Ciguatera (or Ciguatera Poisoning, CP) is a foodborne illness due to the consumption of fish and marine invertebrate from tropical reefs, in perfect freshness and usually safe to eat, contaminated by neurotoxins (the ciguatoxins, CTXs) produced by a micro-algae, called Gambierdiscus.



The true origin of ciguatera poisoning was elucidated in the mid 1970s and involves a benthic unicellular dinoflagellate, Gambierdiscus spp., whose populations preferentially grow on algal "turf" that cover damaged reef ecosystems. The genus Gambierdiscus is widely spread around the globe. To date, at least 18 species of Gambierdiscus are discribded worldwide: G. australes, G. balechii, G. belizeanus, G. caribaeus, G. carolinianus, G. carpenter, G. cheloniae, G. excentricus, G. holmesii, G. honu, G. jejuensis, G. lewisii, G. lapillus, G. pacificus, G. polynesiensis, G. scabrosus, G. silvae, G. toxicus.


Cells of the benthic dinoflagellate Gambierdiscus spp.

(A): Optical microscope view ; B): Scanning electron microscope view.


Under the influence of environmental factors, generally related to natural events (hurricanes, tsunami…)  or anthropogenic activities (pollution, constructions...), populations of Gambierdiscus, already present in the environment, will proliferate.

For unclear reasons, only some strains of this dinoflagellate have the ability to produce ciguatoxins. In other terms, it is not the presence of high densities of Gambierdiscus that is responsible for ciguatera, but the strains present in the environment.

The massive colonization of the coral reef ecosystem by Gambierdiscus toxic strains constitutes the starting point of the reef’s food chain contamination. CTXs produced by the dinoflagellate are gradually accumulated in herbivorous fish when they graze on the microalgal turfs covering damaged or dead corals. The transfer of theses toxins to carnivorous fish occurs though predation, when carnivorous fish prey on contaminated herbivorous fish. Note that some invertebrates also bioaccumulate CTXs by filtration or grazing. The bioaccumulation of CTXs is associated to a biotransformation to more toxic compounds that lead to the poisoning in humans, which are at the top of the food chain.


Note that a new genus of ciguaterigenic dinoflagellate, called Fukuyoa, has been identified. Do date, 3 species are known: F. yasumutoi, F. paulensis and F. ruetzeli.


 Global distribution of Gambierdiscus and Fukuyoa species.



The ciguatera vectors are mainly from tropical and intertropical reefs ecosystems. To date, about 400 fish species are considered as potential ciguatera vectors. 

Any fish that has been exposed to the efflorescence of the toxic micro-algae, Gambierdiscus, or that has ingested other fish themselves contaminated by ciguatoxins, should be considered as a potential vector of ciguatera. The species responsible for CP vary from a region to another, but some families are more at risk than others:


Online catalog of species implicated in CP

recorded in French Polynesia



Although Gambierdiscus is considered the main causative agent of ciguatera, studies have shown that some marine cyanobacteria could also contribute to a "ciguatera-like" syndrome.

Examples of cyanobacteria. Macroscopic observations: A) Hydrocoleum cf. floccosum, B) Anabaena sp.; C) Aulosira schauinslandii; D) optical microscope view of Oscillatoria bonnemaisonii trichomes, © S. Golubic.


The wide polymorphism of ciguatera symptoms, would partly be related to the diversity of toxin-producing marine organisms. Reef fish have long been regarded as the only vectors of ciguatoxins, however, some marine invertebrates such as clams, sea urchins and gastropods may also be involved in atypical forms of ciguatera.

A)Tridacna maxima (giant clam) © M. Roué,  B) Tectus niloticus (Trocus) © C. Gatti and Tripneustes gratilla (sea urchin) © JJ. Eckert, other potential vectors of ciguatera.


The clinical manifestations associated to marine invertebrates poisoning include most of the characteristic signs of ciguatera, often accompagnied by severe additional symptoms such as, immediate and intense burning of the mouth and throat and transiant paralysis. The hypothesis of the existence of a new way of contamination due to cyanobacterias, involving bivalves was suggested. This new phenomenon is called “Ciguatera Shellfish Poisoning” (CSP).


Ciguatera-like toxins transfer across the food chain. Main vectors of "Ciguatera Fish Poisoning" are marine vertebrates (herbivorous and carnivorous lagoon fish). "Ciguatera Shellfish Poisoning" preferentially involves marine invertebrates such as clams and sea urchins; © F. Rossi.



The genus Gambierdiscus can synthesize at least two major families of toxins: one lipid-soluble, the Ciguatoxins (CTXs) and another water-soluble, the Maitotoxins (MTXs). It is generally agreed that only CTXs are responsible for ciguatera fish poisoning, MTXs are usually not involved in human poisonings.

In humans, the average dose at which 50% of humans develop the symptomsl, is estimated to be as low as 2 ng/kg of body weight, making CTXs one of the most potent natural substances known.

Other molecules such as gambieric acids, which exhibit antifungal activity, and gambierol have also been isolated from cultures of this micro-algae, but their role in ciguatera poisoning is still to be confirmed.

