Tetrodotoxin

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (28 February 2018) | Viewed by 56601

Special Issue Editors


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Guest Editor
Centre for Environment, Fisheries and Aquaculture Science, Weymouth Laboratory, Lowestoft, UK
Interests: assessment of new marine toxin threats; cyanobacterial toxins; method development; reference materials; rapid testing methods; one health impacts
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Guest Editor
Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki, Nagasaki 852-8521, Japan
Interests: tetrodotoxin; pufferfish; shellfish toxins; harmful algae; palytoxin; food poisoning

Special Issue Information

Dear Colleagues,

Tetrodotoxin (TTX) is a highly potent neurotoxin responsible for many human fatalities, most commonly following consumption of pufferfish. It has the highest fatality rate of all marine intoxications, with many hundreds reported annually. Various species of marine bacteria are thought to be the source of this toxin, but this has yet to be conclusively proven. TTX, together with a number of TTX analogues (together termed TTXs) have been well studied in pufferfish, other fish species, gastropods, amphibians and other terrestrial species. More recently, there have even been several reports of TTXs occurring in bivalve shellfish, including those harvested from Japan, New Zealand, the UK, Greece, and the Netherlands. As such, TTXs are now known to occur in the temperate waters of Europe, as well as in warmer waters.

This Special Issue, entitled "Tetrodotoxins", is being put together to collate papers describing this common theme. The aim is to bring together the work of researchers throughout the world who are currently working on this important group of toxins. This Special Issue is focused on the occurrence of TTXs in new areas of the globe and in new species, emerging risks, evidence for production of TTX and accumulation mechanisms and physiologic functions of toxins in fish, crustacean, bivalves and other marine species of relevance. It will also collect work on methods of detection and data concerning the presence of TTX analogues and associated toxicity.

Dr. Andrew Turner
Prof. Dr. Osamu Arakawa
Guest Editors

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Keywords

  • tetrodotoxins
  • pufferfish
  • shellfish
  • marine bacteria
  • food poisoning
  • detection methods
  • emerging risks
  • accumulation mechanisms
  • physiological function
  • toxicity

Published Papers (9 papers)

