Tetrodotoxin

Progenitors

Name

Vibrio parahaemolyticus

Note

No conclusive production. TTX detected in cultures isolated from bivalve molluscs (England)

Name

Vibrio cholerae

Note

No conclusive production. TTX detected in cultures isolated from bivalve molluscs (England)

Name

Prorocentrum cordatum

Note

Potential links to P. minimum but not proven or subsequently confirmed in other studies

Name

Pseudomonas

Note

TTX detected in Pseudomonas sp isolated from TTX -positive organisms e.g. pufferfish

Name

Pseudoalteromonas

Note

Linked to potential production from Genus

Name

Actinobacteria

Note

Linked to potential production from Genus

Name

Bacillus

Note

Linked to potential production from Genus

Name

Roseobacter

Note

Linked to potential production from Genus

Name

Alteromonas

Note

Linked to potential production from Genus

Name

Aeromonas

Note

Linked to potential production from Genus

Name

Nocardiopsis

Note

Linked to potential production from Genus

Vector Species

Name

Tutufa

Note

T. Noguchi, J. Maruyama, H. Narita, K. Hashimoto Occurrence of tetrodotoxin in the gastropod mollusk Tutufa lissostoma (frog shell) Toxicon, 22 (1984), pp. 219-226

Name

Pugilina

Note

H. Narita Tetrodotoxin, with special reference to its origin and the mechanism of toxification Seikatsu Eisei, 35 (1991), pp. 2-15

Name

Hapalochlaena maculosa

Note

Posterior salivary gland D.D. Sheumack, M.E.H. Howden, I. Spence Occurrence of a tetrodotoxin-like compound in the eggs of the venomous blue-ringed octopus (Hapalochlaena maculosa) Toxicon, 2 (1984), pp. 811-812

Name

Pseudopotamilla occelata

Note

T. Yasumoto, M. Yotsu, A. Endo, M. Murata, C.Y. Kao Interspecies distribution and biogenetic origin of tetrodotoxin and its derivatives Pure Appl. Chem., 61 (1989), pp. 505-508

Name

Atergatis floridus

Note

T. Noguchi, A. Uzu, K. Koyama, K. Hashimoto Occurrence of tetrodotoxin as the major toxin in xanthid crab Atergatis floridus Bull. Jpn. Soc. Sci. Fish, 49 (1983), pp. 1887-1892

Name

Zosimus aeneus

Note

D. Yasumura, Y. Oshima, T. Yasumoto, A.C. Alcala, L.C. Alcala Tetrodotoxin and paralytic shellfish toxins in Philippine crabs Agric. Biol. Chem., 50 (1986), pp. 593-598

Name

Carcinoscorpius rotundicauda

Note

A. Kungsuwan, Y. Nagashima, T. Noguchi, Y. Shida, S. Suvapeepan, P. Suwansakornkul, K. Hashimoto Tetrodotoxin in the horseshoe crab Carcinoscorpius rotundicauda inhabiting Thailand Nippon Suisan Gakkaishi, 53 (1987), pp. 261-266

Name

Parasagitta

Note

E.V. Thuesen, K. Kogure, K. Hashimoto, T. Nemoto Poison arrowworms: a tetrodotoxin venom in the marine phylum Chaetonnatha J. Exp. Mar. Biol. Ecol., 116 (1988), pp. 249-256

Name

Pleurobranchaea maculata

Note

Very high concentrations quantified from New Zealand Sea Slugs

Name

Lagocephalus sceleratus

Note

Pufferfish

Name

Flaccisagitta

Note

E.V. Thuesen, K. Kogure, K. Hashimoto, T. Nemoto Poison arrowworms: a tetrodotoxin venom in the marine phylum Chaetonnatha J. Exp. Mar. Biol. Ecol., 116 (1988), pp. 249-256

Name

Astropecten

Note

J. Maruyama, T. Noguchi, J.K. Jeon, T. Harada, K. Hashimoto Occurrence of tetrodotoxin in the starfish Astropecten latespinosus Experientia, 40 (1984), pp. 1395-1396

