9 Gambierdiscus, the cause of ciguatera fish poisoning

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thic dinoflagellate in ciguatera fish poisoning (CFP) brought increased ...... eels, which is the principal toxin in the carnivorous fish from the Pacific [62, 63]. Two.
Gurjeet S. Kohli, Hazel Farrell, and Shauna A. Murray

9 Gambierdiscus, the cause of ciguatera fish poisoning: an increased human health threat influenced by climate change 9.1 The genus Gambierdiscus Recent advances in population and species genetics for phytoplankton have revealed immense biodiversity at different taxonomic levels [1]. Vast numbers of species remain to be documented, aided by rapidly developing molecular methods [2]. To date, there are only approximately 160 described benthic (sand dwelling and epiphytic) dinoflagellates [3]. The first report by Yasumoto et al. [4] of the involvement of a benthic dinoflagellate in ciguatera fish poisoning (CFP) brought increased attention to this group. This species was described as Gambierdiscus based on the type species Gambierdiscus toxicus, from samples collected in the Gambier Islands, French Polynesia [5]. Species of the genus Gambierdiscus have now been recognized as the main producers of ciguatoxins (CTXs) and maitotoxins (MTXs) [6–12]. CFP is the most common nonbacterial illnesses associated with fish consumption [13], affecting between 50 000 and 500 000 people per year [14]. The ingestion of herbivorous and carnivorous fish that have orally accumulated effective levels of CTXs, and possible MTXs, can cause CFP in humans [15–17]. Recent reviews have illustrated the global increase in the frequency and intensity of harmful algal events [18, 19]. Despite being significantly underreported, CFP occurrence worldwide is increasing, with reports of a 60 % increase in CFP in the Pacific Islands over the last decade [20]. Once considered a monotypic taxon, new species of Gambieriscus are being discovered every year with evidence showing that each species might have its own characteristic toxin profile [9, 11, 12]. As in the case of other dinoflagellate genera such as Alexandrium or Karenia, the production or not of certain toxin groups appears to generally vary at the species level, rather than being consistent within the genus. For this reason, species of harmful algal bloom (HAB)-forming taxa are monitored, acting as early warning systems for shellfish and seafood safety. This review highlights the significant advances in the study of Gambierdiscus. We provide a summary of the morphology and phylogenetics of species of Gambierdiscus, their toxicology, distribution, chemistry and methods for the detection of CTXs and MTXs in seafood. The review further outlines the major gaps in our current understanding of Gambierdiscus and outlines goals for future research in this field.

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9.2 Morphology and phylogenetics When originally described [5], Gambierdiscus was considered as a monotypic taxon, however, variability in the morphology, differences in ribosomal RNA (rRNA) genes, toxicity and physiological characteristics [5, 6, 21–27] led to the description of new species. Currently, 11 species of Gambierdiscus have been described, based on their distinct morphological and molecular genetic characteristics (Tab. 9.1). The following is an overview of the main morphological characteristics for each described species of Gambierdiscus. The original species descriptions consist of a comprehensive account of their characteristics. Gambierdiscus cells are large (60–100 μm), armoured, have a distinct plate pattern and fishhook shaped apical pore. Species are either anterio-posteriorly compressed (lenticular) or slightly laterally compressed (globular) (Fig. 9.1). The two globular species (G. yasumotoi and G. ruetzleri) can be distinguished from each other by cell size, size and shape of the 2󸀠 apical and 2󸀠󸀠󸀠󸀠 antapical plate and depth to width ratio, described in detail in Litaker et al. (2009) [28]. The remaining nine species are anterio-posteriorly compressed and broadly classified by either a narrow (G. australes, G. belizeanus, G. pacificus and G. excenreicus) or broad (G. polynesiensis, G. carolinianus, G. toxicus, G. caribaeus and G. carpenteri) 1p posterior intercalary plate. Among the species with a narrow 1p posterior intercalary plate, further distinguishing characteristics are either heavily areolated cell surface (G. belizeanus) or smooth cell surface species (G. australes, G. pacificus and G. excentricus). Species with a smooth cell surface can be distinguished by either having a hatchet-shaped 2󸀠 apical plate (G. pacificus) or more conventional rectangular shaped 2󸀠 apical plate (G. australes and G. excentricus). G. excentricus is at least 1.5 times wider and deeper than G. australes; further specifics distinguishing the two are described in detail in the original descriptions of the species [8, 11]. Species that have a broad 1p posterior intercalary plate can be further differentiated as having a rectangular shaped 2󸀠 apical plate (G. caribeaus and G. carpenteri) or a hatchet shaped 2󸀠 apical plate (G. toxicus, G. polynesiensis and G. carolinianus). G. toxicus can be further discerned by a pointed dorsal end to the 1p posterior intercalary plate. Further differences between G. polynesiensis & G. carolinianus are detailed in Litaker et al. [28]. G. caribeaus and G. carpenteri, both possessing a rectangular shaped 2󸀠 apical plate, are distinguished by the shape of 4󸀠󸀠 precingular plate, which is symmetric in G. caribaeus and asymmetric in G. carpenteri. The size and shape of the sulcal plates and various other specific morphological characteristics have also been described in the original descriptions of the species [7, 8, 11, 28, 29]. These features are straightforward to observe using light and scanning electron microscopy; however, within some species, a considerable amount of variability in features such as the size and shape of individual plates may be present. Another technique to identify different species of Gambierdiscus is to compare sequences that are known to be characteristic at the species level, such as regions of rRNA genes. Based on phylogenetic analysis of regions of the SSU (small ribosomal

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Smaller size cell width less than 42 μm

(45.5 ± 3.3) × (37.5 ± 3.0) × (51.6 ± 4.9)

G. ruetzleri (Vandersea, Litaker, Faust, Kibler, Holland et Tester)

Narrow 1p plate heavily aerolated cell surface different 2󸀠 plate symmetry and size Narrow 1p plate smooth cell surface 2󸀠 hatch shaped Narrow 1p plate smooth cell surface 2󸀠 rectangular shaped cell size bigger than G. australes (1.5 times wider and deeper)

(61.7 ± 3.1) × (60.0 ± 4.5) × (48.1 ± 4.2) (58.5 ± 3.9) × (53.6 ± 4.1) × (40.4 ± 3.6) (97.8 ± 8) × (83 ± 10) × (37 ± 3)

G. belizeanus (Faust)

G. pacificus (Chinain et Faust)

G. excentricus (Fraga)

Anterio-posteriorly compressed species

Larger cell size cell width larger than 42 μm

Morphological characteristics (plate formula)

(56.8 ± 5.6) × (51.7 ± 5.6) × (62.4 ± 4.3)

Cell size (μm) (depth × width × length)

G. yasumotoi (Holmes)

Globular species

Species

Tab. 9.1: Taxonomic and genetic identifications of different species of Gambierdiscus.

D1-D3 LSU: HQ877874, JF303063, JF303065-71 D8-D10 LSU: JF303073-76

SSU: EF202861-65 D1-D3 LSU: EF202944-47 D8-D10 LSU: EF498012-13, EF498015-16

SSU: EF202876-77 D1-D3 LSU: EF202940-43 D8-D10 LSU: EF498028-34

SSU: EF202853-60 D1-D3 LSU: EF202962-64 D8-D10 LSU: EF498081-85

SSU: EF202846-52 D1-D3 LSU: EF202965-68 D8-D10 LSU: EF498087-89

Genetics

[11]

[8, 28]

[28, 29]

[28]

[7, 28]

References

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Morphological characteristics (plate formula) Narrow 1p plate smooth cell surface 2󸀠 rectangular shaped smaller than G. excentricus Broad 1p plate 2󸀠 Rectangular shaped Symmetric 4󸀠󸀠 Broad 1p plate 2󸀠 Rectangular shaped Asymmetric 4󸀠󸀠 Bad 1p plate 2󸀠 Hatchet shaped Dorsal end 1p pointed Broad 1p plate 2󸀠 Hatchet shaped Dorsal end 1p oblique smaller cell size than G. carolinianus

