Next Article in Journal
Study on the Mechanism of Mesaconitine-Induced Hepatotoxicity in Rats Based on Metabonomics and Toxicology Network
Next Article in Special Issue
Effects of Various Marine Toxins on the Mouse Intestine Organoid Model
Previous Article in Journal
Impact of Cyanotoxin Ingestion on Liver Cancer Development Using an At-Risk Two-Staged Model of Mouse Hepatocarcinogenesis
Previous Article in Special Issue
Toxic Responses of Different Shellfish Species after Exposure to Prorocentrum lima, a DSP Toxins Producing Dinoflagellate
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Toxins
Volume 14
Issue 7
10.3390/toxins14070485
toxins-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Gambierdiscus and Its Associated Toxins: A Minireview

by
Da-Zhi Wang
*,
Ye-Hong Xin
and
Ming-Hua Wang
State Key Laboratory of Marine Environmental Science, College of the Environment and Ecology, Xiamen University, Xiamen 361105, China
*
Author to whom correspondence should be addressed.
Toxins 2022, 14(7), 485; https://doi.org/10.3390/toxins14070485
Submission received: 2 May 2022 / Revised: 11 July 2022 / Accepted: 12 July 2022 / Published: 14 July 2022
(This article belongs to the Special Issue Marine Biotoxins: Predicting and Cumulative Risk Assessment)
Browse Figures
Review Reports Versions Notes

Abstract

:
Gambierdiscus is a dinoflagellate genus widely distributed throughout tropical and subtropical regions. Some members of this genus can produce a group of potent polycyclic polyether neurotoxins responsible for ciguatera fish poisoning (CFP), one of the most significant food-borne illnesses associated with fish consumption. Ciguatoxins and maitotoxins, the two major toxins produced by Gambierdiscus, act on voltage-gated channels and TRPA1 receptors, consequently leading to poisoning and even death in both humans and animals. Over the past few decades, the occurrence and geographic distribution of CFP have undergone a significant expansion due to intensive anthropogenic activities and global climate change, which results in more human illness, a greater public health impact, and larger economic losses. The global spread of CFP has led to Gambierdiscus and its toxins being considered an environmental and human health concern worldwide. In this review, we seek to provide an overview of recent advances in the field of Gambierdiscus and its associated toxins based on the existing literature combined with re-analyses of current data. The taxonomy, phylogenetics, geographic distribution, environmental regulation, toxin detection method, toxin biosynthesis, and pharmacology and toxicology of Gambierdiscus are summarized and discussed. We also highlight future perspectives on Gambierdiscus and its associated toxins.
Keywords:
Gambierdiscus; ciguatoxins; maitotoxin; ciguatera fish poisoning
Key Contribution: We summarize the progress concerning the taxonomy, phylogenetics, geographic distribution, role of environmental factors, toxin detection method, toxin biosynthesis, pharmacology, and toxicology of Gambierdiscus and discuss the future perspectives for Gambierdiscus and its associated toxins.

Graphical Abstract

1. Introduction

Gambierdiscus is a marine benthic dinoflagellate genus widely distributed throughout the world’s tropical and subtropical regions [1]. Gambierdiscus species are autotrophic benthic microalgae living on macrophytes, corals, and sand grains [2,3]. Members of this genus are notorious for producing a group of potent polycyclic polyether neurotoxins that can specifically activate voltage-gated sodium channels (Nav) [4] and inhibit neuronal potassium channels (Kv) [5], which increases neuronal excitability and, consequently, results in human disease. Ciguatoxins (CTXs) and maitotoxins (MTXs) are the two major toxins produced by Gambierdiscus [6,7]. CTXs can accumulate in benthic-feeding organisms and can subsequently bioconcentrate in top-predator reef fishes through transfer along the food chain [8]. When humans ingest CTX-contaminated fish or shellfish, they can develop a type of food poisoning known as ciguatera fish poisoning (CFP; or just ciguatera) [6,9,10,11]. Although the symptoms of CFP are nonspecific, they primarily manifest in the digestive, joint, muscle, cardiovascular, and nervous systems [12]. It was estimated that ciguatera affects 50,000–500,000 people worldwide every year [13]. Although this disease has existed for centuries, its diagnosis, prevention, treatment, and management still present major challenges [14,15].
Over the past few decades, substantial research effort has been devoted to Gambierdiscus and its toxins [16,17,18], and great advancements have been made in deciphering its taxonomy, phylogenetics, geographic distribution, toxin detection method, biosynthesis, toxicology, and pharmacology [19,20,21,22]. Notably, the occurrence and geographic distribution of CFP have undergone a considerable expansion due to intensive anthropogenic activities and global climate change, rendering it a worldwide concern [23]. The clinical features, pathophysiological basis [15], distribution [24], and detection method [25] of Gambierdiscus-induced CFP have been reviewed, but a systematic review of Gambierdiscus and its associated toxins is still lacking. In this review, we seek to fill the above knowledge gaps and refresh our understanding of Gambierdiscus and its associated toxins. We summarize the progress concerning the taxonomy, phylogenetics, geographic distribution, role of environmental factors, toxin detection method, toxin biosynthesis, pharmacology, and toxicology of Gambierdiscus and discuss the future perspectives for Gambierdiscus and its associated toxins.

2. Taxonomy and Phylogenetics of Gambierdiscus

Gambierdiscus (Gonyaulacales, Dinophyceae) species are armored, benthic dinoflagellates predominantly living in coral reef ecosystems attached through mucous filaments to the surfaces of macroalgae, seagrasses, and other substrata [3,26]. The morphology of Gambierdiscus has been extensively studied since 1978. Cells are large-sized (diameter 42 to 140 µm) [27], with strong anteroposterior compression and an ascending cingulum with a recurved distal end, and contain several yellow to brown chloroplasts [28]. Gambierdiscus species are traditionally identified based on subtle differences in their thecal plate morphology as observed under light microscopy and scanning electron microscopy [28,29]. According to the Kofoidian nomenclature of dinoflagellate thecal plate series for armored species, the theca is divided into various plates, such as apical pore (Po), apicals (′), precingulars (″), postcingulars (′′′), and antapicals (′′′′), among others. For Gambierdiscus, the plate formula is Po, 3′, 7″, 6c, 6-8s, 5′′′, 1p, 2′′′′ (Figure 1) [30,31]. Litaker et al. used dichotomous trees to distinguish 10 Gambierdiscus species based on their cell size, shape, and plate structure [30]. To date, a total of 18 Gambierdiscus species have been identified, including G. australes, G. balechii, G. belizeanus, G. caribaeus, G. carolinianus, G. carpenteri, G. cheloniae, G. excentricus, G. honu, G. jejuensis, G. lapillus, G. pacificus, G. lewisii, G. holmesii, G. polynesiensis, G. scabrosus, G. silvae, and G. toxicus [32], while some have yet to be classified.
However, it remains challenging to distinguish different Gambierdiscus species based on morphology alone because of their high similarities (Figure 1). Furthermore, the morphological approach alone does not properly allow an accurate identification at the species level and should be combined with molecular analysis. The sequencing of ribosomal (r) RNA-encoding DNA, including SSU rRNA, D1–D3 LSU rRNA, and D8–D10 rRNA genes, has been employed for the identification of Gambierdiscus species since the 1990s [33,40,41]. Gambierdiscus species show similar phylogenetic relationships in phylogenetic trees constructed based on different rRNA gene regions (Figure 2). The SSU region exhibits a lower substitution rate among species and a higher substitution rate among genera, while the LSU region displays the opposite trend (Figure 2). This is consistent with a study that showed that, in some dinoflagellates, the D1–D6 regions of the LSU rRNA gene have a substitution rate 4–8% faster than that for the whole SSU rRNA gene sequence [42]. The D8–D10 rRNA gene is the most commonly reported of the three sequences in the NCBI database, suggesting that the D8–D10 rRNA gene is the most suitable for identifying Gambierdiscus species. Notably, the classification of G. carpenteri in the phylogenetic trees constructed using D8–D10 rDNA and SSU rDNA is not uniform (marked in black in Figure 2), indicating that care must be taken when using these sequences to identify this species.
It should be pointed out that some species from the genus Fukuyoa, other important benthic algae resulting in CFPs [43,44], were classified in Gambierdiscus before 2015 due to their high morphological similarity and were often studied and discussed alongside Gambierdiscus [44,45,46]. However, recent studies showed that these two genera not only differ in morphology (species in Gambierdiscus with lenticular shape, and species in Fukuyoa with globular shape) but also belong to different branches based on the sequencing results of LSU (large subunit) and SSU (small subunit) ribosomal DNA [47]. Therefore, the following discussion is focused on Gambierdiscus, considering its more diverse and broader distribution than Fukuyoa in the ocean, as well as its ecological and human health concern.