Name

Yongeichthys criniger

Note

T. Noguchi, Y. Hashimoto Isolation of tetrodotoxin from a goby Gobius criniger Toxicon, 11 (1973), pp. 305-307

Name

Atelopus

Note

Y.H. Kim, G.B. Brown, H.S. Mosher Tetrodotoxin: occurrence in atelopid frogs of Costa Rica Science, 189 (1975), pp. 151-152

Name

Steromphala umbilicalis

Note

Silva, M., Azevedo, J., Rodriguez, P., Alfonso, A., Botana, L.M. & Vasconcelos, V. 2012. New gastropod vectors and tetrodotoxin potential expansion in temperate waters of the Atlantic Ocean. Marine Drugs 10(4): 712–726. Portugal - LC-MS/MS

Name

Phorcus lineatus

Note

Silva, M., Azevedo, J., Rodriguez, P., Alfonso, A., Botana, L.M. & Vasconcelos, V. 2012. New gastropod vectors and tetrodotoxin potential expansion in temperate waters of the Atlantic Ocean. Marine Drugs 10(4): 712–726. Portugal - LC-MS/MS

Name

Charonia

Note

Europe - first TTX poisoning case Confirmed in patient's blood LC-MS and MBA

Name

Mytilus edulis

Note

Mussels from around N. Europe including England LC-MS/MS confirmation

Name

Mytilus edulis

Note

Mussels from around N. Europe including England, Netherlands LC-MS/MS confirmation

Name

Planocera

Note

Miyazawa et al. (1986) Whole body flatworms

Name

Lineus fuscoviridis

Note

Whole body ribbonworms Miyazawa et al. (1986)

Name

Tubulanus punctatus

Note

Whole body ribbonworms Miyazawa et al. (1986)

Name

Cephalothrix linearis

Note

Whole body ribbonworms Ali et a 1990 high toxicity, of up to 22,000 MU/g proboscis and 13,600 MU/g body, in terms of TTX

Name

Babylonia japonica

Note

T. Noguchi, J. Maruyama, Y. Ueda, K. Hashimoto, T. Harada Occurrence of tetrodotoxin in the Japanese ivory shell Babylonia japonica Bull. Jpn. Soc. Sci. Fish., 47 (1981), pp. 901-913 Toxin isolated and crystalised + MBA

References

Noguchi et al, 2011

Pufferfish Gastropods

Noguchi, T, Arakawa, O, 2008

Flatworms: Planocera spp. Ribbonworms: Lineus fuscoviridis, Tubulanus punctatus, Cephalothrix linearis Gastropoda: Charonia sauliae, Charonia lampas lampas, Babylonia japonica, Tutufa lissostoma, Zeuxis siquijorensis, Niotha clathrata, Niotha lineata, Cymatium echo, Pugilina ternotoma, Pleurobranchaea maculata Polychaeta: Pseudopolamilla occelata Xanthidae crabs: Atergatis floridus, Zosimus aeneus Horseshoe crab: Carcinoscorpius rotundicauda Arrowworms: Parasagitta spp., Flaccisagitta spp. Starfish: Astropecten spp. Pisces, Goby, Amphibia: Yongeichthys criniger, Tarica spp., Notophthalmus spp. Newts: Cynopsis spp., Triturus spp. Frogs: Atelopus spp., Colostethus sp., Polypedates sp., Brachycephalus spp.

Sonoyama et al, 2020

Pufferfish Canthigaster valentini

Tsai et al, 2006

Xanthid crabs: Demania cultripes, Demania toxica, Demania reynaudi, Lophozozymus incisus, Lophozozymus pictor and Atergatopsis germaini

Noguchi et al, 2006

Pufferfish: Takifugu snyderi

Rodriguez et al, 2008

Charonia lampas lampas - Spain

McNabb PS et al, 2014

Paphies australis Pleurobranchaea maculata New Zealand

Gerssen et al, 2018

Mussels and oysters Netherlands

Cole et al, 2015

Dried pufferfish

Vlamis et al, 2015

Greek shellfish plus potential links to Prorocentrum minimum

Bentur et al, 2008

Lagocephalus sceleratus in the eastern Mediterranean

Leao et al, 2018

Bivalve molluscs from NW Spain

Yotsu et al, 1987

Pufferfish and Pseudomonas sp.

Turner, A.D et al, 2017

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).