Cell size (μm) (depth × width × length) (72.5 ± 3.8) × (63.4 ± 5.0) × (38.7 ± 3.8) (82.2 ± 7.6) × (81.9 ± 7.9) × (60 ± 6.2) (81.7 ± 6.4) × (74.8 ± 5.9) × (50.2 ± 6.1) (93 ± 5.5) × (83 ± 2.3) × (54 ± 1.5) (66.3 ± 3) × (60.5 ± 5.9) × (44.3 ± 5.1)

Species

G. australes (Faust et Chinain)

G. caribaeus (Vandersea, Litaker, Faust, Kibler, Holland et Tester)

G. carpenteri (Vandersea, Litaker, Faust, Kibler, Holland et Tester)

G. toxicus (Adachi et Fukuyo) Chinain, Faust, Holmes, Litaker et Tester)

G. polynesiensis (Chinain et Faust)

Tab. 9.1 (continued)

SSU: EF202902-07 D1-D3 LSU: EF202976-82 D8-D10 LSU: EF498076-80

SSU: EF202878-90 D1-D3 LSU: EF202951-61 D8-D10 LSU: EF498017-27

SSU: EF202908-13 D1-D3 LSU: EF202938-39, EF202984 D8-D10 LSU: EF498038-44

SSU: EF202914-28 D1-D3 LSU: EF202929-37, EF202983, EF202985 D8-D10 LSU: EF498045-71

SSU: EF202891-96 D1-D3 LSU: EF202969-72 D8-D10 LSU: EF498072-74

Genetics

[8, 28]

[5, 6, 25, 28]

[28]

[28]

[8, 28]

References

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Not described

Not described

Not described Not described

Gambierdiscus ribotype 2

Gambierdiscus sp. type 1

Gambierdiscus sp. type 2

Gambierdiscus sp. type 3

Gambierdiscus ribotype 1

Not described

Broad 1p plate 2󸀠 Hatchet shaped Dorsal end 1p oblique larger cell size than G. polynesiensis

(78.2 ± 4.8) × (87.1 ± 7.1) × (51.4 ± 5.2)

G. carolinianus (Vandersea, Litaker, Faust, Kibler, Holland et Tester)

Genetically described phylotypes

Morphological characteristics (plate formula)

Cell size (μm) (depth × width × length)

Species

Tab. 9.1 (continued)

SSU: AB764296-300 LSU D8-D10: AB765923-24

SSU: AB764277-96 LSU D8-D10: AB765913-18

SSU: AB64229-76, AB605799-800, AB605811-12 LSU D8-D10: AB765908-13

D8-D10 LSU: GU968499-500, GU968503, GU968505, GU968507-11

D8-D10 LSU: GU968512-20, GU968523

SSU: EF202897-EF202901 D1-D3 LSU: EF202973-75 D8-D10 LSU: EF498035-37

Genetics

[32]

[30, 32]

[30, 32]

[31]

[31]

[28]

References

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Gambierdiscus ruetzleri

Gambierdiscus belizeanus

4” 5” 3’ 2’ 3” 6” Po 2” 1’

4”

6”

7” 1”

Gambierdiscus yasumotoi

1’

2’

3” 3’

5”

Gambierdiscus polynesiensis 4”

5” 3’ 2’ 3”

2’

3’

5”

1’

1’

2”

7”

1”

Gambierdiscus carolinianus 4”

3”

2’

Po

6” 7”

2” 1”

3’

5”

7”

2”

1’

1”

7”

4” 5”

3’ 6”

Gambierdiscus australes

1’

2”

Gambierdiscus excentricus

4”

2’ 3” Po

4” 2’

5” 3’

3” Po

6”

Gambierdiscus pacificus

3” Po

2” 6”

4”

6” Po 2” 1’ 1”

4”

2’ Po

5” 3’

Gambierdiscus caribaeus

3”

2’

3”

Po

6” 1’

5”

2”

3’ 6”

Po 1’

2”

7” 1” Gambierdiscus carpenteri

4” 2’

6”

1’ 7”

4”

3”

Po

5” 3’

Gambierdiscus toxicus

2”

2’ 3’

5”

3” Po

1”

1’

6” 7”

1”

Fig. 9.1: Comparative line drawings of the epitheca for 11 Gambierdiscus species. Sale bar equals 50 μm. Modified from Litaker et al., 2009 [28].

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subunit) rDNA, LSU (large ribosomal subunit) rDNA and ITS (internal transcribed spacer) rDNA, the genus Gambierdiscus is monophyletic [8, 11, 25, 28, 30–32]. Further, the lenticular and globular species form two distinct clades. Phylogenetic analysis has shown that the two globular species (G. ruetzleri and G. yasumotoi) diverged relatively early in the evolution of the genus Gambierdiscus [28, 32]. Also, G. ruetzleri and G. yasumotoi are the two most closely related species in the genus. Based on LSU rDNA D08-D10 sequences, the mean p distance within species is 0.002±0.002, and between species is 0.121 ± 0.036 (calculated based on sequences from 10 species/phylotypes) where minimum p distance between G. ruetzleri and G. yasumotoi is 0.007 [32]. Using SSU rDNA sequences, the mean p distance within species is 0.003 ± 0.002 and between species is 0.139 ± 0.042 (calculated based on sequences from 10 species/ phylotypes) where minimum p distance between G. ruetzleri and G. yasumotoi is 0.004 [32]. These statistics are indicative of putative unknown species and can be very useful in cases where morphological, physiological or other data is not yet available, or a strain is not present in culture. Based on D8-D-10 LSU rDNA phylogenetic analysis, two new putative phylotypes Gambierdiscus ribotype 1 and Gambieridsuc ribotype 2 were reported [31], as the two clusters/clades separated from the others and their genetic distances equalled or exceeded those among the 11 described species [31] (Tab. 9.1). Similarly, three new putative species/phylotypes of Gambieridiscus (Gambieridsucs sp. type 1, type 2 and type 3) have been described from Japan based on differences in the regions D8-D10 of the LSU and SSU rDNA [30, 32] (Tab. 9.1). In this case, the p distances between these two novel clades and known species of Gambierdiscus were larger than those separating G. yasumotoi from G. ruetzleri. Although the genetic data indicates that these phylotypes may be new species, their morphological circumscriptions are needed to support their status as new species. As sampling around the world becomes more intensive, it is likely that new species of Gambierdiscus will be described.

9.3 Geographic distribution and abundance Gambierdiscus is widely distributed in coastal zones at tropical and subtropical latitudes. However, the distribution of species of Gambierdiscus is still poorly understood, as the discrimination of different species of Gambierdiscus has only occurred recently (Tab. 9.2).

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MBA-positive [8]

HELA-positive [12]

MBA-negative [8], RBA-positive [9] RBA-positive [9]

MBA-positive [7]

Tahiti, French Polynesia [5, 8], Mexican Caribbean [50], New Caledonia, Reunion Island, Indian Ocean [8], Nha Trang – Vietnam [136, 137]

Belize [29], Florida [28] , Mexican Caribbean [50], Malaysia [138], Pakistan [139], Queensland, Australia (murray unpubl. Data), St. Barthelemy Island – Caribbean [31]

Singapore [7], Japan [32], Mexican Caribbean [50], Queensland, Australia (murray unpubl. Data), Nha Trang – Vietnam [137]

French Polynesia [8], Japan [32], Cook Islands [10], Hawaii USA [28], Pakistan [139]

G. belizeanus

G. yasumotoi

G. australes

G. pacificus

MBA-positive [8]

MBA-positive [8] HELA-positive [12]

MBA-positive [8]

MBA-positive [8], RBA-positive [9] N/K

French Polynesia [8], Marshall Islands & Society Islands Micronesia [31], Kota Kinabalu and Sipandan Island [140], Nha Trang – Vietnam [137]

French Polynesia [8], Canary Islands [11], Pakistan [139], Nha Trang – Vietnam [137]

Florida, Belize – Caribbean, Tahiti, Palau, Hawaii [28], Flower Gardens – Gulf of Mexico, Osho Rios – Jamaica [12], Bahamas, Grand Caymam Island, Tol-truk Micronesia [31], Jeju Island Korea [141]

G. polynesiensis

G. caribaeus

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N/K

Yes [9]

N/K

N/K

N/K

Yes

N/D [10] HELA-positive, MBA-positive [8, 10, 32]

MBA-positive [8, 10, 32], RBA-positive [9]

N/K

N/K

N/K

N/K

N/K

MTX

N/K

N/K

N/K

CTX

MTX

CTX

G. toxicus

LC-MS

Toxicity various assays

Geographical distribution

Species

Tab. 9.2: Geographic distribution and toxicity of different Gambierdiscus species.

