Tetrodotoxin is a weakly basic, low molecular weight (319.27 Da) neurotoxin, consisting of a positively charged and poisonous guanidinium moiety. Existing as a zwitterion in acidic solutions, tetrodotoxin is highly polar as a result of the abundance of OH and NH groups. The particularly potent neurotoxin is a selective inhibitor of voltage-gated sodium channels (VGSCs), leading to symptoms of numbness, paralysis, and hypotension, as well as ultimately death (Chau et al., 2011).
First isolated from the pufferfish of the genus Tetraodontidae. tetrodotoxin has since been found in a variety of other species, including newts of the genus Taricha, toads of the genus Atelopus, octopuses of the genus Hapalochlaena, and sea stars of the genus Astropecten. In fact, since its initial discovery, the presence of tetrodotoxin has been reported in at least six phyla of organisms, including the Chordata, Mollusca, Echinodermata, Chaetognatha, Arthropoda, and Platyhelminthes (Chau et al., 2011). The wide distribution of the neurotoxin amongst unrelated species has led to the emergence of different theories regarding the biogenic origins of the molecule.
A possible explanation for the origin of tetrodotoxin is that it is a product of a bacterium, acquired via the food chain or by bacterial symbiosis, a mutualistic relationship existing between bacteria and other organisms. Particularly common in marine animals, the symbiotic bacteria live within organs where the conditions are optimum for the production of secondary metabolites, which are ultimately used by the host organism for chemical defence (Chau et al., 2011). Supporting the theory of bacterial symbiosis is the vast variety of tetrodotoxin-producing bacteria, which have been isolated from the large variety of species reported to contain the neurotoxin. For instance, species of the bacterium genus Vibrio have been found to occur in Atergatis floridus (Noguchi et al., 1983), Fugu vermicularis vermicularis (Noguchi et al., 1987), Fugu vermicularis radialis (Lee et al., 2000), Hapalochlaena maculosa (Hwang et al., 1989), Astropecten polyacanthus (Narita et al., 1987), Nassarius semiplicatus (Wang et al., 2008), and Niotha clathrata (Cheng et al., 1995). However, no evidence of symbiotic bacteria has been found in newts, thus demanding explanations of non-bacterial origin (Chau et al., 2011).
Mode of Action
Tetrodotoxin binds to amino acid residues on receptor site 1 of voltage-gated sodium channels (VGSCs). As key proteins in the initiation and propagation of action potentials, VGSCs are abundant in many different types of tissue. However, there exist nine different VGSC subtypes in mammals, each with distinct properties, and as a result, certain VGSC subtypes are more sensitive to tetrodotoxin than others (Nieto et al., 2012). The extent to which tetrodotoxin is able to block each VGSC subtype depends on its concentration; while nanomolar concentrations are sufficient to block subtypes Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7, micromolar concentrations are required for Nav1.5, Nav1.8, and Nav1.9 (Nieto et al., 2012).
By blocking VGSCs, tetrodotoxin is able to reduce the permeability of sodium ions in axon membranes without affecting the diffusion of potassium ions, thereby blocking the transmission of signals from the central nervous system (Fuhrman, 1967). It is this inhibition of the ion channel and interference with conduction that ultimately leads to paralysis, a common symptom of tetrodotoxin poisoning.
Potential Therapeutic Use
VGSCs are essential components of nociception due to the transmission of nerve impulses depending largely on the protein. However, as each VGSC subtype has specific properties and thus contributes to a specific type of pain, it is essential that drugs be produced to block each channel selectively. Due to tetrodotoxin being a selective blocker of the protein, its potential to be used as a painkiller has been researched extensively. Nevertheless, before it can be used as a common local anaesthetic, it must be made more selective for specific VGSC subtypes (Fuhrman, 1967).
Based on studies in:
USA: New York, Long Island (Marine)
This list may not be complete but is based on published studies.
Known prey organisms
Based on studies in:
USA: New York, Long Island (Marine)
This list may not be complete but is based on published studies.
Molecular Biology and Genetics
Statistics of barcoding coverage
Specimens with Sequences:1570
Specimens with Barcodes:1326
Species With Barcodes:134
Tetraodontidae is a family of primarily marine and estuarine fish of the order Tetraodontiformes. The family includes many familiar species, which are variously called pufferfish, puffers, balloonfish, blowfish, bubblefish, globefish, swellfish, toadfish, toadies, honey toads, sugar toads, and sea squab. They are morphologically similar to the closely related porcupinefish, which have large external spines (unlike the thinner, hidden spines of Tetraodontidae, which are only visible when the fish has puffed up). The scientific name refers to the four large teeth, fused into an upper and lower plate, which are used for crushing the shells of crustaceans and mollusks, their natural prey.
Pufferfish are generally believed to be the second-most poisonous vertebrates in the world, after the golden poison frog. Certain internal organs, such as liver, and sometimes the skin, contain tetrodotoxin and are highly toxic to most animals when eaten; nevertheless, the meat of some species is considered a delicacy in Japan (as 河豚, pronounced as fugu), Korea (as 복 bok or 복어 bogeo ), and China (as 河豚 hétún) when prepared by specially trained chefs who know which part is safe to eat and in what quantity.
They are typically small to medium in size, although a few species can reach lengths of greater than 100 cm (39 in).
Ecology and life history
Although most species live in inshore and estuarine waters, 29 species spend their entire lifecycles in fresh water. These species are found in disjunct tropical regions of South America (one species), Central Africa (three species) and Southeast Asia (25 species).
The puffer's unique and distinctive natural defenses help compensate for its slow locomotion. It moves by combining pectoral, dorsal, anal, and caudal fins. This makes it highly maneuverable, but very slow, and therefore a comparatively easy predation target. Its tail fin is mainly used as a rudder, but it can be used for a sudden evasive burst of speed that shows none of the care and precision of its usual movements. The puffer's excellent eyesight, combined with this speed burst, is the first and most important defense against predators.