Turner, A.D et al, 2015

Mussels and oysters - England (Mytilus Edulis and Crassostrea gigas) Vibrio parahaemolyticus and one strain of V. cholerae isolated from TTX-positive Pacific oysters

Jal and Khora, 2015

Bacterial production possible vectors

Magarlamov et al, 2017

TTX-producing bacteria (detection, distribution and migration in aquatic systems)

Katikou and Vlamis, 2017

Prevalence of TTXs in European vectors Pufferfish Bivalves Gastropods

Fernandez-Ortega et al, 2008

First TTX intoxication case in Europe - Trumpet Shellfish Charonia sauliae

Turner, A.D. et al, 2018

Marine nemertean Cephalothrix simula Pseudomonas luteola isolated from C. simula Vibrio alginolyticus from the nemertean Tubulanus annulatus

Dhanji-Rapkova et al, 2021

Pacific Oysters (Crassostrea gigas)

Magarlamov et al, 2017

Vibrio, Bacillus, Pseudomonas, Alteromonas, Streptomyces, Roseobacter

Biessy et al, 2020

Paphies australis

Vlasenko, A.E., 2020

Cephalothrix simula

Suo et al, 2022

Planocera multitentaculata

Bedry et al, 2021

Lagocephalus sceleratus Torquigener flavimaculosus

Katikou, P, 2017

Torquigener flavimaculosus

Lage et al, 2023

The Edible Crabs Afruca tangeri and Carcinus maenas

Structure

Formula

C11H17N3O8

Exact mono-isotopic mass

319.101563

Molfile

n/a

Alternative molfiles

n/a

SMILES

C([C@@]1([C@H]2[C@@H]3[C@H](N=C(N[C@@]34[C@@H]([C@@H]1O[C@]([C@H]4O)(O2)O)O)N)O)O)O

Alternative SMILES

C(C1(C2C3C(N=C(NC34C(C1OC(C4O)(O2)O)O)N)O)O)O

InChi key

CFMYXEVWODSLAX-QOZOJKKESA-N

Alternative InChi keys

n/a

InChi

1S/C11H17N3O8/c12-8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-20H,1H2,(H3,12,13,14)/t2-,3-,4-,5+,6-,7+,9+,10-,11+/m1/s1

Alternative InChis

Spectra available

True

Chem files

References

Moczydlowski E.G, 2013

Chemical structure, chemistry, molecular biology, action mechanisms

Bane et al, 2014

Chemistry, toxicity, source, distribution and detection

Certified

True

Certified links

• National Research Council Canada
  NRC CRM-TTX is a certified instrument calibration solution for use in the analytical determination of tetrodotoxin (TTX). Each ampoule contains approximately 0.5 mL of a solution of TTX dissolved in filtered, aqueous 1 mM acetic acid.
• Merck (Sigma Aldrich)
  >98% powder - product T8024 - not certified
• Enzo
  Product BML-NA120-0001 >98% powder - not certified
• CIFGA
  Product CRM-03-TTXs Certified solution containing TTX, plus additional analogues 4,9-anhydro TTX and 4-epi TTX Purity >97% Solution 1mM acetic acid; 0.5 mL supplied
• Thermo Scientific Chemicals
  1mg material - product code 13187663 (Fisher Scientific) Thermo Scientific Acros product = 328560010 99% purity - not certified
• Nacalai tesque
  1mg TTX in citric acid buffer Product 32775-51(purity ≥94%, Kyoto, Japan) - not certified
• Wako
  Wako pure chemical industries (purity >99%, Osaka, Japan) - not certified
• Affixscientific Corporation
  Affixscientific Corporation (purity ≥98%, Fremont, CA, USA) - not certified
• Tocris Bioscience
  Tocris Bioscience (purity ≥98.8%, Bristol, UK), Cat number = 1078 Sold as TTX citrate - not certified
• Biorbyt Ltd
  Biorbyt Ltd. (Cambridge, UK) Sell 4,9-anhydroTTX (Cat No: orb1693171) CAS 13072-89-4 Purity 98% SMILES: O[C@H]1[C@]23[C@@]4([C@@]5([C@](CO)(O)[C@]1(O[C@](O)([C@]2(O[C@@]4(N=C(N)N3)[H])[H])O5)[H])[H])[H] Formula: C11H15N3O7 - not certified
• Latoxan
  Latoxan (Valence, France) - not certified