3. Geographic Distribution and Role of Environmental Factors

Traditionally, Gambierdiscus species were viewed as pantropical organisms and widely distributed throughout tropical and subtropical regions of the world [28,30,42], especially in coastal areas of the Caribbean Sea [48,49], Indian Ocean [50], and Pacific Ocean [51] (Figure 3). However, the presence of Gambierdiscus has also been reported in temperate waters, including the nearshore waters of Australia [20], Japan [52], and the Mediterranean [28].
To further understand the global distribution of Gambierdiscus, we constructed a phylogenetic evolutionary tree using the D8–D10 LSU and SSU rRNA regions combined with the distribution information obtained from the Ocean Biodiversity Information System and the IOC Harmful Algal Bloom Programme [44,53,54]. In a phylogenetic analysis-based study, Litaker et al. (2010) reported that five Gambierdiscus species are endemic to the Atlantic (including the Caribbean/West Indies and the Gulf of Mexico), five are endemic to the tropical Pacific, and that two (G. carpenteri and G. caribaeus) are globally distributed. However, G. belizeanus, an Atlantic species following Litaker et al. [55], was later reported in the Central Pacific by Xu et al. [56], suggesting that some Gambierdiscus species might have been transferred via modern shipping activities [57]. Rodríguez et al. suggested that the Canary Islands (North-East Atlantic) could represent ancient settlement sites for Gambierdiscus as suggested by the high species diversity in the area [58], however, there is still not enough evidence to prove this hypothesis. The dispersal–vicariance analysis performed in this study using RASP (Figure 3) [59] shows that some widely distributed species, such as G. carpenteri and G. caribaeus, are scattered in different clades of the tree.
The growth and proliferation of Gambierdiscus cells are influenced by diverse environmental factors, among which temperature, salinity, and irradiance are thought to be key [60,61,62,63,64,65]. Laboratory studies have shown that the capacity for environmental adaptation of Gambierdiscus shows marked variation among species and even within species [66]. For example, G. belizeanus, G. caribaeus, G. carpenteri, and G. pacificus generally exhibit a wider range of tolerance to environmental conditions [66], consistent with their broad geographic distribution (Figure 3). In contrast, G. silvae, G. australes, G. scabrosus, and G. jejuensis showed a narrow range of tolerance to temperature, salinity, or irradiance [33,66,67]. Gambierdiscus achieves maximum cell growth in the temperature range of 25–31 °C. Both field observations and laboratory experiments have shown that some Gambierdiscus species, such as G. carolinianus and G. caribaeus, can tolerate low-temperature environments (<20 °C) [62,68]. Unlike most strains of G. caribaeus and G. carpenteri, which can survive at temperatures ranging from 33.6 and 35.4 °C, G. jejuensis strains cannot tolerate water temperatures above 30 °C [33]. G. jejuensis and G. carpenteri share the same clade in the phylogenic tree (marked in red lines in Figure 2), indicating that evolutionarily similar species can have differential capabilities for environmental adaptation. Several pan-genome analyses have been undertaken to examine the adaptation to the environment and the evolution of organisms from different habitats [69,70,71], however, no publicly available genome database currently exists for any Gambierdiscus species. If the warmer waters can meet their growth requirements, there may be a positive correlation between temperature and Gambierdiscus abundance [72]. Over the past 10 years, the number of Gambierdiscus occurrence areas and the number of CFP cases reported from tropical and subtropical regions have increased due to ocean warming [73,74]. Irrespective of whether these distributions in temperate habitats are temporary or permanent, the expanding distribution of some Gambierdiscus species is linked to the risk of broadening the endemic range of CFP occurrence.
Salinity is another important environmental factor affecting the distribution and growth of Gambierdiscus. The global distribution of Gambierdiscus species is linked to their capacity for adaptation to varying salinity [62]. Most species achieve their maximum growth in the salinity range of 25–35 [60,61,64,65]; however, some species, such as G. caribaeus, can adapt to a wider salinity range (15–40) [67].
Members of the Gambierdiscus genus depend on light to produce energy for their physiological activities [75]. As a typical benthic genus, Gambierdiscus achieves optimum growth under low irradiance conditions (49–231 μmol photons m−2 s−1) in the laboratory [62,75]. In the natural environment, deeper water layers may have weaker light conditions. But in the study of Xv et al., higher abundances of Gambierdiscus species were observed in shallower waters than in deeper waters, however, this is not yet certain to be related to the difference in light intensity [56]. Another study showed that there is no significant relationship between depth and Gambierdiscus [76]. Notably, not all Gambierdiscus are affected by photoinhibition (e.g., G. silvae) [75]. The strategies used by different Gambierdiscus species to adapt to different light intensities, especially low light intensity, remain to be explored.
Interestingly, nutrients are key factors affecting phytoplankton growth, but there are still no studies demonstrating significant effects of their concentration, types, and ratios on the cell growth of Gambierdiscus [68,77]. In addition to temperature, salinity, and irradiance, grazing pressure is also an important factor regulating Gambierdiscus abundance in the field. As an epiphytic dinoflagellate, Gambierdiscus cells are first consumed by herbivorous fish grazing on macroalgae that host them, then these cells are further transferred to carnivorous fish, such as grouper or snapper, through the trophic chain, which affects cell abundance. Meanwhile, ciguatoxins produced by Gambierdiscus are accumulated in these fishes, especially in fatty tissues, liver, viscera, and eggs, which provides new insights to address the prevalence of toxicity in the food web [76]. Overall, these studies indicated that the effect of environmental factors on Gambierdiscus is complicated, and more efforts should be devoted to interactions between different Gambierdiscus species and environmental factors to enhance our understanding of Gambierdiscus in future marine environments under the frame of global climate change.

4. Gambierdiscus-Associated Toxins

Many species in the genus Gambierdiscus can produce CTXs and/or MTXs, as well as their analogs (Table 1) [28,31]. These toxins are responsible for cases of CFP worldwide and pose a potential risk to human health. To date, more than 30 CTX congeners have been identified. They are classified into CTX3C, Caribbean Sea CTXs (C-CTXs) [78], Pacific Ocean CTXs (P-CTXs/CTX4A) [12], and Indian Ocean CTXs (I-CTXs) [79] based on the make-up of the structural backbone of each molecule [80]. CTXs are lipophilic, ladder-shaped polyethers with 13–14 cyclic consecutively connected rings (Figure 4) [81] and have similar structures to yessotoxins and brevetoxins.
Although some MTXs display higher toxicity than CTXs, their roles in CFP are still unknown [10], likely because MTXs have lower oral potency and greater water solubility than CTXs, the latter of which renders it difficult for MTXs to accumulate in fish and invertebrates [91]. Although MTX was first isolated from surgeonfish (Ctenochaetus striatus, “maito” in Tahiti) [92], it was then found to be produced by G. polynesiensis, G. australes, G. belizeanus, and G. excentricus. To date, six congeners of MTX have been identified, and most have been structurally elucidated [93,94]. Using ChemDraw (v20), we predicted and compared the 2D and 3D structures of Gambierdiscus-associated toxins (Figure 4). Like CTXs, MTXs are also polyether compounds, but the molecular masses of different MTXs vary greatly. Most MTXs are larger than CTXs, but part of their structure is similar to that of CTXs (Figure 4) [95].
In addition to CTXs and MTXs, members of the genus Gambierdiscus also produce gambieric acids (GAs), gambieroxide, gambierol, and gambierones [24,96]. GAs are polycyclic ethers first isolated from indoor-cultured G. toxicus [88]. They have since been detected, together with CTX homologs, in shark tissues [97]. Four types of GA have been identified, named GA A–D. GAs have antifungal activities, especially against filamentous fungi [88]. In addition to defense functions, GAs are also thought to have a role in the regulation of G. toxicus growth [24]. Gambieroxide is a type of epoxy polyether compound first isolated from G. toxicus strain GTP2 from Tahiti (French Polynesia). Gambieroxide has putatively been detected in G. australes strains from Menorca and Mallorca (Balearic Islands, Spain) [83]. The structure of gambieroxide is very similar to that of yessotoxin, containing 12 contiguous trans-fused rings comprising 6–8 carbons, one sulfate ester group, one epoxide, and two olefins in their side chains [89]. Gambierol is a ladder-shaped, trans-fused, octacyclic ring system with 43 carbons and high lipophilicity [98]. This toxin can bind to voltage-gated potassium channels in several tissues, thereby inhibiting K+ currents [99,100]. Gambierones are also polyketide compounds isolated from G. belizeanus (strain CCMP401). They contain a noncyclic polyether core with a complex side chain at both extremes. Gambierones purified from G. cheloniae CAWD232 exhibit substantially lower toxicity than P-CTX1B, indicating that gambierones are unlikely to be hazardous to human health [86]. Overall, these biologically active substances render Gambierdiscus potentially suitable for application in the field of biomedicine.