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MBA-negative [32] MBA-negative [32]

Japan [32]

Japan [32]

Gambierdiscus sp. type 2

Gambierdiscus sp. type 3

MBA-positive [32]

MBA-negative [32]

MBA-positive [32]

HELA-positive [12]

N/K

NCBA-positive [11]

HELA-positive [12]

N/K

N/K

N/K

N/K

N/K

N/K

N/K

N/K

HELA, human erythrocyte lysis assay,

MBA-positive [32]

Japan [32]

Gambierdiscus sp. type 1

RBA, receptor-binding assay,

N/K

Belize – Caribbean, Martinique – Caribbean [31], Puerto Rico [12]

Gambierdiscus ribotype 2

The abbreviations are: N/K, not known, N/D, not detected, MBA, mouse bioassay, cell binding assay.

N/K

N/K

N/K

N/K

N/K

N/K

N/K

N/K

N/K

N/K

MTX

NCBA, neuro-2a

NCBA-positive [11]

Canary Islands [11]

G. excentricus

Belize – Caribbean [31]

N/K

North Carolina, USA, Belize – Caribbean [28]

G. ruetzleri

Gambierdiscus ribotype 1

N/K

Belize, Guam, Fiji [28], Hawaii [31], Dry Tortugas – Florida, Flower Gardens – Gulf of Mexico, Osho Rios – Jamaica [12]

G. carpenteri

HELA-positive [12]

HELA-positive [12]

N/K

North Carolina, USA, Atlantic ocean [28], Bermuda, Mexico [31], Puerto Rico, Flower Gardens – Gulf Of Mexico, Osho Rios – Jamaica, Crete – Greece [12]

N/K

CTX

G. carolinianus

LC-MS MTX

CTX

Toxicity various assays

Geographical distribution

Species

Tab. 9.2 (continued)

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9.3.1 The Pacific and Indian Ocean Regions Gambierdiscus is named after the Gambier Islands in French Polynesia, where it was first identified, [5], and since then, G. toxicus, G. belizeanus, G. yasumotoi, G. australes, G. pacificus, G. polynesiensis, G. caribaeus and G. carpenteri have been reported from various Pacific islands, Hawaii, Australia, Southeast Asia and the Northern Indian Ocean (Tab. 9.2). Recently, three genetically distinct species from coastal and temperate waters of Japan were reported [32] (Tab. 9.2). In addition, Gambierdiscus has been reported from the Philippines [16], Hong Kong [33], Indonesia [34] and Mauritius [35], although species diversity in these areas is not known. Gambierdiscus has also been reported from the Mexican Pacific coast [36] and regions around Madagascar [37], where cases of CFP have also been previously reported [38, 39].

9.3.2 The Atlantic Ocean Region Early accounts of Gambierdiscus “look-alike” species date back to 1948 from Cape Verde Islands [40] and 1979 from Key Largo, Florida [41]. So far, G. toxicus, G. belizeanus, G. yasumotoi, G. polynesiensis, G. caribaeus, G. carolinianus, G. carpenteri, G. ruetzleri, G. excentricus, Gambierdiscus ribotype 1 and Gambierdiscus ribotype 2 have been reported from the east coast of the USA, Caribbean and the Mediterranean regions (Tab. 9.2). There are many other regions where Gambierdiscus has been reported; however, the exact species are yet to be determined. These include Cyprus, Rhodes, Saronikos Gulf [42, 43], French West Indies [44], Cuba [45] and Veracruz [46]. Other confirmed reports of Gambierdiscus occurrence in Central and South America in the literature are from Costa Rica and Brazil (M. Montero pers. comm. in [47]). From Africa, there has been only one direct observation of Gambierdiscus, from the coast of Angola [48]; however, CFP cases from the west coast (Canary Islands and Cameroon) [49] of Africa have been reported, indicating the presence of Gambierdiscus in that region. Certain species of Gambierdiscus have been designated as being endemic to either the Pacific or the Atlantic regions [31, 48]. So far, G. australes and G. pacificus have only been reported from the Pacific, and G. ruetzleri, G. excentricus and Gambierdisucs ribotype 1 and 2 are only reported from the Atlantic region (Tab. 9.2). G. belizeanus, G. caribeaus, G. carpenteri and G. carolinianus are widely distributed in the Atlantic and Pacific Oceans [28, 31, 48]. G. yasumotoi is widely distributed in the Pacific; however, there is only one report of its occurrence in the Mexican-Caribbean [50], which was reported before the discovery of the other globular species G. ruetzleri, which is widely distributed in the Atlantic region [28]. The distribution of G. toxicus needs to be refined, due to numerous misidentifications in the literature. G. polynesiensis is widespread in the Pacific (Tab. 9.2) with only one confirmed report from the Canary Islands in the Atlantic region [11]. Both, Litaker et al, 2010 and Berdalet et al.,

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2012 [31, 48] mention that none of the Pacific-specific species have been observed in hundreds of field samples analysed from Atlantic regions (Caribbean/Gulf of Mexico/West indies/Southeast US coast from Florida to North Carolina). The absence of Atlantic-specific species in the Pacific region has not been confirmed, as the majority of the vast Pacific region remains unexplored. As under-sampling and underreporting have occurred worldwide, but particularly in the Pacific region, much more work needs to be undertaken in order to determine whether endemism or restricted distributions exist in species of Gambierdiscus. While multiple species of Gambierdiscus can co-occur in one region, equally, there are regions from where only one species has been reported. For example, in Heron Island (Queensland, Australia) there are at least three species of Gambierdiscus that co-occur, however further south in Merimbula, New South Wales only G. carpenteri is known to occur (Murray, unpublished data). Localized benthic blooms of Gambierdiscus have been noted in the literature from both the Pacific and Atlantic regions [51–54]. Cell densities in such blooms can range from anywhere between 10 000 to 100 000 cells g−1 wet weight algae [31]. There are no accurate estimates of cell densities at which a Gambierdiscus bloom leads to a CFP epidemic. The onset of CFP may also depend on other factors, such as the fact that different species of Gambierdiscus have varying toxicities. For example, in 2010, an unidentified species of Gambierdiscus was reported in Greece, however no CFP outbreaks have been reported there [55]. In most habitats where species of Gambierdiscus occur, cell densities are below 1000 cells g−1 wet weight algae [31], however in some environments Gambierdiscus spp are known to occur year-round at such cell densities [51]. A constant exposure of low densities of cells could also lead to a build up of CFP-related toxins in fish. Much more research needs to be done in order to understand the relationship between Gambierdiscus abundance and CFP outbreaks. This is particularly challenging, as benthic dinoflagellates inhabit areas where quantitative sampling of microbial eukaryotes is not straightforward, for example, in sediments and on the surface of dead corals. Also, Gambierdiscus cell distribution can be very patchy, even over small distances, making it hard to estimate mean Gambierdiscus cell densities over a larger area [31, 44, 56].