One might wonder about the ecological benefit for Gambierdiscus to produce these toxins. One hypothesis is that these metabolites provide an environmental benefit (e.g. defense mechanism) over potential competitors or predators.



Ciguatoxins (CTXs) are polycyclic polyether compounds, lipid-soluble, with a molecular weight between 1.023 and 1.159 Da. There are 3 main groups of CTXs throughout the main areas affected by ciguatera: Pacific ciguatoxins or P-CTXs, Caribbean ciguatoxins or C-CTXs and Indian Ocean ciguatoxins or I-CTXs. P-CTXs, composed of 13 ether rings, are described in two types, 1 and 2, the difference residing mainly in the E cycle. C-CTXs are composed of 14 cyclic ethers. To date, the structure of I-CTXs is yet to discover. In total, there are more than 40 different CTXs, which have been isolated primarily from Gambierdiscus cells and toxic fish.

ctxs engTR

Chemical structures of Pacific ciguatoxins (P-CTXs) differentiated by two different types (type-1 and -2), and a Caribbean ciguatoxin (C-CTX -1), (modified from Caillaud et al.)

 The panel of CTXs in contaminated fish can also vary significantly from one fish species to another. One single species may host several types of CTXs. So, one may talk about a “toxic profile” for a given trophic level.

Algal CTXs produced by Gambierdiscus undergo transformations from their accumulation in herbivorous fish until they pass through carnivorous fish. As a result, CTXs polarity as well as their toxicity increase. Thus, P-CTX-1B only found in carnivorous fish is 30 times more toxic than P-CTX-4B present in Gambierdiscus. This biotransformation phenomenon is responsible for the wide variability of the toxic profiles with respect to the fish and trophic level considered.

These understandings partly illustrate the complex mechanisms underlying the significant variation of ciguatera outbreaks severity.



CTXs’ main molecular targets are voltage sensitive sodium channels (VSSC), which are responsible for action potentials initiation and propagation. CTXs binding to electrically excitable cells, prolongs the opening of VSSC even at resting membrane potential, which results in a continuous inflow of Na+ ions in the cells. To counter this intracellular increase of sodium level, cellular mechanisms are put into place allowing an outward flow of Na+ against an inward flow of Ca2+, leading to an increase of intracellular calcium levels. This quasi-irreversible binding of CTXs on VSSC results in both, nerve conduction and nervous cells morphology impairments. Moreover, studies have shown that L-type calcium channels is another potential target of CTXs. CTXs binding to these calcium channels would lead to a cascade of enzymatic events resulting in an overproduction of NO radicals. 



A well-known consequence of the CTXs binding to VSSC is the appearance of spontaneous and/or repetitive discharge of action potentials. This increase of nervous excitability then leads to a sustained release of neurotransmitters at nerve endings, resulting in a modification of synaptic efficiency or a nerve transmission deficiency. Some symptomatic treatment of ciguatera aims at counterbalance or eliminate these “disturbed” action potentials, by giving local anesthetics such as lidocaine or with intravenous (IV) D-mannitol or sucrose infusions.



The swelling of the nodes of Ranvier, due to water inflow in the cells, is another consequence of the constant inflow of Na+ ions. This wide set of CTXs-induced modifications ( depolarization and hyper-excitability, increased intracellular levels of Na+ and Ca2+, anarchic release of neuromediators, swelling associated to water inflow…) is responsible for the diversity of the clinical signs observed in CP cases. Neurological symptoms such as motor, sensation, cerebellar or psychiatric disorders, result, in part, from the alteration of the peripheral, central and autonomic nervous system fibers. The high intracellular levels of Ca2+, would lead to profuse diarrhea. Bradycardia and hypotension result from a parasympathetic hyperstimulation and a low sympathetic tone. The increased intracellular calcium level is responsible for an increased frequency and intensity of muscular contractions, while spontaneous and repetitive action potential discharges induce uncoordinated muscle contractions. These effects are more significant when they concern the heart muscle, as both nerve supply and heart muscle are affected.

After their ingestion, CTXs circulate freely into the blood stream for a few days. A part of them are directly excreted in urine and feces.

Due to their high lipophilic properties, the un-excreted CTXs  diffuse and strongly fix in different organs and tissues, such as the liver, muscles, fat and brain.


Even if the process of  “detoxification” in humans remains unknown, toxicokinetic experiences conducted on eels have shown that the complete elimination of the toxins was long but possible (several months or years).


To date, no treatment has shown the capability to improve CTXs elimination yet.



CTXs detection represents a significant technical challenge, due to their chemical nature, the multiplicity of congeners and the low levels of toxins present in contaminated organisms. However, even if several detection tests are now available, currently there is no standard test duly validated by the scientific community, that could enable public authorities to establish a seafood security regulation at an international level. To date, the only reliable methods to detect CTXs are laboratory tests based on toxins mode of action (functional tests), or chemical properties.