5. Toxin Detection Methods

Identifying toxic species and/or strains is an efficient strategy for the prevention of CFP at the source. However, the ability of different Gambierdiscus species to produce toxins cannot be predicted based on rDNA. Although different Gambierdiscus species can produce the same toxins (Table 1), suggesting that members of this genus may have acquired the ability to produce toxins early in their evolution, even different strains of the same species can display widely varying capabilities for toxin production [44,101,102,103]. Accordingly, there is an urgent need to develop in situ methods that can measure the toxicity of Gambierdiscus species. Techniques involving fluorescence in situ hybridization (FISH) probes and recombinase polymerase amplification have been developed and applied in the field for the in situ detection of Gambierdiscus spp. as well as other species that cause CFP [104,105,106]. FISH probes allow the in situ counting of Gambierdiscus. Recombinase polymerase amplification can detect the presence of even a single Gambierdiscus cell and shows high species specificity [107]. Notably, probe design in these methods is still based on rDNA sequences [104]. Toxin gene-based species detection techniques have been widely used to detect pathogenic bacteria and have achieved good results [108,109,110]. Similar methods, based on toxin-related genes, need to be also widely applied to Gambierdiscus.
CTXs are colorless, odorless, and thermally stable and cannot be destroyed by cooking or freezing [111]. Although the concentrations of toxins in Gambierdiscus and fish samples are low, they have a high toxicity. Because diverse toxin analogs exist [18], detecting these toxins in environmental samples has been challenging. Over the past few decades, various analytical methods, including biological, chemical, and immunological methods, have been introduced to detect and characterize CTXs to support fish product monitoring and protect human health. Bioassay methods that use the mongoose, mouse, cat [112], brine shrimp, mosquito, chicken, and dipteran larvae have been developed to detect CTXs in fish [113]. However, due to ethical and cost concerns, it is unlikely that large animals will continue to be used for CTX detection. The use of two of the above-mentioned test animals, brine shrimp and mosquitoes, has also been banned [113]; brine shrimp cannot effectively detect toxins contributing to CFP and it is unsuitable to cultivate mosquitoes in the laboratory [114]. The mouse bioassay is the only animal assay that continues to be applied [115]. Cell-based assays can help detect CTXs [116]. Regardless of the shortcomings of this method (Table 2), it is often employed in combination with other CTX detection methods [80,117,118]. Immunoassays such as radioimmunoassays [119], enzyme immunoassays [120], antibody-based immunoassays [121,122], membrane immunobead assays [123], enzyme-linked immunosorbent assays [124], and capillary electrophoresis-based immunoassays [125] are also utilized to detect CTXs. However, these immunoassays all have their limitations, and they have not been widely applied, even though some have been commercialized (Table 1) [126,127,128]. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is the most widely used method for the accurate identification of CTX types in toxin-contaminated samples [129,130,131]. However, this method is also limited by the lack of toxin standards and the impossibility of field application [25]. Electrochemical immunosensors have been designed to measure in situ CTXs in recent years, as they can be integrated into compact analytical devices such as smartphones [118]. It is expected that this method will be applied with good results to the detection of CTXs in the future. Although many methods have been developed, none are widely used in detecting and identifying CTXs in fish and fishery products because of cost and efficiency concerns and the complexity of the procedures involved [25].

6. Toxin Biosynthesis

Several studies have shown that environmental factors affect toxin production and accumulation in Gambierdiscus. By comparing the growth rate and toxin production of G. carpenteri under different temperatures, light, and salinity, Vacarizas et al. found that cells produce more toxins during the slowest growth rate at a certain range of environmental conditions, and the highest cellular toxin content recorded was 7.48 ± 0.49 pg Pbtx eq/cell at culture conditions of 25 °C, 100 μmol photons m−2 s−1, and salinity of 26 [134]. The asynchrony between the abundance and toxicity of Gambierdiscus was also observed in a field study [135]. These results suggest that Gambierdiscus allocates more energy to growth and division than to toxins synthesis under suitable conditions. Although temperature affects cell growth and proliferation of Gambierdiscus, it is not regarded as an essential factor in the regulation of toxin production of Gambierdiscus spp. [49]. Longo et al. compared the levels of CTXs and its congeners in G. polynesiensis under different pH, N:P ratios, and nitrogen sources, and they found that more oxidized P-CTX analogs with higher potential toxicity are produced under low pH conditions [77]. These studies provide us with a snapshot of toxin production in Gambierdiscus.
Although the cellular processes underlying the biosynthesis of CTXs and MTXs remain unclear, some studies provide hints as to some of the cellular processes involved in the biosynthesis of the two toxins. Both CTXs and MTXs are polyether toxins. The synthesis of polyketides mediated by polyketide synthase (PKS) is regarded as essential for the biosynthesis of both toxin types [136]. Typically, PKS builds carbon chains in a manner similar to fatty acid synthase (FAS), where the starting substrate, usually acetyl-coenzyme A (acetyl CoA), is joined to malonyl CoA through a series of successive Claisen ester condensation reactions. The core structure of PKS consists of ketosynthase (KS), acyltransferase (AT), and acyl carrier protein (ACP) domains. Other domains, such as the dehydratase (DH), ketoreductase (KR), and enoylreductase (ER) domains that serve to modify the condensed acyl-units, are not essential for PKS function but are important for the synthesis of mature toxins. Another domain often found in PKS is thioesterase (TE), which is proposed to release polyketide compounds from megasynthase [137]. Epoxide-opening cascade reactions are also postulated to be involved in toxin biosynthesis, but this possibility remains to be confirmed [138].
Recently, transcriptome-based studies have been undertaken to investigate the PKSs in Gambierdiscus [138,139,140]. A comprehensive transcriptomic analysis of two gonyaulacaleaen and MTX-producing Gambierdiscus species, G. australes and G. belizeanus, identified genes putatively involved in the biosynthesis of polyether ladder compounds. Among these genes, 306 were found to be involved in polyketide biosynthesis, including 192 encoding ketoacyl synthases, and formed five unique phylogenetic clusters [139]. Interestingly, two clusters were unique to these maitotoxin-producing species, suggesting that they might be associated with MTX biosynthesis [140]. Furthermore, a putative biosynthetic pathway for MTX-1 is proposed, in which the carbon backbone is synthesized via polyketide biosynthesis followed by epoxidation, polyepoxide cyclization, and sulfonation carried out by PKSs, epoxidases, epoxide hydrolases, and sulfotransferases, respectively [139]. A recent comparative transcriptomic study of a CTX-producing strain and a non-CTX-producing strain of G. balechii identifies 52 PKS genes that were upregulated in the CTX-producing strain, including transcripts encoding both single-domain and multi-domain PKSs, suggesting that PKSs are likely to be involved in polyketide synthesis and also potentially CTX synthesis in G. balechii [103]. Collectively, these studies laid the foundation for elucidating the mechanisms involved in the biosynthesis of CTXs and MTXs and provided candidate biomarkers for the identification of toxin-producing Gambierdiscus species.
Dimethylsulfoniopropionate (DMSP), an organosulfur compound and zwitterionic metabolite, has been identified in many marine algal species [141,142,143]. DMSP is involved in numerous important biological processes, including cryoprotection [144], the scavenging of reactive oxygen species [145], and osmoregulation [145]. Gambierdiscus species are important producers of DMSP in the ocean and present a potential connection between DMSP and toxin production, given that DMSP has been proposed to serve as a signaling molecule for toxin synthesis [141]. However, this supposition requires further verification.
Chemical methods are also used to artificially synthesize CTXs and MTXs for potential biological applications as well as further studies of these toxins. Hirama et al. first reported the total synthesis of a CTX (CTX3C) [81]. Since then, a variety of strategies have been developed for the chemical synthesis of CTXs, including the most toxic ones and 51-hydroxyCTX3C [81]. MTXs are thought to be the largest and most toxic secondary metabolites isolated and identified to date; however, only fragments of this toxin have been synthesized. In summary, the chemical synthesis of CTXs and/or MTXs may help shed light on the mechanisms involved in their biosynthesis in Gambierdiscus. Additionally, synthetic toxins can be employed in toxicological and pharmacological studies.