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10 pages, 1414 KiB  
Article
Pufferfish Saxitoxin and Tetrodotoxin Binding Protein (PSTBP) Analogues in the Blood Plasma of the Pufferfish Arothron nigropunctatus, A. hispidus, A. manilensis, and Chelonodon patoca
by Mari Yotsu-Yamashita, Yuuma Nagaoka, Koji Muramoto, Yuko Cho and Keiichi Konoki
Mar. Drugs 2018, 16(7), 224; https://doi.org/10.3390/md16070224 - 29 Jun 2018
Cited by 24 | Viewed by 6085
Abstract
Pufferfish saxitoxin and tetrodotoxin (TTX) binding protein (PSTBP) is a glycoprotein that we previously isolated from the blood plasma of the pufferfish Takifugu pardalis; this protein was also detected in seven species of the genus Takifugu. We proposed that PSTBP is [...] Read more.
Pufferfish saxitoxin and tetrodotoxin (TTX) binding protein (PSTBP) is a glycoprotein that we previously isolated from the blood plasma of the pufferfish Takifugu pardalis; this protein was also detected in seven species of the genus Takifugu. We proposed that PSTBP is a carrier protein for TTX in pufferfish; however, PSTBP had not yet been found in genera other than Takifugu. In this study, we investigated the presence of PSTBP-like proteins in the toxic pufferfish Arothron nigropunctatus, A. hispidus, A. manilensis, and Chelonodon patoca. On the basis of ultrafiltration experiments, TTX was found to be present and partially bound to proteins in the plasma of these pufferfish, and Western blot analyses with anti-PSTBP antibody revealed one or two bands per species. The observed decreases in molecular mass following deglycosylation with glycopeptidase F suggest that these positive proteins are glycoproteins. The molecular masses of the deglycosylated proteins detected in the three Arothron species were larger than that of PSTBP in the genus Takifugu, whereas the two bands detected in C. patoca had molecular masses similar to that of tributyltin-binding protein-2 (TBT-bp2). The N-terminal amino acid sequences of 23–29 residues of these detected proteins were all homologous with those of PSTBP and TBT-bp2. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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11 pages, 910 KiB  
Article
Preliminary Results on the Evaluation of the Occurrence of Tetrodotoxin Associated to Marine Vibrio spp. in Bivalves from the Galician Rias (Northwest of Spain)
by Jose Manuel Leão, Antonio Lozano-Leon, Jorge Giráldez, Óscar Vilariño and Ana Gago-Martínez
Mar. Drugs 2018, 16(3), 81; https://doi.org/10.3390/md16030081 - 6 Mar 2018
Cited by 51 | Viewed by 5347
Abstract
Tetrodotoxins (TTX) are a potent group of natural neurotoxins putatively produced by symbiotic microorganisms and affecting the aquatic environment. These neurotoxins have been recently found in some species of bivalves and gastropods along the European Coasts (Greece, UK, and The Netherlands) linked to [...] Read more.
Tetrodotoxins (TTX) are a potent group of natural neurotoxins putatively produced by symbiotic microorganisms and affecting the aquatic environment. These neurotoxins have been recently found in some species of bivalves and gastropods along the European Coasts (Greece, UK, and The Netherlands) linked to the presence of high concentrations of Vibrio, in particular Vibrio parahaemolyticus. This study is focused on the evaluation of the presence of Vibrio species and TTX in bivalves (mussels, oysters, cockles, clams, scallops, and razor clams) from Galician Rias (northwest of Spain). The detection and isolation of the major Vibrio spp. and other enterobacterial populations have been carried out with the aim of screening for the presence of the pathways genes, poliketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) possibly involved in the biosynthesis of these toxins. Samples containing Vibrio spp. were analyzed by biochemical (API20E-galery) and genetic tests (PCR-RT). These samples were then screened for TTX toxicity by a neuroblastoma cell-based assay (N2a) and the presence of TTX was further confirmed by LC-MS/MS. TTX was detected in two infaunal samples. This is the first confirmation of the presence of TTX in bivalve molluscs from the Galician Rias. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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11 pages, 10697 KiB  
Article
TTX-Bearing Planocerid Flatworm (Platyhelminthes: Acotylea) in the Ryukyu Islands, Japan
by Hiroyuki Ueda, Shiro Itoi and Haruo Sugita
Mar. Drugs 2018, 16(1), 37; https://doi.org/10.3390/md16010037 - 19 Jan 2018
Cited by 18 | Viewed by 5406
Abstract
Polyclad flatworms comprise a highly diverse and cosmopolitan group of marine turbellarians. Although some species of the genera Planocera and Stylochoplana are known to be tetrodotoxin (TTX)-bearing, there are few new reports. In this study, planocerid-like flatworm specimens were found in the sea [...] Read more.