Its backup defense mechanism, used if successfully pursued, is to fill its extremely elastic stomach with water (or air when outside the water) until it is much larger and almost spherical in shape. Even if they are not visible when the puffer is not inflated, all puffers have pointed spines, so a hungry predator may suddenly find itself facing an unpalatable, pointy ball rather than a slow, tasty fish. Predators which do not heed this warning (or which are "lucky" enough to catch the puffer suddenly, before or during inflation) may die from choking, and predators that do manage to swallow the puffer may find their stomachs full of tetrodotoxin, making puffers an unpleasant, possibly lethal, choice of prey. This neurotoxin is found primarily in the ovaries and liver, although smaller amounts exist in the intestines and skin, as well as trace amounts in muscle. It does not always have a lethal effect on large predators, such as sharks, but it can kill humans.
Not all puffers are necessarily poisonous; Takifugu oblongus, for example, is a fugu puffer that is not poisonous, and toxin level varies wildly even in fish that are. A puffer's neurotoxin is not necessarily as toxic to other animals as it is to humans, and puffers are eaten routinely by some species of fish, such as lizardfish and tiger sharks. Also, Japanese fish farmers have grown nonpoisonous puffers by controlling their diets.
Puffers are able to move their eyes independently, and many species can change the color or intensity of their patterns in response to environmental changes. In these respects, they are somewhat similar to the terrestrial chameleon. Although most puffers are drab, many have bright colors and distinctive markings, and make no attempt to hide from predators. This is likely an example of aposematism.
Many marine puffers have a pelagic, or open-ocean, life stage. Spawning occurs after males slowly push females to the water surface or join females already present. The eggs are spherical and buoyant. Hatching occurs after roughly four days. The fry are tiny, but under magnification have a shape usually reminiscent of a pufferfish. They have a functional mouth and eyes, and must eat within a few days. Brackish-water puffers may breed in bays in a similar manner to marine species, or may breed more similarly to the freshwater species, in cases where they have moved far enough upriver.
Reproduction in freshwater species varies quite a bit. The dwarf puffers court with males following females, possibly displaying the crests and keels unique to this subgroup of species. After the female accepts his advances, she will lead the male into plants or another form of cover, where she can release eggs for fertilization. The male may help her by rubbing against her side. This has been observed in captivity, and they are the only commonly captive-spawned puffer species.
Target-group puffers have also been spawned in aquariums, and follow a similar courting behavior, minus the crest/keel display. However, eggs are laid on a flat piece of slate or other smooth, hard material, to which they adhere. The male will guard them until they hatch, carefully blowing water over them regularly to keep the eggs healthy. His parenting is finished when the young hatch, and the fry are on their own.
Information on breeding of specific species is very limited. T. nigroviridis, the green-spotted puffer, has recently been artificially spawned under captive conditions. It is believed to spawn in bays in a similar manner to saltwater species, as their sperm was found to be motile only at full marine salinities, but actual wild breeding has never been observed.
In 2012, male pufferfish were documented carving large geometric, circular structures in the seabed sand in Amami Ōshima, Japan. The structures apparently serve to attract females and provide a safe place for them to lay their eggs.
Elaborate skin pattern of the giant puffer
The tetraodontids have been estimated to diverge from diodontids between 89 and 138 million years ago. The four major clades diverged during the Cretaceous between 80 and 101 million years ago. The oldest known pufferfish genus is Eotetraodon, from the Lutetian epoch of Middle Eocene Europe, with fossils found in Monte Bolca and the Caucasus Mountains. The Monte Bolca species, E. pygmaeus, coexisted with several other tetraodontiforms, including an extinct species of diodontid, primitive boxfish (Proaracana and Eolactoria), and other, totally extinct forms, such as Zignoichthys and the spinacanthids.
Pufferfish can be lethal if not served properly. Puffer poisoning usually results from consumption of incorrectly prepared puffer soup, fugu chiri, or occasionally from raw puffer meat, sashimi fugu. While chiri is much more likely to cause death, sashimi fugu often causes intoxication, light-headedness, and numbness of the lips, and is often eaten for this reason. Pufferfish tetrodotoxin deadens the tongue and lips, and induces dizziness and vomiting, followed by numbness and prickling over the body, rapid heart rate, decreased blood pressure, and muscle paralysis. The toxin paralyzes diaphragm muscles and stops the person who has ingested it from breathing. People who live longer than 24 hours typically survive, although possibly after a coma lasting several days. In Korea blowfish is made into a soup called Bokeo.
Pufferfish, called pakpao in Thailand, are usually consumed by mistake. They are often cheaper than other fish, and because they contain inconsistent levels of toxins between fish and season, there is little awareness or monitoring of the danger. Consumers are regularly hospitalized and some even die from the poisoning.
Cases of neurological symptoms, including numbness and tingling of the lips and mouth, have been reported to rise after the consumption of puffers caught in the area of Titusville, Florida, U.S. The symptoms generally resolve within hours to days, although one affected individual required intubation for 72 hours. As a result, Florida banned the harvesting of puffers from certain bodies of water.
The Bureau of Fisheries and Aquatic Resources issued a warning not to eat puffer fish, locally known as butete, after local fishermen died upon consuming puffer fish for dinner. The warning indicated that puffer fish toxin is 100 times more potent than cyanide.
Treatment consists of supportive care and intestinal decontamination with gastric lavage and activated charcoal. Case reports suggest anticholinesterases such as edrophonium may be effective.
- Fugu, the Japanese dish containing pufferfish meat, famous for its potent toxicity when improperly prepared
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