7. Toxicology and Pharmacology

All CTXs can activate voltage-gated sodium channels and block potassium channels [146,147,148]. They can also transverse the blood–brain barrier, causing neurologic symptoms in both the central and peripheral nervous systems, as well as affecting the cardiovascular system [15,149]. The major symptoms of ciguatoxin poisoning occur within 1–3 h of ingesting toxin-contaminated fish and manifest as vomiting, diarrhea, numbness in the extremities, numbness in the mouth and lips, reversal of hot and cold sensations, and muscle and joint aches [150]. Moreover, 20% of people affected may develop chronic ciguatera poisoning, and chronic weakness may last for years [151]. Despite some efforts, there is still no antidote for any natural marine toxin [152]. Transcriptome-level studies have been devoted to studying the effects of CTXs on mice, both in vitro and in vivo, as well as on the whole blood of patients [153,154,155]. This will contribute to the understanding of the mechanisms associated with the symptoms and the responses of organisms to these toxins. Indeed, dysregulation of the immune and inflammatory systems due to CTX ingestion has been reported in the mouse in vivo and in studies involving the whole blood of humans [156].
As hydrophilic compounds, MTXs affect cellular Ca2+ homeostasis by mediating Ca2+ influx [95]. MTX-mediated Ca2+ influx induces numerous cellular responses, such as calcium-dependent depolarization in neuronal cells [157], phosphoinositide breakdown [158], and the contraction of intestinal smooth muscle [159]. Given their potent toxicity, research attention has increasingly focused on the potential medicinal value of MTXs. However, although they represent a unique pharmacological tool for investigating calcium transport, MTXs have not been employed for this purpose owing to the difficulties associated with their purification and artificial synthesis.

8. Conclusions and Perspectives

During the past half-century, considerable effort has been dedicated to elucidating Gambierdiscus biology, and substantial progress has been made regarding the taxonomy, phylogenetic, geographic distribution, toxin detection method, and toxin biosynthesis of these dinoflagellates. These advances benefit the prevention and management of CFP worldwide. However, owing to their large genome size, unique gene structure, and high gene copy number, little is known about the genome of Gambierdiscus. Although a few transcriptome-based studies have been undertaken, this knowledge gap impedes our understanding of Gambierdiscus as well as the subsequent efficient prevention and management of CFP. Accordingly, whole-genome sequencing of different Gambierdiscus species is urgent and necessary. It will contribute to unveiling the genetic features, evolutionary history, environmental adaptability, and mechanisms of toxin biosynthesis of this genus. The combination of second and third-generation DNA sequencing technologies provides the opportunity to decode the genome of Gambierdiscus.
Although various biological and chemical methods have been developed to detect and characterize CTXs and MTXs, fast, simple, specific, and sensitive detection methods are still lacking, primarily owing to the complex structure and diversity of toxin congeners. Additionally, there is an acute lack of purified CTXs and MTXs globally, which impedes the development of toxin detection methods and applications. Thus, there is a need for the isolation and large-scale culture of different Gambierdiscus species with different toxin-producing abilities. These will provide sufficient amounts of purified toxins for developing specific detection methods as well as for other applications such as toxicology and pharmacology.
Finally, the responses and adaption of Gambierdiscus to the intensification of anthropogenic activities and global warming should be taken into consideration in future studies on the toxicity of these organisms to human beings. Laboratory studies of different Gambierdiscus species under various environmental conditions are needed, especially those relating to temperature, irradiance, and nutrients. Meanwhile, a field survey of the geographic distribution and toxicity of Gambierdiscus species in all the oceans of the world will aid our understanding of the responses and adaption of Gambierdiscus to environmental changes caused by the above-mentioned stresses.