Non certified reference material

True

Chemical analysis

Research

True

Standardized

True

Validated

True

Official

n/a

Structure recognition assays

Research

True

Standardized

Unknown

Validated

Unknown

Official

n/a

Functional assays

Research

True

Standardized

Unknown

Validated

Unknown

Official

n/a

Animal assays

Research

True

Standardized

True

Validated

True

Official

Puffer toxin. Environmental Health Bureau, ministry of Health and Welfare. The Manual for Methods of Food Sanitation Tests II, vol 2, Environmental Health Bureau, Food Hygiene Association, Tokyo, Japan (1978) pp21-22

References

Moczydlowski E.G, 2013

Structure recognition

Wang et al, 2015

Functional assay using cardiomyocyte-based impedance biosensor

Turner et al, 2017

HILIC-MS/MS validation (single lab)

Turner et al, 2023

Interlaboratory evaluation of multiple LC-MS/MS methods and a commercial ELISA for TTX in mussels and oysters

Bane et al, 2014

Detection method review plus chemistry, source and distribution

Kogure et al, 1988

Tissue culture assay

Hamasaki et al, 1996

Tissue culture assay

Katikou and Vlamis, 2017

Advances in analysis methods

EFSA, 2017

Includes detection methods at time of risk assessment opinion

Rodriguez et al, 2012

LC-MS/MS - applied to pufferfish

Silva et al, 2012

LC-MS/MS applied to gastropods

EURL, 2017

https://www.aesan.gob.es/en/CRLMB/web/public_documents/seccion/crlmb_standard_operating_procedures.htm

Regulatory status

False

References

EFSA, 2017

Risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods

Staatscourant 38280 - Dutch legislation, 2017

https://zoek.officielebekendmakingen.nl/stcrt-2017-38280.pdf Legislation for TTX in the Netherlands, 29th June 2017 - NVWA/2017/5265 A limit value of 44 μg/kg in live bivalve molluscs from Dutch production areas shall be set for the presence of TTX in live bivalve molluscs. Above this value, the NVWA will take measures as referred to in Annex II, Chapter II, under C and D of Regulation (EC) No 854/2004 and Article 6 of the Commodities Act Regulation on live bivalve molluscs

Human toxic syndrome(s)

Paralytical Shellfish Poisoning

Organ system toxicity

Neurotoxicity

Risk assessment

True

Molecular targets known

True

Molecular targets

Voltage dependent sodium channel (site 1)

Toxic to aquatic animals

True

TEF available

True

Risk assessment References

EFSA, 2017

Risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods

TEF References

EFSA, 2017

WHO, 2016

Based on the i.p. toxicity to mice, relative toxicities of TTX analogues 10 μg/kg b.w. for TTX (Noguchi, Onuki and Arakawa, 2011), 70 μg/kg b.w. for 11-deoxy-TTX (Bane et al., 2014), 420 μg/kg b.w. for 6,11-dideoxy TTX (Jang and Yotsu-Yamashita, 2007), 16 μg/kg b.w. for 11-oxo-TTX (Nakamura and Yasumoto, 1985; Yotsu-Yamashita et al., 2003), 64 μg/kg b.w. for 4-epi-TTX (Nakamura and Yasumoto, 1985; Munday, 2014), 60 μg/kg b.w. for 6-epi-TTX (Yasumoto et al., 1988b), 490 μg/kg b.w. for 4,9-Anhydro-TTX (Nakamura and Yasumoto, 1985), 54 μg/kg b.w. for 11-nor-TTX–6(S)-ol (Yotsu et al., 2014) 70 μg/kg b.w. for 11-nor-TTX–6(R)-ol (Endo et al., 1988). WHO expert group concludes currently that: • Need to establish TEFs for TTX analogues commonly found in bivalves. • Need for comparative studies on the oral toxicity of TTX congeners. World Health Organization & Food and Agriculture Organization of the United Nations. (‎2016)‎. Toxicity equivalence factors for marine biotoxins associated with bivalve molluscs. World Health Organization. https://iris.who.int/handle/10665/250663

Notes

Andrew Turner

Contact