9.4 CTXs and MTXs CTXs are sodium channel activators, particularly affecting the voltage sensitive channels located along the nodes of Ranvier (peripheral nerve cells) [57–59]. When the sodium channels are activated, there is a massive influx of Na+ ions, resulting in cell depolarization [57–59]. This leads to the onset of spontaneous action potentials in effected cells, causing various symptoms in humans. Symptoms can include but are not limited to gastrointestinal, neurological and in cases of severe intoxication sometimes cardiovascular [17], and can vary depending on geographical region [59, 60]. This can be due to the structural differences of CTXs in different regions, therefore it

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is very important to characterize CTXs from Pacific, Caribbean and the Indian Oceans. Local understanding of CTX accumulation patterns in different fish species can also help prevent CFP. However, the accurate identification of exact congeners of CTXs is necessary, in order to understand the toxicology and evaluate the local risks of CFP. Structurally, CTXs are thermostable, cyclic polyether ladders, which are liposoluble (Fig. 9.2). They have been isolated from fish and different species of Gambierdiscus (Tab. 9.3). Based on their origin and differences in the structure of these toxins, they are divided into P-CTXs (Pacific Ocean), C-CTXs (Caribbean region) and I-CTXs (Indian Ocean). Due to their structural differences, P-CTXs are further divided into type I and type II, as suggested by Legrand et al. [61]. Type I P-CTXs have 13 rings and 60 carbon atoms [62–65]. This category consists of the first CTX to be fully structurally described as CTX1B [62] (or CTX-1 as described by Lewis et al. 1991, [63]) from moray eels, which is the principal toxin in the carnivorous fish from the Pacific [62, 63]. Two other type I P-CTXs, i.e. CTX-2 and CTX-3, were also described from the same extracts; they have slight variations in their structures leading to different toxicities in mice [63] (Tab. 9.3). It has also been suggested that CTX-1, CTX-2 and CTX-3 may be derived from dinoflagellate precursors known as CTX-4A and CTX4B (also named as GTX-4B in [62]) [64, 65]. Recently, CTX-4A and CTX-4B have been isolated from G. polynesiensis culture extracts [9]. CTX3C is a type II P-CTX with 13 rings, 57 carbon atoms and was first isolated from cultures of Gambierdiscus sp. [66] and later from G. polynesiensis [9]. Two more congeners of CTX3C called as 49-epi-CTX-3C (also called as CTX-3B in [9]) and M-seco-CTX-3C have also been isolated from Gambierdiscus sp. [66] and G. polynesiensis [9]. Later, 2 new type II P-CTXs, i.e. 2,3 dihydroxyCTX3C (also called as CTX2-A1) and 51-hydroxyCTX3C, were isolated from Moray eel [67] that might be oxygenated metabolites of CTX3C [65]. Caribbean CTXs are slightly bigger than P-CTXs and have 14 rings and 62 carbon atoms [68–71]. Many congeners of C-CTXs have been isolated from carnivorous fish, including C-CTX1, C-CTX-2, C-CTX-1141, C-CTX-1127, C-CTX-1143, C-CTX-1157, C-CTX-1159 [68–71]. Unlike P-CTXs, there have been no reports of C-CTXs originating from Gambierdiscus sp. However, recently G. excentricus has been identified as a major CTX producer in the Caribbean [11], and CTXs from this strain are being characterized. Recently 4 CTXs (I-CTX-1, I-CTX-2, I-CTX-3, I-CTX-4) have been isolated from carnivorous fish from Indian Ocean and have higher molecular ion masses than P-CTXs and C-CTXs [55, 72, 73]. However, their structures need to be elucidated [72, 73]. I-CTX-1 is toxic to mice via intraperitoneal injection [73]. Based on mouse bioassays (MBA), different congeners of CTXs can have variable toxicities (Tab. 9.3), however this needs to be further validated as well.

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Tab. 9.3: Different congeners of CTXs and MTXs. Origin

Toxin Name

Molecular Ion [M + H]+

Source

Toxicity*

CTX1B [62], CTX-1[63]

1111.6 [62, 63]

Moray eel (Gymnothorax javanicus) [62] Moray eel (Lycodontis javanicus, Muraenidae) [63]

CTX1B: 0.35 μg/kg [62] CTX-1: 0.25 μg/kg [63]

CTX-2

1095.5 [63]

Moray eel (Lycodontis javanicus, Muraenidae) [63]

2.3 μg/kg [63]

CTX-3

1095.5 [63]

Moray eel (Lycodontis javanicus, Muraenidae) [63]

0.9 μg/kg [63]

CTX4A

1061.6 [65]

Gambierdiscus sp. [65] G. polynesiensis [9]

12 μg/kg [9]

CTX4B

1061.6 [65]

Gambierdiscus sp. [65] G. polynesiensis [9]

20 μg/kg [9]

CTX3C

1023.6 [66]

Gambierdiscus sp. [66] G. polynesiensis [9]

2.5 μg/kg [9]

49-epi-CTX-3C

1023.6 [9]

Gambierdiscus sp. [66] G. polynesiensis [9]

8 μg/kg [9]

M-seco-CTX-3C

1041.6 [9]

Gambierdiscus sp. [66] G. polynesiensis [9]

10 μg/kg [9]

C-CTX-1

1141.6 [68, 70]

Horse-eye jack (Caranx latus)

3.6 μg/kg [68]

C-CTX-2

1141.6 [68, 70]

Horse-eye jack (Caranx latus)

Toxic [68]

I-CTX-1

1141.6 [73]

Red bass (Lutjanus bohar) and red emperor (Lutjanus sebae) [73]

Toxic [73]

MTX-1

3422 [74, 82]

Gambierdiscus sp. [82]

0.05 μg/kg [74]

MTX-2

3298 [82]

Gambierdiscus sp. [82]

0.08 μg/kg [82]

MTX-3

1060 [82]

Gambierdiscus sp. [82]

Toxic [82]

Ciguatoxins Pacific (type I)

Pacific (type II)

Caribbean

Indian

Maitotoxins Pacific

* LD50 doses calculated via i. p. injection in mice.

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CH3

OH O

CH3

O

O

R2

O

HO

O

O

CH3

O O

O

O

OH O H3C

Type I CTX backbone Ciguatoxin, R1;R2 P-CTX-1, OH; CH(OH)CH2OH P-CTX-2, H; CH(OH)CH2OH P-CTX-4B, H; CH=CH2

CH3

O

O HO

H3C

CH3

O O

O

O

R1

O

O

O

OH O

Type II P-CTX-3C

CH3

O HO

CH3

O O

O

O

OH CH3 O

O Type III C-CTX-1 H

OH

O

H

H O

OH

H

H O

H

O

O

H

O

O

OH

OH

O

H

H

O

O H

O

H3C H3C

H

O HO

R1

O

O

O

O

H3C

CH3

OH O

O

H3C

HO O

O

CH3

OH O

O

O

H

H

H

H

H

O

O H O H O OH HO

HO O

H O OH

OSO3Na

OH H HO

O H H OH

H

O O

H

OH

NaO3SO OH OH

H

H

H OH

O H

H OH

OH

H

O

H

O H

H

OH

H H

OH

H OH

O

HO H O

O H

H O

OH H

O H

O

H

H HO OH

H

O

H

OH

HO H

O

OH

OH

H

Maitotoxin-1 Fig. 9.2: Structure of Ciguatoxins (CTX) and Maitotoxin-1. P-CTX-1, P-CTX-2 and C-CTX-1 were derived from fish and P-CTX-3C, P-CTX-4B and Maitotoxin-1 were derived from Gambierdisucs spp.