Author Contributions

Data re-analysis, visualization and, manuscript preparation, Y.-H.X.; supervision and writing-review and editing, D.-Z.W. and M.-H.W.; funding acquisition, D.-Z.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (No. 42030404) and the Ministry of Science and Technology (No. 2019YFC0312601).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The code and data for this study are available at: https://github.com/yayan-web, accessed on 1 May 2022.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hoppenrath, M.; Murray, S.A.; Chomérat, N.; Horiguchi, T. Marine Benthic Dinoflagellates—Unveiling Their Worldwide Biodiversity; Kleine Senckenberg-Reihe; Band 54; Schweizerbart: Stuttgart, Germany, 2014; ISBN 978-3-510-61402-8. [Google Scholar]
  2. Faust, M.A. Observation of sand-dwelling toxic dinoflagellates (Dinophyceae) from widely differing sites, including two new species. J. Phycol. 1995, 31, 996–1003. [Google Scholar] [CrossRef]
  3. Rains, L.K.; Parsons, M.L. Gambierdiscus species exhibit different epiphytic behaviors toward a variety of macroalgal hosts. Harmful Algae 2015, 49, 29–39. [Google Scholar] [CrossRef]
  4. Strachan, L.C.; Lewis, R.J.; Nicholson, G.M. Differential actions of pacific ciguatoxin-1 on sodium channel subtypes in mammalian sensory neurons. J. Pharmacol. Exp. Ther. 1999, 288, 379–388. [Google Scholar]
  5. Birinyi-Strachan, L.C.; Gunning, S.J.; Lewis, R.J.; Nicholson, G.M. Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons. Toxicol. Appl. Pharmacol. 2005, 204, 175–186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Munday, R.; Murray, S.; Rhodes, L.L.; Larsson, M.E.; Harwood, D.T. Ciguatoxins and Maitotoxins in Extracts of Sixteen Gambierdiscus Isolates and One Fukuyoa Isolate from the South Pacific and Their Toxicity to Mice by Intraperitoneal and Oral Administration. Mar. Drugs 2017, 15, 208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Rhodes, L.; Harwood, T.; Smith, K.F.; Argyle, P.A.; Munday, R. Production of ciguatoxin and maitotoxin by strains of Gambierdiscus australes, G. pacificus and G. polynesiensis (Dinophyceae) isolated from Rarotonga, Cook Islands. Harmful Algae 2014, 39, 185–190. [Google Scholar] [CrossRef]
  8. Leite, I.d.P.; Sdiri, K.; Taylor, A.; Viallon, J.; Gharbia, H.B.; Mafra Júnior, L.L.; Swarzenski, P.; Oberhaensli, F.; Darius, H.T.; Chinain, M.; et al. Experimental Evidence of Ciguatoxin Accumulation and Depuration in Carnivorous Lionfish. Toxins 2021, 13, 564. [Google Scholar] [CrossRef] [PubMed]
  9. Costa, P.R.; Estevez, P.; Castro, D.; Solino, L.; Gouveia, N.; Santos, C.; Rodrigues, S.M.; Leao, J.M.; Gago-Martinez, A. New Insights into the Occurrence and Toxin Profile of Ciguatoxins in Selvagens Islands (Madeira, Portugal). Toxins 2018, 10, 524. [Google Scholar] [CrossRef] [Green Version]
  10. Pisapia, F.; Holland, W.C.; Hardison, D.R.; Litaker, R.W.; Fraga, S.; Nishimura, T.; Adachi, M.; Nguyen-Ngoc, L.; Séchet, V.; Amzil, Z.; et al. Toxicity screening of 13 Gambierdiscus strains using neuro-2a and erythrocyte lysis bioassays. Harmful Algae 2017, 63, 173–183. [Google Scholar] [CrossRef] [Green Version]
  11. Chateau-Degat, M.-L.; Chinain, M.; Cerf, N.; Gingras, S.; Hubert, B.; Dewailly, É. Seawater temperature, Gambierdiscus spp. variability and incidence of ciguatera poisoning in French Polynesia. Harmful Algae 2005, 4, 1053–1062. [Google Scholar] [CrossRef]
  12. Lehane, L.; Lewis, R.J. Ciguatera: Recent advances but the risk remains. Int. J. Food Microbiol. 2000, 61, 91–125. [Google Scholar] [CrossRef]
  13. Soliño, L.; Costa, P.R. Global impact of ciguatoxins and ciguatera fish poisoning on fish, fisheries and consumers. Environ. Res. 2020, 182, 109111. [Google Scholar] [CrossRef] [PubMed]
  14. Friedman, M.A.; Fernandez, M.; Backer, L.C.; Dickey, R.W.; Bernstein, J.; Schrank, K.; Kibler, S.; Stephan, W.; Gribble, M.O.; Bienfang, P.; et al. An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management. Mar. Drugs 2017, 15, 72. [Google Scholar] [CrossRef] [PubMed]
  15. L’Herondelle, K.; Talagas, M.; Mignen, O.; Misery, L.; Le Garrec, R. Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis. Cells 2020, 9, 2291. [Google Scholar] [CrossRef]
  16. Tudó, À.; Gaiani, G.; Rey Varela, M.; Tsumuraya, T.; Andree, K.B.; Fernández-Tejedor, M.; Campàs, M.; Diogène, J. Further Advance of Gambierdiscus species in the Canary Islands, with the First Report of Gambierdiscus belizeanus. Toxins 2020, 12, 692. [Google Scholar] [CrossRef] [PubMed]
  17. Wang, D.-Z. Neurotoxins from Marine Dinoflagellates: A Brief Review. Mar. Drugs 2008, 6, 349–371. [Google Scholar] [CrossRef] [PubMed]
  18. Rossignoli, A.E.; Tudó, A.; Bravo, I.; Díaz, P.A.; Diogène, J.; Riobó, P. Toxicity Characterisation of Gambierdiscus species from the Canary Islands. Toxins 2020, 12, 134. [Google Scholar] [CrossRef] [Green Version]
  19. Lyu, Y.; Richlen, M.L.; Sehein, T.R.; Chinain, M.; Adachi, M.; Nishimura, T.; Xu, Y.; Parsons, M.L.; Smith, T.B.; Zheng, T.; et al. LSU rDNA based RFLP assays for the routine identification of Gambierdiscus species. Harmful Algae 2017, 66, 20–28. [Google Scholar] [CrossRef] [Green Version]
  20. Larsson, M.E.; Laczka, O.F.; Harwood, D.T.; Lewis, R.J.; Himaya, S.W.A.; Murray, S.A.; Doblin, M.A. Toxicology of Gambierdiscus spp. (Dinophyceae) from Tropical and Temperate Australian Waters. Mar. Drugs 2018, 16, 7. [Google Scholar] [CrossRef] [Green Version]
  21. Neves, R.A.F.; Pardal, M.A.; Nascimento, S.M.; Silva, A.; Oliveira, P.J.; Rodrigues, E.T. High sensitivity of rat cardiomyoblast H9c2(2-1) cells to Gambierdiscus toxic compounds. Aquat. Toxicol. 2020, 223, 105475. [Google Scholar] [CrossRef]
  22. Roué, M.; Darius, H.T.; Viallon, J.; Ung, A.; Gatti, C.; Harwood, D.T.; Chinain, M. Application of solid phase adsorption toxin tracking (SPATT) devices for the field detection of Gambierdiscus toxins. Harmful Algae 2018, 71, 40–49. [Google Scholar] [CrossRef] [PubMed]
  23. Gingold, D.B.; Strickland, M.J.; Hess, J.J. Ciguatera Fish Poisoning and Climate Change: Analysis of National Poison Center Data in the United States, 2001–2011. Environ. Health Perspect. 2014, 122, 580–586. [Google Scholar] [CrossRef] [PubMed]
  24. Soliño, L.; Costa, P.R. Differential toxin profiles of ciguatoxins in marine organisms: Chemistry, fate and global distribution. Toxicon 2018, 150, 124–143. [Google Scholar] [CrossRef] [PubMed]
  25. Pasinszki, T.; Lako, J.; Dennis, T.E. Advances in Detecting Ciguatoxins in Fish. Toxins 2020, 12, 494. [Google Scholar] [CrossRef]
  26. Nakahara, H.; Sakami, T.; Chinain, M.; Ishida, Y. The role of macroalgae in epiphytism of the toxic dinoflagellate Gambierdiscus toxicus (Dinophyceae). Phycol. Res. 1996, 44, 113–117. [Google Scholar] [CrossRef]
  27. Adachi, R.; Fukuyo, Y. The Thecal Structure of a Marine Toxic Dinoflagellate Gambierdiscus toxicus gen. et sp. nov. Collected in a Ciguatera-endemic Area. Bull. Jpn. Soc. Sci. Fish 1979, 45, 67–71. [Google Scholar] [CrossRef] [Green Version]
  28. Aligizaki, K.; Nikolaidis, G. Morphological identification of two tropical dinoflagellates of the genera Gambierdiscus and Sinophysis in the Mediterranean Sea. J. Biol. Res.-Thessalon. 2008, 9, 75–82. [Google Scholar]
  29. Nascimento, S.M.; Melo, G.; Salgueiro, F.; Diniz, B.d.S.; Fraga, S. Morphology of Gambierdiscus excentricus (Dinophyceae) with emphasis on sulcal plates. Phycologia 2015, 54, 628–639. [Google Scholar] [CrossRef]
  30. Litaker, R.W.; Vandersea, M.W.; Faust, M.A.; Kibler, S.R.; Chinain, M.; Holmes, M.J.; Holland, W.C.; Tester, P.A. Taxonomy of Gambierdiscus including four new species, Gambierdiscus caribaeus, Gambierdiscus carolinianus, Gambierdiscus carpenteri and Gambierdiscus ruetzleri (Gonyaulacales, Dinophyceae). Phycologia 2009, 48, 344–390. [Google Scholar] [CrossRef]
