.28 h, 0.82 ± 0.09 L/h/kg, and 12.23 ± 1.35 μg·h/mL, respectively. After intraperitoneal administration, the T1/2, Clβ/F and AUC0→∞ were 2.64 ± 0.72 h, 4.08 ± 1.14 L/h/kg, and 2.52 ± 0.81 μg·h/mL, respectively, while for the oral route were 2.91 ± 0.81 h, 6.31 ± 2.26 L/h/kg, 1.67 ± 0.66 μg·h/mL, respectively. Furthermore, we evaluated the antimicrobial activity of amphenmulin in an experimental model of MRSA wound infection. Amphenmulin enhanced wound closure and promoted the healing of wound, which inhibited MRSA bacterial counts in the wound and decreased serum levels of the pro-inflammatory cytokines TNF-α, IL-6, and MCP-1.

scholarly journals Oral Toxicity of Okadaic Acid in Mice: Study of Lethality, Organ Damage, Distribution and Effects on Detoxifying Gene Expression

Toxins ◽  
2013 ◽  
Vol 5 (11) ◽  
pp. 2093-2108 ◽  
Author(s):  
Andres Vieira ◽  
Juan Rubiolo ◽  
Henar López-Alonso ◽  
José Cifuentes ◽  
Amparo Alfonso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Okadaic Acid ◽  
Organ Damage ◽  
Oral Toxicity ◽  
Damage Distribution

scholarly journals The in Vitro Antischistosomal Activity and Genotoxicity of the Active Ingredients of Allium sativum (allicin) and Curcuma longa (curcumin)

2021 ◽  
Author(s):  
Hadeer Abd El-Hak RASHED ◽  
Ali Hussein ABU ALMAATY ◽  
Maha Farid Mohamed SOLIMAN ◽  
Nahla Soliman EL-SHENAWY
Keyword(s):  
Dna Fragmentation ◽  
Allium Sativum ◽  
Curcuma Longa ◽  
Surface Damage ◽  
Ultrastructural Changes ◽  
Active Ingredients ◽  
Ultrastructural Studies ◽  
Antischistosomal Activity ◽  
Port Said

Background: In this study, we assessed the in vitro antischistosomal activity of the active ingredients of Allium sativum (allicin) and Curcuma longa (curcumin) on Schistosoma mansoni.  Methods: This study was conducted in Faculty of Science, Port said University, Egypt (2018). Adult worms were exposed to a range of concentrations of AL or CU, and worm survival was assessed 24 h post-exposure to calculate the lethal concentration of the compounds. Scanning electron microscopy was used to assess ultrastructural changes in the surface of AL- or CU- treated worms. The genotoxicities of AL and CU on S. mansoni were determined by DNA fragmentation analysis. Results: We determined the concentrations of AL and CU required to kill 50% of S. mansoni (LC50). The LC50 of AL was 8.66 µL/mL, whereas 100% mortality of S. mansoni was achieved by AL at concentrations of 50 µL/mL. The LC50 of CU was 87.25 µL/mL, with the highest mortality of 91.3% seen after 24 h exposure to 100 µg/mL CU. Ultrastructural studies revealed that exposure to either AL or CU led to mild or severe surface damage to S. mansion, respectively. The degree of damage in the worms was sex-dependent. Interestingly, while CU exposure resulted in DNA fragmentation in S. mansoni worms, we observed no genotoxic effects of AL. Conclusion: Both AL and CU exhibit antischistosomal activity; the study provided evidence suggesting that these compounds act through distinct mechanisms. These promising results encourage further investigation into these compounds as potential antischistosomal agents, either alone or as complementary treatments to praziquantel.

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