Polyclad flatworms comprise a highly diverse and cosmopolitan group of marine turbellarians. Although some species of the genera Planocera and Stylochoplana are known to be tetrodotoxin (TTX)-bearing, there are few new reports. In this study, planocerid-like flatworm specimens were found in the sea bottom off the waters around the Ryukyu Islands, Japan. The bodies were translucent with brown reticulate mottle, contained two conical tentacles with eye spots clustered at the base, and had a slightly frilled-body margin. Each specimen was subjected to TTX extraction followed by liquid chromatography with tandem mass spectrometry analysis. Mass chromatograms were found to be identical to those of the TTX standards. The TTX amounts in the two flatworm specimens were calculated to be 468 and 3634 μg. Their external morphology was found to be identical to that of Planocera heda. Phylogenetic analysis based on the sequences of the 28S rRNA gene and cytochrome-c oxidase subunit I gene also showed that both specimens clustered with the flatworms of the genus Planocera (Planocera multitentaculata and Planocera reticulata). This fact suggests that there might be other Planocera species that also possess highly concentrated TTX, contributing to the toxification of TTX-bearing organisms, including fish. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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10 pages, 1876 KiB  
Communication
Difference in Uptake of Tetrodotoxin and Saxitoxins into Liver Tissue Slices among Pufferfish, Boxfish and Porcupinefish
by Yuji Nagashima, Akira Ohta, Xianzhe Yin, Shoichiro Ishizaki, Takuya Matsumoto, Hiroyuki Doi and Toshiaki Ishibashi
Mar. Drugs 2018, 16(1), 17; https://doi.org/10.3390/md16010017 - 8 Jan 2018
Cited by 19 | Viewed by 5263
Abstract
Although pufferfish of the family Tetraodontidae contain high levels of tetrodotoxin (TTX) mainly in the liver, some species of pufferfish, boxfish of the family Ostraciidae, and porcupinefish of the family Diodontidae do not. To clarify the mechanisms, uptake of TTX and saxitoxins (STXs) [...] Read more.
Although pufferfish of the family Tetraodontidae contain high levels of tetrodotoxin (TTX) mainly in the liver, some species of pufferfish, boxfish of the family Ostraciidae, and porcupinefish of the family Diodontidae do not. To clarify the mechanisms, uptake of TTX and saxitoxins (STXs) into liver tissue slices of pufferfish, boxfish and porcupinefish was examined. Liver tissue slices of the pufferfish (toxic species Takifugu rubripes and non-toxic species Lagocephalus spadiceus, L. cheesemanii and Sphoeroides pachygaster) incubated with 50 µM TTX accumulated TTX (0.99–1.55 µg TTX/mg protein) after 8 h, regardless of the toxicity of the species. In contrast, in liver tissue slices of boxfish (Ostracion immaculatus) and porcupinefish (Diodon holocanthus, D. liturosus, D. hystrix and Chilomycterus reticulatus), TTX content did not increase with incubation time, and was about 0.1 µg TTX/mg protein. When liver tissue slices were incubated with 50 µM STXs for 8 h, the STXs content was <0.1 µg STXs/mg protein, irrespective of the fish species. These findings indicate that, like the toxic species of pufferfish T. rubripes, non-toxic species such as L. spadiceus, L. cheesemanii and S. pachygaster, potentially take up TTX into the liver, while non-toxic boxfish and porcupinefish do not take up either TTX or STXs. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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2014 KiB  
Article
Detection of Tetrodotoxin Shellfish Poisoning (TSP) Toxins and Causative Factors in Bivalve Molluscs from the UK
by Andrew D. Turner, Monika Dhanji-Rapkova, Lewis Coates, Lesley Bickerstaff, Steve Milligan, Alison O’Neill, Dermot Faulkner, Hugh McEneny, Craig Baker-Austin, David N. Lees and Myriam Algoet
Mar. Drugs 2017, 15(9), 277; https://doi.org/10.3390/md15090277 - 30 Aug 2017
Cited by 67 | Viewed by 8291
Abstract
Tetrodotoxins (TTXs) are traditionally associated with the occurrence of tropical Pufferfish Poisoning. In recent years, however, TTXs have been identified in European bivalve mollusc shellfish, resulting in the need to assess prevalence and risk to shellfish consumers. Following the previous identification of TTXs [...] Read more.
Tetrodotoxins (TTXs) are traditionally associated with the occurrence of tropical Pufferfish Poisoning. In recent years, however, TTXs have been identified in European bivalve mollusc shellfish, resulting in the need to assess prevalence and risk to shellfish consumers. Following the previous identification of TTXs in shellfish from southern England, this study was designed to assess the wider prevalence of TTXs in shellfish from around the coast of the UK. Samples were collected between 2014 and 2016 and subjected to analysis using HILIC-MS/MS. Results showed the continued presence of toxins in shellfish harvested along the coast of southern England, with the maximum concentration of total TTXs reaching 253 µg/kg. TTX accumulation was detected in Pacific oysters (Crassostrea gigas), native oysters (Ostrea edulis) common mussels (Mytilus edulis) and hard clams (Mercenaria mercenaria), but not found in cockles (Cerastoderma edule), razors (Ensis species) or scallops (Pecten maximus). Whilst the highest concentrations were quantified in samples harvested during the warmer summer months, TTXs were still evident during the winter. An assessment of the potential causative factors did not reveal any links with the phytoplankton species Prorocentrum cordatum, instead highlighting a greater level of risk in areas of shallow, estuarine waters with temperatures above 15 °C. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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1286 KiB  
Article
Urinary Excretion of Tetrodotoxin Modeled in a Porcine Renal Proximal Tubule Epithelial Cell Line, LLC-PK1
by Takuya Matsumoto, Yui Ishizaki, Keika Mochizuki, Mitsuru Aoyagi, Yoshiharu Mitoma, Shoichiro Ishizaki and Yuji Nagashima
Mar. Drugs 2017, 15(7), 225; https://doi.org/10.3390/md15070225 - 17 Jul 2017
Cited by 3 | Viewed by 4222
Abstract