Biological test on mouse or “Mouse bio-assay” (MBA) was the first CTXs detection test used. It is based on the symptoms and mice survival time observed after a 24h-48h period, following an intraperitoneal (ip) or intravenous (iv) injection of toxic fish extract. Several animal species other than mice have been used: cats, chicken or mongooses that have a better CTXs sensitivity but require large amount of extracts or, conversely, methods using invertebrates, such as mosquitoes, crayfish, fly larvae or shrimps, which require lesser amounts of the extract. These tests were gradually replaced by other methods following the 3R rule: “Reduce, Refine, Replace”, based on CTXs chemical, pharmacological and immunological properties.


 The radioligand-receptor test or “Receptor binding-assay” (RBA) is a neuropharmacological test based on the specific affinity of CTXs and brevetoxins (PbTxs) to the site 5 of VSSC’s alpha subunits found on excitables cells membranes. Concerning CTXs detection, RBA measures the binding of a radiolabelled toxin, tritiated PbTx ([3H]PbTx-3), to this receptor, which compete with unradiolabled CTXs contained within the extract to analyse. Well adapted to CTXs detection in complex and varied biological matrices, RBA offers a high sensitivity (10-10M detection limit) and allows the use of untreated or partially purified extracts. It is economically more viable than the mouse bioassay, as it is easily automated to allow maximum processing capacity, making it an ideal tool for large-scale ciguatera risk monitoring programs. However, due to the regulatory constraints imposed by radioelements storing and handling, it appears difficult to generalize this test. But, recent labeling of brevetoxin with a fluorescent element gives hope for a greater applicability of this test.

 Cell toxicity test or “Cell based-assay” (CBA) is another functional test allowing to measure the “overall toxicity” of a sample, by measuring the viability of a cultured cells line exposed to toxic extracts. This test is commonly used for the detection of a wide range of marine toxins: e.g. those active on VSSCs (saxitoxins, tetrodotoxins, brevetoxins and ciguatoxins), those active on Na+/K+ ATPases pumps (palytoxins), maitotoxins acting on voltage sensitive calcium channels or VSCC, okadaic acid which inhibits serine / threonine protein phosphatases, or pectenotoxins and dinophysistoxins…Besides its capacity to detect a wide range of marine biotoxins, CBA is also very sensitive (10-12M) and replicable, making it an excellent CTXs standard detection test candidate.

 Various immunological assays have been developed for CTXs screening: the radioimmunoassay (RIA) or the “sandwichtest or enzyme-linked immunosorbent assay (ELISA). These tests are based on the principle of a highly specific recognition between an antibody (CTXs anti-antibody) and its antigen (CTXs). Theoretically, this approach seems to be the most promising one for the implementation of a fast, reliable, sensitive (up to 5×10-12M) and cheaper screening test. Its operating principle could also enable high-throughput screening of marine samples, and, most of all, its direct use on the field by individuals. Two trials of developing such a test have been tried: the CIGUATECT ™ and Cigua-Check ® (ToxiTec Inc. / Oceanit). But, these test kits have been withdrawn from the market, partly due to high false positives and false negatives reactions.

 CTXs’ complexity and chemical diversity, their low natural immunogenicity related to their polycyclic polyether nature, as well as the limited availability of pure standards of CTXs, partially, explains the apparent difficulties to develop a reliable test.


Physicochemical tests (e.g. HPLC, LC-MS / MS) are based on high performance liquid chromatography techniques coupled with detection of each toxins families using Ultra-violet (UV), fluorescence, or tandem mass spectrometry. With a great sensitivity, these tests allow distinction and quantization of the different CTXs congeners within the same toxic family, but they require, as a prerequisite, to have the corresponding pure standards of the toxins. Therefore, the main limitations of this technique are that it does not detect new toxic families and, unlike the so-called functional tests, it doesn’t provide indication on the fish sample “whole toxicity”. Also, this type of methodology appears difficult to adapt to a CTXs high-throughput screening due to the several preliminary purification steps of the biological matrices. Therefore, these tests are most of the time used as confirmatory testing.


 As the contaminated organisms cannot be identified by their appearance, odor, color or taste, island populations (which are highly exposed  to CP risk), have gradually developed a wide range of traditional tests in attempt to detect ciguatoxic specimens. Across south pacific territories, several detection methods coming form popular beliefs or long ancestral practices are used. These traditional tests consist in 1/ giving a piece of flesh or liver of the suspicious fish to an animal or insect and observing its reaction; 2/ observing the oxydation of a silver coin or some matches in contact with the flesh; or 3/ observing the appearance of the whole fish or some of its organs.

 A study has verified the effectiveness of two traditional detection tests used in French Polynesia (the rigor mortis method and hemorrhagic test). The ciguatoxic status of fisf samples, based on the use of the two tests by local fishermen, was  compared to toxicity analysis, of the same samples, by Receptor Binding Assay (RBA). Despite a predictability rate not exceeding 70%, the use of these tests combined with the population knowledge on suspicious toxic species and fishing areas, may help to significantly reduce the risk of CP within fish dependent communities, at the condition that the test users are accustomed to these tests. The opportunity for island populations of remote archipelagos to use on site and cost-effective validated traditional tests may therefore represent a day to day valuable asset in ciguatera risk management.

test toxico eng PT

Examples of traditional tests used by French Polynesia’s fishermen to differentiate toxic fish over healthy fish.




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