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Maitotoxins (MTXs) are one of the largest non-proteinous and highly toxic natural products known [74, 75]. This polyether ladder type compound was first discovered as a water-soluble toxin in the guts of herbivorous fish Acanthurids (surgeonfish) in 1976 [76]. In the 1990s, stereoscopic studies and partial synthesis were used to determine the structural elucidation and stereochemistry of the extraordinary complex and large MTX [74, 77–81]. Simultaneously, Holmes & Lewis described two large (MTX-1, MTX-2) and one small MTX (MTX-3) from different strains of Gambierdiscus sp. isolated from Queensland, Australia [82] (Tab. 9.3). MTX-1 from this study may have been the MTX originally described from guts of Acanthurids, however it is not clearly proven. When compared to other natural toxins, MTX is a highly potent calcium channel inhibitor (LD50 0.05 μg/kg, i.p., mice), only exceeded by a handful bacterial proteinous toxins [74, 75]. Despite its high level of potency, the complete mode of action and the primary target of MTX in mammalian cells have not yet been fully elucidated. In fact, the activation of voltage dependent calcium channels induced via MTXs is a secondary effect of membrane depolarization (for review and more details see [83]). Recently, it has been reported that the biophysical mechanisms of pacific MTXs are different to Caribbean MTXs [84]. Whether this is due to a structural difference is not known, as the Caribbean MTXs have not been fully characterized. Although MTX appears to have a low tendency of accumulating in fish flesh, as compared to stomach or intestines [76], its possible role in CFP cannot be disregarded, as eating non-eviscerated fish is a common practice in many Pacific Island nations. The sulphate esters in the structures of MTXs make it amenable to detect and quantify MTX by LC_ESI_MS (Liquid chromatography-electronspray ionisation-Mass spectrometry) (T. Harwood, pers. comm.), and Solvolysis (desulphonation) reduces the toxicity of MTXs significantly, at least 100-fold [85]. However, more research is essential to understand the exact role of MTXs in CFP including its mode of action and target in mammalian cells. Cyclic polyether ladders are almost exclusively known to be produced by dinoflagellates. Other than CTXs and MTXs, this class of secondary metabolites also includes Brevetoxins (BTXs), produced by Karenia spp [86] and Yessotoxins (YTXs), produced by a wide array of dinoflagellates including Lingulodinium polydrum [87], Gonyaulax spinifera [88] and Protoceratium reticulatum [89]. Based on their high structural similarities, the synthesis of these compounds likely involves common biosynthetic mechanisms [90–92]. Stable-isotope labeling of precursors to elucidate the biosynthesis pathway of CTXs and MTXs has never been performed. However, precursor studies to reveal the biosynthesis pathways of BTXs and YTXs have indicated the polyketide origin of these cyclic polyether ladders [93, 94]. Several schematic pathways involving different enzymes have been suggested and are detailed in Kalaitzis et al. [95] and Kellmann et al. [94]. It is speculated that the biosynthesis involves the normal polyketide synthase (PKS) enzyme complex with a few additional enzymes, i.e. expoxidases and thioesterases [96]. Essential domains present in the PKS are: acyltransferase domain (AT); β-ketosynthase domain (KS); and acyl carrier protein (ACP) [97]. In addition, PKS can include β-ketoacyl reductase (KR), enoyl reductase (ER) and dehydrogenase (DH)

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domains [97]. In the past 10 years, a few genes that encode the essential domains of the PKSs, particularly KS domains in dinoflagellates, have been identified for the first time. However, with the availability of next generation sequencing tools, a few candidate genes encoding KS and KR domains in Karenia brevis have been associated with biosynthesis of BTXs [98]. A recent study published a comprehensive transcriptome library of Lingulodinium polydrum for which genes encoding KS domains were reported, however no link between these genes and YTX production has been established [99]. In the past, a few studies have identified genes encoding KS domains in Amphidinium sp. [100], which produces numerous macrolides (cyclised linear polyethers) such as amphidinolides. No studies have been done to identify genes involved in CTX and MTX biosynthesis. However, an extensive marine microbial eukaryote transcriptome project, undertaken by the Moore Foundation, is in the process of sequencing 652 trancriptomes, which includes 2 strains of Gambierdiscus species. Analysis of data obtained for such diverse arrays of dinoflagellate species may shed light on the genes involved in secondary metabolite synthesis in dinoflagellates.

9.5 Toxicity of different species of Gambierdiscus There is clear evidence that Gambierdiscus species produce CTXs and/or MTXs [24, 62, 66, 82, 101]. However, many wild and cultured strains of Gambierdiscus have not been found to produce detectable amounts of CTXs [23, 102]. Unfortunately, most of these studies describe the identity of the cultures as Gambierdiscus toxicus, since it was the only known species of Gambieriscus at that time. It is imperative to study the toxin profile of all of the species and genotypes now known (Tab. 9.2). Tab. 9.2 provides the data available on the toxicity of each species of Gambierdiscus detected via various assays and LC-MS (liquid chromatography-mass spectrometry)-based detection. In 2010, Chinain et al. [9] described the toxin profile of G. polynesiensis based on LC-MS analysis and receptor binding assay (RBA). This species produces both Type 1 (CTX-4A, CTX-4B) and Type 2 P-CTXs (CTX-3C, M-seco-CTX-3C, 49-epiCTX-3C), however P-CTX-3C was the major toxin produced by this species. Two different strains of G. polynesiensis were tested and found to produce same suite of toxins, in different proportions [9]. Similar results were found in a study of 56 strains of six different species (G. belizeanus, G. caribaeus, G. carolinianus, G. carpenteri, Gambierdiscus ribotype 2) over a period of two years, using the human erythrocyte lysis assay (HELA) [12]. The intraspecific toxicity varied slightly among different strains of same species, however the level of toxicity of each strain remained unchanged over the period of the study [12]. HELA assay toxicity is indicative of MTX production by the species. The water-soluble fraction of the extracts of G. polynesiensis has been found to be toxic via MBA [8], indicating the presence of MTXs. However, the toxins that produced this effect have not been characterized from this strain. Another species from the Caribbean, G. excentricus, may produce CTXs and MTXs (as determined via Neuro-2a cell based assay) [11], how-

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ever the exact toxin profile needs to be verified via LC-MS analysis. The toxicities of the liposoluble and water-soluble fractions of G. australes extracts, isolated from the Cook Islands, were found to be toxic via MBA, indicating the presence of CTXs and MTXs [10]. However no CTXs were detected via LC-MS analysis [10]. Another strain of G. australes from French Polynesia tested positive for CTXs via the RBA; however, the level of toxicity was low when compared to G. polynesiensis [9]. These results are intriguing and require further analysis. While bioassays are important to determine toxicity, only LC-MS-based analysis techniques can determine the exact toxin profile of different species of Gambierdiscus. As we only know the partial toxin profiles of two species of Gambierdiscus via LC-MS-based techniques, this area of research needs urgent attention.

9.6 Detection of CTXs and MTXs in seafood Originally, CFP was derived from the word “cigua”, used by native Cubans to describe a turban-shelled snail and implicated in an outbreak of the sickness in Spanish explorers to Cuba in the 1500s [103]. The occurrence of CTX in the turban snail Turbo argyrostoma has been confirmed [104]. However, to date, the majority of cases reporting occurrences of CFP have followed consumption of large reef fish (e.g. [105–108]). This circumstance has been a critical factor in the diagnosis of the disease, as in many cases there has been no fish sample retained for chemical verification or the appropriate test facilities have not been available. Although hundreds of cases of CFP have been documented worldwide, it is estimated that less than 20 % of actual cases have been reported [109]. There is a high likelihood of misdiagnosis for CFP. The number of documented symptoms, which are in excess of 175 [17], may vary depending on portion size [110], individual susceptibility or accumulation of toxin with age [15, 111] and could also be associated with other illnesses (e.g. decompression sickness [112], chronic fatigue syndrome, multiple sclerosis [113, 114] and brain tumors [113]). The number of fish species implicated in ciguatera outbreaks is suggested to be of the order of several hundred (Halstad, 1978, FAO, 2004). However, with the above limitations and the absence of a reliable, commercially available test kit, it is difficult to express an exact figure. While carnivorous fish are the main culprits, herbivorous fish (e.g. surgeonfish and parrotfish), a key component of the toxic food chain [115, 116], have also been linked to CFP outbreaks. Tab. 9.4 provides a summary of over 90 fish species and other marine fauna that have tested positive for CTXs, from ciguatera prone regions and following reported outbreaks.

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C-CTX-1 [71, 107]

CTX – positive [150]

The Bahamas [147], West Africa [49], Florida Keys, USA [107], French West Indies [71], St. Barthelemy, Caribbean Sea [144, 148], Guadeloupe [148], French Polynesia [149]

Hervey Bay, Queensland, Australia [150]

Sphyraena barracuda (Great barracuda)

Sphyraena jello (Pickhandle barracuda)

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TLC & MBA [150]

Cat BA [149], Chick BA [148], MQBA [149], MBA [149], N2A [147]

LCMS/MS [146], BSBA [126], MGBA [126], ELISA [129, 130], N2A [129, 130, 146]

C-CTX-1 [146]

Canary Islands [146], Hawaii [129, 130], St. Thomas, Carribean Sea [126]

Seriola rivoliana (Almaco jack-Kahala)

BarracudaC

LCMS/MS [145], UPLC/MS) [143]

C-CTX-1 [145], CTX-1B [143], CTX-3C and CTX analogues from Carribean or Indic waters) [143]

Selvagens Islands (Madeira Arquipelago) [143], West Africa [145]

UPLC/MS [143], HPLC/MS [134], TLC [144], BSBA [126], MGBA [124, 126], MBA [128, 131, 144], S-EIA [131], SPIA [143], RIA [128], ELISA [128, 129], N2A [129, 142], RBA [134]

Method of detection

Seriola fasciata (Lesser amberjack)

C-CTX-1 [134], CTX-1B [143], CTX-3C and CTX analogues from Carribean or Indic waters [143]

CTX (if detected)

Canary Islands [142], Selvagens Islands (Madeira Arquipelago) [143], Hawaii [124, 128, 129, 131], Haiti [134], St. Barthelemy, Caribbean Sea [144], St. Thomas, Carribean Sea [126]

Source

Seriola dumerili (Greater amberjack- Kahala)

AmberjackC

Latin name (Common name)

Tab. 9.4: Different congeners of Ciguatoxins detected by various assays in seafood and other animals.