This study examined the urinary excretion of tetrodotoxin (TTX) modeled in a porcine renal proximal tubule epithelial cell line, LLC-PK1. Time course profiles of TTX excretion and reabsorption across the cell monolayers at 37 °C showed that the amount of TTX [...] Read more.
This study examined the urinary excretion of tetrodotoxin (TTX) modeled in a porcine renal proximal tubule epithelial cell line, LLC-PK1. Time course profiles of TTX excretion and reabsorption across the cell monolayers at 37 °C showed that the amount of TTX transported increased linearly for 60 min. However, at 4 °C, the amount of TTX transported was approximately 20% of the value at 37 °C. These results indicate that TTX transport is both a transcellular and carrier-mediated process. Using a transport inhibition assay in which cell monolayers were incubated with 50 µM TTX and 5 mM of a transport inhibitor at 37 °C for 30 min, urinary excretion was significantly reduced by probenecid, tetraethylammonium (TEA), l-carnitine, and cimetidine, slightly reduced by p-aminohippuric acid (PAH), and unaffected by 1-methyl-4-phenylpyridinium (MPP+), oxaliplatin, and cefalexin. Renal reabsorption was significantly reduced by PAH, but was unaffected by probenecid, TEA and l-carnitine. These findings indicate that TTX is primarily excreted by organic cation transporters (OCTs) and organic cation/carnitine transporters (OCTNs), partially transported by organic anion transporters (OATs) and multidrug resistance-associated proteins (MRPs), and negligibly transported by multidrug and toxic compound extrusion transporters (MATEs). Full article
(This article belongs to the Special Issue Tetrodotoxin)
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1248 KiB  
Article
Effects of Tetrodotoxin in Mouse Models of Visceral Pain
by Rafael González-Cano, Miguel Ángel Tejada, Antonia Artacho-Cordón, Francisco Rafael Nieto, José Manuel Entrena, John N. Wood and Cruz Miguel Cendán
Mar. Drugs 2017, 15(6), 188; https://doi.org/10.3390/md15060188 - 21 Jun 2017
Cited by 28 | Viewed by 8073
Abstract
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect [...] Read more.
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor‑specific Nav1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Nav1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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2111 KiB  
Article
A Study of 11-[3H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats
by Bihong Hong, Hui Chen, Jiacai Han, Quanling Xie, Jianlin He, Kaikai Bai, Yanming Dong and Ruizao Yi
Mar. Drugs 2017, 15(6), 159; https://doi.org/10.3390/md15060159 - 2 Jun 2017
Cited by 15 | Viewed by 6653
Abstract
Tetrodotoxin (TTX) is a powerful sodium channel blocker that in low doses can safely relieve severe pain. Studying the absorption, distribution, metabolism and excretion (ADME) of TTX is challenging given the extremely low lethal dose. We conducted radiolabeled ADME studies in Sprague-Dawley rats. [...] Read more.
Tetrodotoxin (TTX) is a powerful sodium channel blocker that in low doses can safely relieve severe pain. Studying the absorption, distribution, metabolism and excretion (ADME) of TTX is challenging given the extremely low lethal dose. We conducted radiolabeled ADME studies in Sprague-Dawley rats. After a single dose of 6 μg/(16 μCi/kg) 11-[3H]TTX, pharmacokinetics of plasma total radioactivity were similar in male and female rats. Maximum radioactivity (5.56 ng Eq./mL) was reached in 10 min. [3H]TTX was below detection in plasma after 24 h. The area under the curve from 0 to 8 h was 5.89 h·ng Eq./mL; mean residence time was 1.62 h and t½ was 2.31 h. Bile secretion accounted for 0.43% and approximately 51% of the dose was recovered in the urine, the predominant route of elimination. Approximately 69% was recovered, suggesting that hydrogen tritium exchange in rats produced tritiated water excreted in breath and saliva. Average total radioactivity in the stomach, lungs, kidney and intestines was higher than plasma concentrations. Metabolite analysis of plasma, urine and feces samples demonstrated oxidized TTX, the only identified metabolite. In conclusion, TTX was rapidly absorbed and excreted in rats, a standard preclinical model used to guide the design of clinical trials. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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5 pages, 392 KiB  
Perspective
Tetrodotoxin, a Candidate Drug for Nav1.1-Induced Mechanical Pain?
by César Mattei
Mar. Drugs 2018, 16(2), 72; https://doi.org/10.3390/md16020072 - 22 Feb 2018
Cited by 10 | Viewed by 5584
Abstract
Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav [...] Read more.
Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav channel, and to discriminating TTX-sensitive and TTX-resistant subtypes. In addition to its role as a pharmacological tool, TTX is now considered a therapeutic molecule, and its development should lead to its use in certain pathologies involving Nav channels, particularly in the field of pain. Specifically, the blockade of Nav channels expressed in nociceptive fibres is one strategy for alleviating pain and its deleterious consequences on health. Recent work has identified, in addition to the Nav1.7, 1.8 and 1.9 channels, the Nav1.1 subtype on dorsal root ganglion (DRG) neurons as a crucial player in mechanical and non-thermal pain. The sensitivity of Nav1.1 to TTX could be exploited at the therapeutic level, especially in chronic pain conditions. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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