  31. Hoppenrath, M.; Kretzschmar, A.L.; Kaufmann, M.J.; Murray, S.A. Morphological and molecular phylogenetic identification and record verification of Gambierdiscus excentricus (Dinophyceae) from Madeira Island (NE Atlantic Ocean). Mar. Biodivers. Rec. 2019, 12, 16. [Google Scholar] [CrossRef] [Green Version]
  32. Guiry, M.D.; Guiry, G.M. AlgaeBase. World-wide electronic publication, National University of Ireland, Galway. Available online: https://www.algaebase.org (accessed on 18 May 2022).
  33. Jang, S.H.; Jeong, H.J.; Yoo, Y.D. Gambierdiscus jejuensis sp. nov., an epiphytic dinoflagellate from the waters of Jeju Island, Korea, effect of temperature on the growth, and its global distribution. Harmful Algae 2018, 80, 149–157. [Google Scholar] [CrossRef]
  34. Rhodes, L.; Smith, K.F.; Verma, A.; Curley, B.G.; Harwood, D.T.; Murray, S.; Kohli, G.S.; Solomona, D.; Rongo, T.; Munday, R.; et al. A new species of Gambierdiscus (Dinophyceae) from the south-west Pacific: Gambierdiscus honu sp. nov. Harmful Algae 2017, 65, 61–70. [Google Scholar] [CrossRef] [PubMed]
  35. Fraga, S.; Rodríguez, F.; Caillaud, A.; Diogène, J.; Raho, N.; Zapata, M. Gambierdiscus excentricus sp. nov. (Dinophyceae), a benthic toxic dinoflagellate from the Canary Islands (NE Atlantic Ocean). Harmful Algae 2011, 11, 10–22. [Google Scholar] [CrossRef] [Green Version]
  36. Fraga, S.; Rodríguez, F. Genus Gambierdiscus in the Canary Islands (NE Atlantic Ocean) with Description of Gambierdiscus silvae sp. nov., a New Potentially Toxic Epiphytic Benthic Dinoflagellate. Protist 2014, 165, 839–853. [Google Scholar] [CrossRef] [PubMed]
  37. Smith, K.F.; Rhodes, L.; Verma, A.; Curley, B.G.; Harwood, D.T.; Kohli, G.S.; Solomona, D.; Rongo, T.; Munday, R.; Murray, S.A. A new Gambierdiscus species (Dinophyceae) from Rarotonga, Cook Islands: Gambierdiscus cheloniae sp. nov. Harmful Algae 2016, 60, 45–56. [Google Scholar] [CrossRef]
  38. Fraga, S.; Rodríguez, F.; Riobó, P.; Bravo, I. Gambierdiscus balechii sp. nov (Dinophyceae), a new benthic toxic dinoflagellate from the Celebes Sea (SW Pacific Ocean). Harmful Algae 2016, 58, 93–105. [Google Scholar] [CrossRef]
  39. Kretzschmar, A.L.; Verma, A.; Harwood, T.; Hoppenrath, M.; Murray, S. Characterization of Gambierdiscus lapillus sp. nov. (Gonyaulacales, Dinophyceae): A new toxic dinoflagellate from the Great Barrier Reef (Australia). J. Phycol. 2017, 53, 283–297. [Google Scholar] [CrossRef]
  40. Chinain, M.; Germain, M.; Sako, Y.; Pauillac, S.; Legrand, A. Genetic diversity in French Polynesian strains of the ciguatera-causing dinoflagellate Gambierdiscus toxicus: RFLP and sequence analysis on the SSU and LSU rRNA genes. In Harmful Algae; United Nations Educational, Scientific, and Cultural Organization: Paris, France, 1998; pp. 287–290. [Google Scholar]
  41. Leung, P.T.Y.; Yan, M.; Lam, V.T.T.; Yiu, S.K.F.; Chen, C.-Y.; Murray, J.S.; Harwood, D.T.; Rhodes, L.L.; Lam, P.K.S.; Wai, T.-C. Phylogeny, morphology and toxicity of benthic dinoflagellates of the genus Fukuyoa (Goniodomataceae, Dinophyceae) from a subtropical reef ecosystem in the South China Sea. Harmful Algae 2018, 74, 78–97. [Google Scholar] [CrossRef]
  42. Subba Rao, D.V. (Ed.) Dinoflagellates: Classification, Evolution, Physiology and Ecological Significance; Marine and Freshwater Biology; Nova Science Publishers: New York, NY, USA, 2020; ISBN 978-1-5361-7888-3. [Google Scholar]
  43. Tester, P.; Wickliffe, L.; Jossart, J.; Rhodes, L.; Enevoldsen, H.; Adachi, M.; Nishimura, T.; Rodriguez, F.; Chinain, M.; Litaker, W. Global distribution of the genera Gambierdiscus and Fukuyoa. Harmful Algae 2018, 138. [Google Scholar] [CrossRef]
  44. Tudó, À.; Toldrà, A.; Rey, M.; Todolí, I.; Andree, K.B.; Fernández-Tejedor, M.; Campàs, M.; Sureda, F.X.; Diogène, J. Gambierdiscus and Fukuyoa as potential indicators of ciguatera risk in the Balearic Islands. Harmful Algae 2020, 99, 101913. [Google Scholar] [CrossRef]
  45. Gaiani, G.; Leonardo, S.; Tudó, À.; Toldrà, A.; Rey, M.; Andree, K.B.; Tsumuraya, T.; Hirama, M.; Diogène, J.; O’Sullivan, C.K.; et al. Rapid detection of ciguatoxins in Gambierdiscus and Fukuyoa with immunosensing tools. Ecotoxicol. Environ. Saf. 2020, 204, 111004. [Google Scholar] [CrossRef] [PubMed]
  46. Gómez, F.; Qiu, D.; Lopes, R.M.; Lin, S. Fukuyoa paulensis gen. et sp. nov., a New Genus for the Globular Species of the Dinoflagellate Gambierdiscus (Dinophyceae). PLoS ONE 2015, 10, e0119676. [Google Scholar] [CrossRef] [PubMed]
  47. Villareal, T.A.; Hanson, S.; Qualia, S.; Jester, E.L.E.; Granade, H.R.; Dickey, R.W. Petroleum production platforms as sites for the expansion of ciguatera in the northwestern Gulf of Mexico. Harmful Algae 2007, 6, 253–259. [Google Scholar] [CrossRef]
  48. Litaker, R.W.; Holland, W.C.; Hardison, D.R.; Pisapia, F.; Hess, P.; Kibler, S.R.; Tester, P.A. Ciguatoxicity of Gambierdiscus and Fukuyoa species from the Caribbean and Gulf of Mexico. PLoS ONE 2017, 12, e0185776. [Google Scholar] [CrossRef]
  49. Holland, W.C.; Litaker, R.W.; Tomas, C.R.; Kibler, S.R.; Place, A.R.; Davenport, E.D.; Tester, P.A. Differences in the toxicity of six Gambierdiscus (Dinophyceae) species measured using an in vitro human erythrocyte lysis assay. Toxicon 2013, 65, 15–33. [Google Scholar] [CrossRef]
  50. Chinain, M.; Faust, M.A.; Pauillac, S. Morphology and molecular analyses of three toxic species of Gambierdiscus (Dinophyceae): G. pacificus, sp. nov., G. australes, sp. nov., and G. polynesiensis, sp. nov. J. Phycol. 1999, 35, 1282–1296. [Google Scholar] [CrossRef]
  51. Gatti, C.M.I.; Lonati, D.; Darius, H.T.; Zancan, A.; Roué, M.; Schicchi, A.; Locatelli, C.A.; Chinain, M. Tectus niloticus (Tegulidae, Gastropod) as a Novel Vector of Ciguatera Poisoning: Clinical Characterization and Follow-Up of a Mass Poisoning Event in Nuku Hiva Island (French Polynesia). Toxins 2018, 10, 102. [Google Scholar] [CrossRef] [Green Version]
  52. Nishimura, T.; Sato, S.; Tawong, W.; Sakanari, H.; Uehara, K.; Shah, M.M.R.; Suda, S.; Yasumoto, T.; Taira, Y.; Yamaguchi, H.; et al. Genetic Diversity and Distribution of the Ciguatera-Causing Dinoflagellate Gambierdiscus spp. (Dinophyceae) in Coastal Areas of Japan. PLoS ONE 2013, 8, e60882. [Google Scholar] [CrossRef] [Green Version]
  53. IOC-UNESCO. The Harmful Algal Event Database (HAEDAT). Available online: https://obis.org (accessed on 23 August 2021).
  54. VIshwas, C.; Achuthankutty, C.T. IndOBIS Catalogue of Life. Available online: http://www.indobis.org/ (accessed on 23 August 2021).
  55. Litaker, R.W.; Vandersea, M.W.; Faust, M.A.; Kibler, S.R.; Nau, A.W.; Holland, W.C.; Chinain, M.; Holmes, M.J.; Tester, P.A. Global distribution of ciguatera causing dinoflagellates in the genus Gambierdiscus. Toxicon 2010, 56, 711–730. [Google Scholar] [CrossRef]
  56. Xu, Y.; Richlen, M.L.; Morton, S.L.; Mak, Y.L.; Chan, L.L.; Tekiau, A.; Anderson, D.M. Distribution, abundance and diversity of Gambierdiscus spp. from a ciguatera-endemic area in Marakei, Republic of Kiribati. Harmful Algae 2014, 34, 56–68. [Google Scholar] [CrossRef] [Green Version]
  57. Hallegraeff, G. Transport of toxic dinoflagellates via ships’ ballast water:bioeconomic risk assessment and efficacy of possible ballast water management strategies. Mar. Ecol. Prog. Ser. 1998, 168, 297–309. [Google Scholar] [CrossRef] [Green Version]
  58. Rodriguez, F.; Fraga, S.; Ramilo, I.; Rial, P.; Figueroa, R.I.; Riobó, P.; Bravo, I. Canary Islands (NE Atlantic) as a biodiversity “hotspot” of Gambierdiscus: Implications for future trends of ciguatera in the area. Harmful Algae 2017, 67, 131–143. [Google Scholar] [CrossRef] [PubMed]
  59. Yu, Y.; Harris, A.J.; Blair, C.; He, X. RASP (Reconstruct Ancestral State in Phylogenies): A tool for historical biogeography. Mol. Phylogenet. Evol. 2015, 87, 46–49. [Google Scholar] [CrossRef] [PubMed]
  60. Bomber, J.W.; Guillard, R.R.L.; Nelson, W.G. Rôles of temperature, salinity, and light in seasonality, growth, and toxicity of ciguatera-causing Gambierdiscus toxicus Adachi et Fukuyo (Dinophyceae). J. Exp. Mar. Biol. Ecol. 1988, 115, 53–65. [Google Scholar] [CrossRef]