290 | Gurjeet S. Kohli, Hazel Farrell, and Shauna A. Murray

California [132]

South Taiwan [151]

Sphyraena sp. (Barracuda)

Sphyraena spp. (Barracuda fish eggs)

Mulloidichthys auriflamma (Goldstriped goatfish)

CTX – positive [132]

CTX – positive [149]

French Polynesia [149]

Monotaxis grandoculis (Big eye bream)

Hawaii [132]

CTX – positive [149]

French Polynesia [149]

Lethrinus miniatus (Trumpet emperor)

GoatfishC

CTX – positive [54]

Nuku Hiva (Marquesas) [54]

Lethrinus olivaceus (Longface emperor)

S-EIA [132], SPIA [132]

Cat BA [149], MQBA [149], MBA [149]

Cat BA [149], MQBA [149], MBA [149]

RBA [54]

HPLC/MS [67, 152], HPLC/HNMR [62, 63, 120], TLC [153], DLBA [125], MBA [67, 152, 153]

CTX-1 [62, 63], CTX-4B [62, 63], CTX-2 [63], CTX-3 [63], P-CTX-1 [152], P-CTX-2 [152], P-CTX-3 [152] and analogues of CTX 3C: 2,3-dihydroxyCTX3C and 51-hydroxyCTX3C [67]

Tuamotu Archipelago and Tahiti (French Polynesia) [62, 120, 125], Tarawa, Republic of Kiribati, central Pacific Ocean [152], Hawaii [153]

Gymnothorax javanicus (Moray eel)

Emperor breamC

TLC [144], MBA [144]

CTX – positive [144]

MBA [151], N2A [151]

S-EIA [132], SPIA [132], N2A [132]

Method of detection

St. Barthelemy, Caribbean Sea [144]

CTX – positive [151]

CTX – positive [132]

CTX (if detected)

Gymnothorax funebris (Green Moray)

EelC

Source

Latin name (Common name)

Tab. 9.4 (continued)

9 Gambierdiscus, the cause of ciguatera fish poisoning |

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291

CTX – positive [155]

Rep. of Vanuatu [155]

Hippopus hippopus (Giant Clam)

CTX – positive[54, 129, 149] P-CTX-1 [60, 156, 157] CTX – positive [133] CTX – positive [158]

Nuku Hiva (Marquesas) [54], Hawaii [129], French Polynesia [149]

Fiji [60, 156], Arafura Sea, Australia [157]

Hong Kong [133]

Hong Kong [158]

Cephalopholis argus (Blue-spotted grouper, Roi)

Cephalopholis miniata (Coral cod/Coral grouper)

Epinephelus coioides (Orange-spotted grouper)

Epinephelus lanceolatus (Giant grouper)

GrouperC

CTX – positive [155]

New Caledonia, French Polynesia [155]

Tridacna sp. (Giant Clam)

Giant ClamH

Conus spp. (Cone snails)

CTX – positive [154]

CTX – positive [54]

Nuku Hiva (Marquesas) [54]

Parupeneus insularis (Twosaddle goatfish)

Hawaii [154]

CTX – positive [144]

St. Barthelemy, Caribbean Sea [144]

Mulloidichthys martinicus (Yellow goatfish)

GastropodC

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

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MBA [158]

MBA [133]

HPLC/MS [157], MBA [157], N2A [60, 156]

Cat BA [149], MQBA [149], MBA [149], ELISA [129], N2A [129], RBA [54]

N2A [155], RBA [155]

MBA [155], N2A [155], RBA [155]

Ciguatect® [154]

RBA [54]

TLC [144], MBA [144]

Method of detection

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CTX – positive [149] CTX – positive [126] CTX – positive [144] CTX – positive [159] C-CTX-1 [60], C-CTX-2 [60]

French Polynesia [149]

St. Thomas, Carribean Sea [126]

St. Barthelemy, Caribbean Sea [144]

Baja California, Mexico [159]

Key Largo, Florida, USA [60]

Epinephelus microdon (Marble grouper)

Epinephelus mystacinus (Misty grouper)

Epinephelus morio (Red grouper)

Epinephelus sp.

Mycteroperca bonaci (Black grouper)

MBA [110] Cat BA [149], MQBA [149], MBA [133, 149, 161], RBA [54]

CTX – positive [148] CTX – positive [133] CTX – positive [110] CTX – positive [54, 133, 149, 161]

Baja California, Mexico [159]

Guadeloupe and St. Barthelemy, Caribbean Sea [148]

Hong Kong [133]

Hong Kong [110]

French Polynesia, Tubuai (Australes) [54], Hong Kong [133], Tahiti [161], French Polynesia [149]

Mycteroperca sp.

Mycteroperca venenosa (Yellowfin grouper)

Plectropomus areolatus (Squaretail coral grouper)

Plectropomus laevis (Blacksaddled coral grouper)

Plectropomus leopardus (Coral trout/leopard coral grouper)

MBA [133]

Chick BA [148]

MBA [159]

CTX – positive [159]

Baja California, Mexico [160]

HPLC/MS [160], MBA [160]

LCMS/MS [60], N2A [60]

MBA [159]

TLC [144], MBA [144]

BSBA [126], MGBA [126]

Cat BA [149], MQBA [149], MBA [149]

Method of detection

Mycteroperca prionura (Sawtail grouper)

CTX-1 [160]

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

9 Gambierdiscus, the cause of ciguatera fish poisoning |

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293

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Caranx ignobilis (Giant trevally (ulua))

Jacks and

French Polynesia, Tubuai (Australes) [54], St. Barthelemy, Caribbean Sea [144]

Hawaii [132]

Bodianus sp.

CTX – positive [54, 131]

CTX – positive [132]

CTX – positive [144]

St. Barthelemy, Caribbean Sea [144]

Bodianus rufus (Spanish hogfish)

ScadsC

CTX – positive [131]

Hawaii [131]

Bodianus bilunulatus (Tarry hogfish (a’awa))

HogfishC

Pomadasys maculatus (Blotched javelin)

CTX-1 [162], CTX-2 [162], CTX-3 [162]

CTX – positive [110]

Hong Kong [110]

Variola albimarginata (Lyretail)

Platypus Bay, Queensland, Australia [162]

C-CTX-1 [70, 163], C-CTX-2 and isomers [70, 163], CTX congeners, other compounds [70, 163]

French West Indies [70, 163]

Serranidae

GruntC

CTX-1 [162], CTX-2 [162], CTX-3 [162]

Great Barrier Reef, Australia [162]

Plectropomus spp. (Coral trout)

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

MBA [131], S-EIA [131], RBA [54]

SPIA [132]

TLC [144], MBA [144]

MBA [131], S-EIA [131]

HPLC/MS [162], MBA [162]

MBA [110]

MBA [70, 163]

HPLC/MS [162], MBA [162]

Method of detection

294 | Gurjeet S. Kohli, Hazel Farrell, and Shauna A. Murray

CTX – positive [54]

French Polynesia, Tubuai (Australes) [54]

Hawaii [131, 132]

Caranx papuensis (Brassy trevally)

Caranx sp. (Trevally (ulua, papio))

LCMS/MS [60], TLC [144], Chick BA [148], MBA [144], N2A [60] HPLC/MS [162], TLC [135], MBA [135, 150, 162]

C-CTX-1 [60], C-CTX-2 [60]

CTX-1 [162], CTX-2 [162], CTX-3 [162]

Hervey Bay, Queensland, Australia [150], Hervey Bay, Queensland, Australia [135]

Scomberomorus commerson (Spanish mackerel)

SPIA [164]

Florida, USA [60], St. Barthelemy, Caribbean Sea [144, 148], Guadeloupe [148]

CTX – positive [164]

MBA [131], S-EIA [131, 132] SPIA [131, 132]

RBA [54]

Cat BA [149], MQBA [149], MBA [149], RBA [54]

Scomberomorus cavalla (King mackerel “Coronado” (Kingfish))

MackeralO

Cnidaria sp.