  61. Morton, S.L.; Norris, D.R.; Bomber, J.W. Effect of temperature, salinity and light intensity on the growth and seasonality of toxic dinoflagellates associated with ciguatera. J. Exp. Mar. Biol. Ecol. 1992, 157, 79–90. [Google Scholar] [CrossRef]
  62. Kibler, S.R.; Litaker, R.W.; Holland, W.C.; Vandersea, M.W.; Tester, P.A. Growth of eight Gambierdiscus (Dinophyceae) species: Effects of temperature, salinity and irradiance. Harmful Algae 2012, 19, 1–14. [Google Scholar] [CrossRef]
  63. Parsons, M.L.; Aligizaki, K.; Bottein, M.-Y.D.; Fraga, S.; Morton, S.L.; Penna, A.; Rhodes, L. Gambierdiscus and Ostreopsis: Reassessment of the state of knowledge of their taxonomy, geography, ecophysiology, and toxicology. Harmful Algae 2012, 14, 107–129. [Google Scholar] [CrossRef]
  64. Yoshimatsu, T.; Yamaguchi, H.; Iwamoto, H.; Nishimura, T.; Adachi, M. Effects of temperature, salinity and their interaction on growth of Japanese Gambierdiscus spp. (Dinophyceae). Harmful Algae 2014, 35, 29–37. [Google Scholar] [CrossRef]
  65. Sparrow, L.; Momigliano, P.; Russ, G.R.; Heimann, K. Effects of temperature, salinity and composition of the dinoflagellate assemblage on the growth of Gambierdiscus carpenteri isolated from the Great Barrier Reef. Harmful Algae 2017, 65, 52–60. [Google Scholar] [CrossRef]
  66. Xu, Y.; Richlen, M.L.; Liefer, J.D.; Robertson, A.; Kulis, D.; Smith, T.B.; Parsons, M.L.; Anderson, D.M. Influence of Environmental Variables on Gambierdiscus spp. (Dinophyceae) Growth and Distribution. PLoS ONE 2016, 11, e0153197. [Google Scholar] [CrossRef]
  67. Tawong, W.; Yoshimatsu, T.; Yamaguchi, H.; Adachi, M. Temperature and salinity effects and toxicity of Gambierdiscus caribaeus (Dinophyceae) from Thailand. Phycologia 2016, 55, 274–278. [Google Scholar] [CrossRef]
  68. Kibler, S.R.; Tester, P.A.; Kunkel, K.E.; Moore, S.K.; Litaker, R.W. Effects of ocean warming on growth and distribution of dinoflagellates associated with ciguatera fish poisoning in the Caribbean. Ecol. Modell. 2015, 316, 194–210. [Google Scholar] [CrossRef] [Green Version]
  69. Zhang, Y.; Sievert, S.M. Pan-genome analyses identify lineage- and niche-specific markers of evolution and adaptation in Epsilonproteobacteria. Front. Microbiol. 2014, 5, 110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Bezuidt, O.K.; Pierneef, R.; Gomri, A.M.; Adesioye, F.; Makhalanyane, T.P.; Kharroub, K.; Cowan, D.A. The Geobacillus Pan-Genome: Implications for the Evolution of the Genus. Front. Microbiol. 2016, 7, 723. [Google Scholar] [CrossRef]
  71. Zhang, X.; Liu, T.; Wang, J.; Wang, P.; Qiu, Y.; Zhao, W.; Pang, S.; Li, X.; Wang, H.; Song, J.; et al. Pan-genome of Raphanus highlights genetic variation and introgression among domesticated, wild, and weedy radishes. Mol. Plant 2021, 14, 2032–2055. [Google Scholar] [CrossRef]
  72. Tester, P.A.; Litaker, R.W.; Berdalet, E. Climate change and harmful benthic microalgae. Harmful Algae 2020, 91, 101655. [Google Scholar] [CrossRef]
  73. Núñez-Vázquez, E.J.; Almazán-Becerril, A.; López-Cortés, D.J.; Heredia-Tapia, A.; Hernández-Sandoval, F.E.; Band-Schmidt, C.J.; Bustillos-Guzmán, J.J.; Gárate-Lizárraga, I.; García-Mendoza, E.; Salinas-Zavala, C.A.; et al. Ciguatera in Mexico (1984–2013). Mar. Drugs 2018, 17, 13. [Google Scholar] [CrossRef] [Green Version]
  74. Boada, L.D.; Zumbado, M.; Luzardo, O.P.; Almeida-González, M.; Plakas, S.M.; Granade, H.R.; Abraham, A.; Jester, E.L.E.; Dickey, R.W. Ciguatera fish poisoning on the West Africa Coast: An emerging risk in the Canary Islands (Spain). Toxicon 2010, 56, 1516–1519. [Google Scholar] [CrossRef]
  75. Leynse, A.K.; Parsons, M.L.; Thomas, S.E. Differences in the photoacclimation and photoprotection exhibited by two species of the ciguatera causing dinoflagellate genus, Gambierdiscus. Harmful Algae 2017, 70, 90–97. [Google Scholar] [CrossRef]
  76. Loeffler, C.; Richlen, M.; Brandt, M.; Smith, T. Effects of grazing, nutrients, and depth on the ciguatera-causing dinoflagellate Gambierdiscus in the US Virgin Islands. Mar. Ecol. Prog. Ser. 2015, 531, 91–104. [Google Scholar] [CrossRef]
  77. Longo, S.; Sibat, M.; Darius, H.T.; Hess, P.; Chinain, M. Effects of pH and Nutrients (Nitrogen) on Growth and Toxin Profile of the Ciguatera-Causing Dinoflagellate Gambierdiscus polynesiensis (Dinophyceae). Toxins 2020, 12, 767. [Google Scholar] [CrossRef] [PubMed]
  78. Lewis, R.J.; Vernoux, J.-P.; Brereton, I.M. Structure of Caribbean Ciguatoxin Isolated from Caranx latus. J. Am. Chem. Soc. 1998, 120, 5914–5920. [Google Scholar] [CrossRef]
  79. Hamilton, B.; Hurbungs, M.; Vernoux, J.-P.; Jones, A.; Lewis, R.J. Isolation and characterisation of Indian Ocean ciguatoxin. Toxicon 2002, 40, 685–693. [Google Scholar] [CrossRef]
  80. Spielmeyer, A.; Loeffler, C.R.; Bodi, D. Extraction and LC-MS/MS Analysis of Ciguatoxins: A Semi-Targeted Approach Designed for Fish of Unknown Origin. Toxins 2021, 13, 630. [Google Scholar] [CrossRef] [PubMed]
  81. Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma, Y.; Kawada, Y.; Komano, K.; Yamashita, S.; Lee, N.; Hirama, M. Total Synthesis of Ciguatoxin and 51-HydroxyCTX3C. J. Am. Chem. Soc. 2006, 128, 9352–9354. [Google Scholar] [CrossRef] [PubMed]
  82. Rhodes, L.L.; Smith, K.F.; Verma, A.; Murray, S.; Harwood, D.T.; Trnski, T. The dinoflagellate genera Gambierdiscus and Ostreopsis from subtropical Raoul Island and North Meyer Island, Kermadec Islands. N. Z. J. Mar. Freshw. Res. 2017, 51, 490–504. [Google Scholar] [CrossRef]
  83. Estevez, P.; Sibat, M.; Leao-Martins, J.M.; Tudo, A.; Rambla-Alegre, M.; Aligizaki, K.; Diogène, J.; Gago-Martinez, A.; Hess, P. Use of Mass Spectrometry to Determine the Diversity of Toxins Produced by Gambierdiscus and Fukuyoa Species from Balearic Islands and Crete (Mediterranean Sea) and the Canary Islands (Northeast Atlantic). Toxins 2020, 12, 305. [Google Scholar] [CrossRef]
  84. Rodríguez, I.; Genta-Jouve, G.; Alfonso, C.; Calabro, K.; Alonso, E.; Sánchez, J.A.; Alfonso, A.; Thomas, O.P.; Botana, L.M. Gambierone, a Ladder-Shaped Polyether from the Dinoflagellate Gambierdiscus belizeanus. Org. Lett. 2015, 17, 2392–2395. [Google Scholar] [CrossRef]
  85. Boente-Juncal, A.; Álvarez, M.; Antelo, Á.; Rodriguez, I.; Calabro, K.; Vale, C.; Thomas, O.P.; Botana, L.M. Structure Elucidation and Biological Evaluation of Maitotoxin-3, a Homologue of Gambierone, from Gambierdiscus belizeanus. Toxins 2019, 11, 79. [Google Scholar] [CrossRef] [Green Version]
  86. Murray, J.S.; Finch, S.C.; Puddick, J.; Rhodes, L.L.; Harwood, D.T.; van Ginkel, R.; Prinsep, M.R. Acute Toxicity of Gambierone and Quantitative Analysis of Gambierones Produced by Cohabitating Benthic Dinoflagellates. Toxins 2021, 13, 333. [Google Scholar] [CrossRef]
  87. Caillaud, A.; de la Iglesia, P.; Barber, E.; Eixarch, H.; Mohammad-Noor, N.; Yasumoto, T.; Diogène, J. Monitoring of dissolved ciguatoxin and maitotoxin using solid-phase adsorption toxin tracking devices: Application to Gambierdiscus pacificus in culture. Harmful Algae 2011, 10, 433–446. [Google Scholar] [CrossRef]
  88. Nagai, H.; Murata, M.; Torigoe, K.; Satake, M.; Yasumoto, T. Gambieric acids, new potent antifungal substances with unprecedented polyether structures from a marine dinoflagellate Gambierdiscus toxicus. J. Org. Chem. 1992, 57, 5448–5453. [Google Scholar] [CrossRef]
  89. Watanabe, R.; Uchida, H.; Suzuki, T.; Matsushima, R.; Nagae, M.; Toyohara, Y.; Satake, M.; Oshima, Y.; Inoue, A.; Yasumoto, T. Gambieroxide, a novel epoxy polyether compound from the dinoflagellate Gambierdiscus toxicus GTP2 strain. Tetrahedron 2013, 69, 10299–10303. [Google Scholar] [CrossRef]
  90. Satake, M.; Murata, M.; Yasumoto, T. Gambierol: A new toxic polyether compound isolated from the marine dinoflagellate Gambierdiscus toxicus. J. Am. Chem. Soc. 1993, 115, 361–362. [Google Scholar] [CrossRef]