American Samoa [164]

CTX – positive [54, 149]

Nuku Hiva (Marquesas) [54], French Polynesia [149]

Caranx melampygus (Bluefin trevally)

JellyfishO

C-CTX-1 and isomers, CTX congeners [70, 163]

French West Indies [70, 163]

Caranx lugubris (Black jack)

CTX – positive [131, 132]

HPLC/MS [68–70, 163], BSBA [126], Cat BA [123], MGBA [126], MBA [68, 70, 163]

12 CTXs (inc C-CTX-1, C-CTX-1a, C-CTX-2) [70, 163], C-CTX-1 [68, 69] and C-CTX-2 [68, 69]

French West Indies [70, 163], St. Barthelemy, Caribbean Sea [68, 69], The Bahamas [123], St. Thomas, Carribean Sea [126]

Caranx latus (Horse-eye jack)

MBA [70, 163]

Method of detection

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

9 Gambierdiscus, the cause of ciguatera fish poisoning |

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295

CTX – positive [54] CTX – positive [54] CTX – positive [54] CTX – positive [54] CTX-4A [101] CTX – positive [149]

French Polynesia, Tubuai (Australes) [54]

French Polynesia, Tubuai (Australes) [54]

French Polynesia, Tubuai (Australes) [54]

French Polynesia, Tubuai (Australes) [54]

French Polynesia [101], Tahiti [161], French Polynesia [149]

French Polynesia [149]

Chlorurus microrhinos (Steephead parrotfish)

Scarus altipinnis (Filament-finned parrotfish)

Scarus ghobban (Blue-barred parrotfish)

Scarus gibbus (Heavy beak parrotfish)

Scarus jonesi

CTX-3C [165]

Chlorurus frontalis (Pacific slopehead parrotfish)

ParrotfishH

Oplegnathus punctatus (Spotted knifejaw)

Miyazaki, Japan [165]

CTX – positive [54]

Nuku Hiva (Marquesas) [54]

Liza vaigiensis (Thinlip grey mullet)

KnifejawO

CTX – positive [54]

CTX (if detected)

Nuku Hiva (Marquesas) [54], French Polynesia [149]

Source

Crenimugil crenilabis (Fringelip mullet)

MulletO

Latin name (Common name)

Tab. 9.4 (continued)

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Cat BA [149], MQBA [149], MBA [149]

HPLC/HNMR [101], MQBA, MBA [101, 149, 161]

RBA [54]

RBA [54]

RBA [54]

RBA [54]

HPLC/MS [165]

RBA [54]

MQBA [149], MBA [149], RBA [54]

Method of detection

296 | Gurjeet S. Kohli, Hazel Farrell, and Shauna A. Murray

CTX – positive [132]

CTX – positive [149]

French Polynesia [149]

Aprion virescens (Bluge green snapper)

P-CTX-3C [171]

CTX – positive [169, 170]

CTX – positive [54]

CTX – positive [167, 168]

Hawaii [132]

Hawaii [171]

Hawaii [169, 170]

French Polynesia, Tubuai (Australes) [54], Nuku Hiva (Marquesas) [54]

Chile [167, 168]

CTX – positive [166]

Aphareus furca (Black forktail snapper (wahanui))

SnapperC

Monachus schauinslandi (Hawaiian monk seal)

SealC

Holothuria spp.

Sea cucumberH

Kyphosus cinerascens (Blue sea chub)

Sea

chubO

Farmed salmon

SalmonO

Siganus rivulatus (Marbled spinefoot)

Eastern Mediterranean [166]

CTX – positive [54]

Nuku Hiva (Marquesas) [54]

Scarus rubroviolaceus (Ember parrotfish)

RabbitfishH

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

Cat BA [149], MQBA [149], MBA [149]

S-EIA [132], SPIA [132]

LCMS/MS [171], N2A [171]

Ciguatect® [169, 170]

RBA [54]

SPIA [167, 168]

Cigua-check® [166]

RBA [54]

Method of detection

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297

HPLC/MS [72, 73], Cat BA [149], MGBA [72, 73], MQBA [149], MBA [72, 73, 149], RBA [54]

I-CTX-1 [72, 73], CTX-1B [165]

CTX – positive [127] CTX – positive [54, 149] C-CTX-1 and isomers [70, 163], CTX congeners [70, 163] CTX – positive [131] CTX – positive [54] I-CTX [72, 73], I-CTX-2 [72, 73], I-CTX-3 [72, 73], I-CTX-4 [72, 73]

Republic of Mauritius [72, 73], Minamitorishima (Marcus) Island, Japan [165], French Polynesia, Tubuai (Australes) [54] ,Nuku Hiva (Marquesas) [54], Hawaii [132], French Polynesia [149]

St. Croix, US Virgin Islands [127]

Nuku Hiva (Marquesas) [54], French Polynesia [149]

French West Indies [70, 163]

Hawaii [131]

Nuku Hiva (Marquesas) [54]

Republic of Mauritius (Nazareth, Saya de Malha, Soudan) [72, 73]

Lutjanus bohar (Two spot red snapper (red bass))

Lutjanus buccanella (Blackfin snapper)

Lutjanus gibbus (Humpback red snapper)

Lutjanus griseus (Grey snapper)

Lutjanus kasmira (Bluestripe snapper (taape))

Lutjanus monostigma (One-spot Snapper)

Lutjanus sebae (Red emperor)

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HPLC/MS [72, 73], HPLC/MS/RLB [72, 73], MGBA [72, 73], MBA [72, 73]

RBA [54]

MBA [131], S-EIA [131], SPIA [131]

MBA [70, 163]

MQBA [149], MBA [149], RBA [54]

TLC [127], MBA [127]

MBA [110]

CTX – positive [110]

Hong Kong [110]

Lutjanus argentimaculatus (Mangrove red snapper)

Method of detection

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

298 | Gurjeet S. Kohli, Hazel Farrell, and Shauna A. Murray

CTX – positive [131]

CTX – positive [131]

Hawaii [131]

Acanthurus nigroris (Bluelined surgeonfish (maiko))

CTX – positive [154]

CTX – positive [54]

CTX – positive [131]

Hawaii [131]

Hawaii [154]

Nuku Hiva (Marquesas) [54]

Hawaii [131]

Acanthurus dussumieri (Dussumier’s surgeonfish (palani))

SurgeonfishH

Ophiocoma spp. (Ophiuroids (brittle stars))

StarfishO

Sargocentron spiniferum (Sabre squirrelfish)

Myripristis kuntee (Epaulette Soldierfish (squirrelfish))

Squirrelfish and SoldeirfishC

MBA [131], S-EIA [131]

MBA [131], S-EIA [131]

Ciguatect® [154]

RBA [54]

MBA [131], S-EIA [131], SPIA [131]

MBA [110]

CTX – positive [110]

Hong Kong [110]

Lutjanus stellatus (Star snapper)

HPLC/MS [165], BSBA [126], MGBA [126], MBA [172], S-EIA [132], SPIA [132], N2A [49]

CTX-1B [165]

Antigua [132], Okinawa, Japan [165], West Africa [49], Baja California, Mexico [172], St. Thomas, Carribean Sea [126]

Lutjanus spp. (Snapper)

Method of detection

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

9 Gambierdiscus, the cause of ciguatera fish poisoning |

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299

CTX – positive [54]

Nuku Hiva (Marquesas) [54]

Acanthurus xanthopterus (Yellowfin surgeonfish)

CTX – positive [54] CTX – positive [54] CTX – positive [54]

Nuku Hiva (Marquesas) [54]

Nuku Hiva (Marquesas) [54]

Naso brevirostris (Spotted unicornfish)

Naso hexacanthus (Sleek unicornfish)

CTX – positive [54]

CTX – positive [144]

Nuku Hiva (Marquesas) [54]

Nuku Hiva (Marquesas) [54], French Polynesia [149]

St. Barthelemy, Caribbean Sea [144]

Naso brachycentron (Humpback unicornfish)

UnicornfishC

Gymnosarda unicolor (Dogtooth tuna)

TunaC

Malacanthus plumieri (Sand tilefish)

TilefishC

CTX – positive [54, 173]

CTX – positive [132]

Hawaii [132]

Acanthurus sp.

Nuku Hiva (Marquesas) [54], Tahiti [173]

CTX – positive [131]

Hawaii [131]

Acanthurus olivaceus (Orangeband surgeonfish (naenae))

Ctenochaetus striatus (Striped Bristletooth)

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

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RBA [54]

RBA [54]

RBA [54]

Cat BA [149], MQBA [149], MBA [149], RBA [54]

TLC [144], MBA [144]

RBA [54]

RBA [54]

S-EIA [132], SPIA [132]

MBA [131], S-EIA [131]

Method of detection

300 | Gurjeet S. Kohli, Hazel Farrell, and Shauna A. Murray

CTX – positive [54, 149] CTX – positive [54]

Nuku Hiva [54, 149] (Marquesas)

Nuku Hiva (Marquesas) [54]

Naso lituratus (Orangespine unicornfish)

Naso unicornis (Bluespine unicornfish)

Baja California, Mexico [159]

Semicossyphus sp.

MBA [159]

RBA [54]

Cat BA [149], MQBA [149], MBA [133, 149]

RBA [54]

Cat BA [149], MQBA [149], MBA [149], RBA [54]

Method of detection

The abbreviations are: LC-MS/MS: liquid chromatography tandem mass spectrometry, UPLC/MS: ultra performance liquid chromatography/mass spectrometry, HPLC/MS: high performance liquid chromatography/mass spectrometry, HPLC/HNMR: high performance liquid chromatography/H nuclear magnetic resonance, HPLC/MS/RLB: high performance liquid chromatography/mass spectrometry/radio ligand binding, TLC: thin layer chromatography, BSBA: brine shrimp bioassay, DLBA: diptera larvae bioassay, MGBA: mongoose bioassay, MQBA: mosquito bioassay, MBA: mouse bioassay, SEIA: stick enzyme immunoassay, SPIA: solid phase immunoassay, RIA: radioimmunoassay, ELISA: enzyme-linked immunosorbent assay, N2A: neuroblastoma cytotoxicity assays, RBA: receptor-binding assay, MA: membrane assay, BA: bioassay.

Typical feeding behavior: C: carnivore, H: herbivore, O: omnivore.

CTX – positive [54]

French Polynesia, Tubuai (Australes) [54]

Coris aygula (Clown coris) CTX – positive [159]

CTX – positive [133, 149]

French Polynesia [149], Hong Kong [133]

Cheilinus undulatus (Humphead Wrasse)

WrasseC

CTX (if detected)

Source

Latin name (Common name)

Tab. 9.4 (continued)

9 Gambierdiscus, the cause of ciguatera fish poisoning |

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301

302 | Gurjeet S. Kohli, Hazel Farrell, and Shauna A. Murray

The CTX-positive cases in Tab. 9.4 are predominantly concerned with the mid-latitude tropical and sub-tropical zones. This is fitting with the distribution of Gambierdiscus as described in Tab. 9.2. However, CFP has also been reported in non-endemic areas because of an increase in seafood imports [114, 117]. While the majority of studies have focused on reef fish, toxin accumulation has been observed in eels, sea cucumbers, starfish, seals and jellyfish (see Tab. 9.4 and references therein). Sharks have also been suspected of causing CFP following outbreaks of human illness, remnant samples for testing were unavailable [118, 119]. Further studies are required to address the deficit in information for species other than fish and to identify potential toxin vectors in coastal systems. For the most part, CFP studies have focused on CTX rather than MTX. The MBA has been used previously to test for MTX, with positive results in Ctenochaetus striatus (striped bristletooth) (Bagnis et al., 1986). A gap in our existing knowledge is whether the presence of MTX in small (herbivorous) fish species is transferred up the food chain to larger carnivorous species. Often, in small island nations, native fishermen are aware of ciguatera prone zones and avoid certain fish species. Such knowledge certainly has its merits; however, a study by [54] in French Polynesia demonstrated the presence of CTXs in fish species that were considered safe to eat by locals. Experimentally, CTX toxin profiles and structures have been determined by chromatographic techniques (HPLC, UPLC and LC-MS), accompanied by nuclear magnetic resonance (NMR) [62, 63, 101, 120] and radio ligand binding (RLB) [72, 73]. However, these methods are not commonplace or practical for routine testing, as they are costly and require special expertise. Confirmation of toxin by UPLC/HPLC followed by LC-MS involves the isolation and fractionation of the various CTX compounds and their known molecular weights (see Tab. 9.3). Although a rapid method for sample analysis has been proposed [121], acquiring purified CTX standards is problematic due to the limited supply of natural CTX compounds [48]; though artificial synthesis of CTX is possible [122], it is highly complex. Without a consistent source of reference material, absolute quantification of CTXs and their congeners is hard to achieve. In addition, technical issues such as co-eluting peaks of similar compounds and inhibiting/promoting matrix effects remain unresolved. Several biological assays have been developed for the detection of ciguateric fish. These have included the use of chickens (Pottier et al., 2000), cats [123], mongooses [124], diptera larva [125], brine shrimp [126] and mosquitos (Bagnis et al., 1987). However, each assay has its own constraints and limitations, largely relating to toxin specificity and quantification, but also due to inefficiencies and ethical considerations (summarized in de Fouw, 2001, [109]). While the MBA by intraperitoneal injection does not provide a linear dose-response relationship with CTX toxicity [127], it remains the most widely used biological assay (see Tab. 9.4). Numerous biochemical assays have been proposed as alternatives to biological assays for testing seafood. The development of a radioimmunoassay [124] progressed to a cheaper alternative enzyme-linked immunosorbent assay (ELISA) with higher throughput [128]. The ELISA test has recently shown promising correlations with

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9 Gambierdiscus, the cause of ciguatera fish poisoning

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303

biological assays [129, 130]. Stick enzyme immunoassay (SEIA) [131] and solid phase immunoassay (SPIA) [132] tests have led to the development of commercial kits (i.e. Cigua-check® and Ciguatect® ). However, these products have yielded a large number of false positive and false negative results [133] and the Cigua-check® test is no longer being manufactured. Other assays utilized for screening CTXs in fish are the sodium channel binding assay (N2A) [60] and RBA [54, 134]. Both of these assays have shown promising results and have been recommended by the European Food Standard Association (EFSA, 2010). These assays cannot quantify specific congeners of CTXs and MTXs. This can only be achieved via further development and validation via LC-MS analysis, and there is an urgent need to do so. The progress has been disadvantaged by the lack of available purified standards (Guzman-Perez and Park, 2000). Other challenges are the presence of more than one type of CTXs, (see Tab. 9.3) being present in fish specimens [68, 135].

9.7 Conclusion Since its recognition as the source of CFP, major advances have been made in the study of Gambierdiscus species.Concurrently, new questions and challenges have also been raised. Here, we outline the major areas needing research efforts to significantly advance our understanding of the causes of the production of toxins leading to CFP: 1. It is highly likely that species of Gambierdiscus vary in their toxicity, whereas intraspecific toxin production appears to be more consistent. Exact Gambierdiscus species identifications in CFP affected areas around the world are therefore required. New molecular and taxonomic tools to identify Gambierdiscus species accurately and simply will therefore be required. 2. Toxin profiles of Gambierdiscus strains and species are needed to identify the exact CTXs and MTXs produced. 3. The development and standardization of chromatographic techniques to accurately quantify different CTXs and MTXs are required. This involves a further characterization of already known and new congeners of CTXs and MTXs. 4. The development of commercially available CTX and MTX standards is very important, as it is one of the major hurdles that prevent further advancement of areas mentioned in the above two goals. 5. The elucidation of genes involved in biosynthesis of CTX and MTX in Gambierdiscus species will allow for an increased understanding of the causes and triggers of toxin production and the potential for the development of novel CFP monitoring tools.

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