  91. Maria Durán-Riveroll, L.; Cembella, A.D.; Okolodkov, Y.B. A Review on the Biodiversity and Biogeography of Toxigenic Benthic Marine Dinoflagellates of the Coasts of Latin America. Front. Mar. Sci. 2019, 6, 148. [Google Scholar] [CrossRef]
  92. Yasumoto, T.; Bagnis, R.; Vernoux, J.P. Toxicity of the surgeonfishes. II. Properties of the principal water-soluble toxin. Nippon Suisan Gakk. 1976, 42, 359–365. [Google Scholar] [CrossRef]
  93. Varela, A.T.; Neves, R.A.F.; Nascimento, S.M.; Oliveira, P.J.; Pardal, M.A.; Rodrigues, E.T.; Moreno, A.J. Exposure to marine benthic dinoflagellate toxins may lead to mitochondrial dysfunction. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 2021, 240, 108937. [Google Scholar] [CrossRef]
  94. Pisapia, F.; Sibat, M.; Watanabe, R.; Roullier, C.; Suzuki, T.; Hess, P.; Herrenknecht, C. Characterization of maitotoxin-4 (MTX4) using electrospray positive mode ionization high-resolution mass spectrometry and UV spectroscopy. Rapid Commun. Mass Spectrom. 2020, 34, e8859. [Google Scholar] [CrossRef]
  95. Martin, V.; Vale, C.; Antelo, A.; Hirama, M.; Yamashita, S.; Vieytes, M.R.; Botana, L.M. Differential Effects of Ciguatoxin and Maitotoxin in Primary Cultures of Cortical Neurons. Chem. Res. Toxicol. 2014, 27, 1387–1400. [Google Scholar] [CrossRef]
  96. Yon, T.; Sibat, M.; Réveillon, D.; Bertrand, S.; Chinain, M.; Hess, P. Deeper insight into Gambierdiscus polynesiensis toxin production relies on specific optimization of high-performance liquid chromatography-high resolution mass spectrometry. Talanta 2021, 232, 122400. [Google Scholar] [CrossRef]
  97. Diogène, J.; Reverté, L.; Rambla-Alegre, M.; del Río, V.; de la Iglesia, P.; Campàs, M.; Palacios, O.; Flores, C.; Caixach, J.; Ralijaona, C.; et al. Identification of ciguatoxins in a shark involved in a fatal food poisoning in the Indian Ocean. Sci. Rep. 2017, 7, 8240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Morohashi, A.; Satake, M.; Yasumoto, T. The absolute configuration of gambierol, a toxic marine polyether from the dinoflagellate, Gambierdiscus toxicus. Tetrahedron Lett. 1999, 40, 97–100. [Google Scholar] [CrossRef]
  99. Molgó, J.; Schlumberger, S.; Sasaki, M.; Fuwa, H.; Louzao, M.C.; Botana, L.M.; Servent, D.; Benoit, E. Gambierol Potently Increases Evoked Quantal Transmitter Release and Reverses Pre- and Post -Synaptic Blockade at Vertebrate Neuromuscular Junctions. Neuroscience 2020, 439, 106–116. [Google Scholar] [CrossRef] [PubMed]
  100. Cuypers, E.; Abdel-Mottaleb, Y.; Kopljar, I.; Rainier, J.D.; Raes, A.L.; Snyders, D.J.; Tytgat, J. Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels. Toxicon 2008, 51, 974–983. [Google Scholar] [CrossRef] [Green Version]
  101. Roeder, K.; Erler, K.; Kibler, S.; Tester, P.; Van The, H.; Nguyen-Ngoc, L.; Gerdts, G.; Luckas, B. Characteristic profiles of Ciguatera toxins in different strains of Gambierdiscus spp. Toxicon 2010, 56, 731–738. [Google Scholar] [CrossRef]
  102. Chinain, M.; Darius, H.T.; Ung, A.; Cruchet, P.; Wang, Z.; Ponton, D.; Laurent, D.; Pauillac, S. Growth and toxin production in the ciguatera-causing dinoflagellate Gambierdiscus polynesiensis (Dinophyceae) in culture. Toxicon 2010, 56, 739–750. [Google Scholar] [CrossRef]
  103. Wu, Z.; Luo, H.; Yu, L.; Lee, W.H.; Li, L.; Mak, Y.L.; Lin, S.; Lam, P.K.S. Characterizing ciguatoxin (CTX)- and Non-CTX-producing strains of Gambierdiscus balechii using comparative transcriptomics. Sci. Total Environ. 2020, 717, 137184. [Google Scholar] [CrossRef]
  104. Pitz, K.J.; Richlen, M.L.; Fachon, E.; Smith, T.B.; Parsons, M.L.; Anderson, D.M. Development of fluorescence in situ hybridization (FISH) probes to detect and enumerate Gambierdiscus species. Harmful Algae 2021, 101, 101914. [Google Scholar] [CrossRef] [PubMed]
  105. Zaghloul, H.; EI-Shahat, M. Recombinase polymerase amplification as a promising tool in hepatitis C virus diagnosis. World J. Hepatol. 2014, 6, 916–922. [Google Scholar] [CrossRef]
  106. Gaiani, G.; Leonardo, S.; Tsumuraya, T.; Rambla, M.; Diogène, J.; O’Sullivan, C.; Alcaraz, C.; Campàs, M. Detection of ciguatoxins in fish and algal samples with an electrochemical biosensor. In Proceedings of the 1st International Electronic Conference on Toxins, Online, 14 January 2021. [Google Scholar]
  107. Gaiani, G.; Toldrà, A.; Andree, K.B.; Rey, M.; Diogène, J.; Alcaraz, C.; O’Sullivan, C.K.; Campàs, M. Detection of Gambierdiscus and Fukuyoa single cells using recombinase polymerase amplification combined with a sandwich hybridization assay. J. Appl. Phycol. 2021, 33, 2273–2282. [Google Scholar] [CrossRef]
  108. Porcar, M.; Juárez-Pérez, V. PCR-based identification of Bacillus thuringiensis pesticidal crystal genes. FEMS Microbiol. Rev. 2003, 26, 419–432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Villafana, R.; Ramdass, A.; Rampersad, S. Selection of Fusarium Trichothecene Toxin Genes for Molecular Detection Depends on TRI Gene Cluster Organization and Gene Function. Toxins 2019, 11, 36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Asakura, M.; Samosornsuk, W.; Hinenoya, A.; Misawa, N.; Nishimura, K.; Matsuhisa, A.; Yamasaki, S. Development of a cytolethal distending toxin (cdt) gene-based species-specific multiplex PCR assay for the detection and identification of Campylobacter jejuni, Campylobacter coli and Campylobacter fetus. FEMS Immunol. Med. Microbiol. 2008, 52, 260–266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Whittle, K.; Gallacher, S. Marine toxins. Br. Med. Bull. 2000, 56, 236–253. [Google Scholar] [CrossRef] [PubMed]
  112. Juranovic, L.R.; Park, D.L. Foodborne Toxins of Marine Origin: Ciguatera. In Reviews of Environmental Contamination and Toxicology; Ware, G.W., Ed.; Reviews of Environmental Contamination and Toxicology; Springer: New York, NY, USA, 1991; Volume 117, pp. 51–94. ISBN 978-1-4612-7777-4. [Google Scholar]
  113. Hallegraeff, G.M.; Anderson, D.M.; Cembella, A.D.; Enevoldsen, H.O. Manual on Harmful Marine Microalgae; Hallegraeff, G.M., Anderson, D.M., Cembella, A.D., Eds.; Monographs on Oceanographic Methodology; UNESCO: Paris, France, 2003; ISBN 978-92-3-103871-6. [Google Scholar]
  114. Martínez, A. Marine Biotoxins. In Springer Handbook of Marine Biotechnology; Kim, S.K., Ed.; Springer Handbooks; Springer: Berlin/Heidelberg, Germany, 2004; pp. 869–904. ISBN 978-3-642-53971-8. [Google Scholar]
  115. Xu, Y.; He, X.; Lee, W.H.; Chan, L.L.; Lu, D.; Wang, P.; Tao, X.; Li, H.; Yu, K. Ciguatoxin-Producing Dinoflagellate Gambierdiscus in the Beibu Gulf: First Report of Toxic Gambierdiscus in Chinese Waters. Toxins 2021, 13, 643. [Google Scholar] [CrossRef]
  116. Caillaud, A.; Eixarch, H.; de la Iglesia, P.; Rodriguez, M.; Dominguez, L.; Andree, K.B.; Diogène, J. Towards the standardisation of the neuroblastoma (neuro-2a) cell-based assay for ciguatoxin-like toxicity detection in fish: Application to fish caught in the Canary Islands. Food Addit. Contam. A 2012, 29, 1000–1010. [Google Scholar] [CrossRef]
  117. Estevez, P.; Castro, D.; Pequeño-Valtierra, A.; Leao, J.; Vilariño, O.; Diogène, J.; Gago-Martínez, A. An Attempt to Characterize the Ciguatoxin Profile in Seriola fasciata Causing Ciguatera Fish Poisoning in Macaronesia. Toxins 2019, 11, 221. [Google Scholar] [CrossRef] [Green Version]
  118. Leonardo, S.; Gaiani, G.; Tsumuraya, T.; Hirama, M.; Turquet, J.; Sagristà, N.; Rambla-Alegre, M.; Flores, C.; Caixach, J.; Diogène, J.; et al. Addressing the Analytical Challenges for the Detection of Ciguatoxins Using an Electrochemical Biosensor. Anal. Chem. 2020, 92, 4858–4865. [Google Scholar] [CrossRef]
  119. Hokama, Y.; Banner, A.H.; Boylan, D.B. A radioimmunoassay for the detection of ciguatoxin. Toxicon 1977, 15, 317–325. [Google Scholar] [CrossRef]
  120. Hokama, Y.; Abad, M.A.; Kimura, L.H. A rapid enzyme-immunoassay for the detection of ciguatoxin in contaminated fish tissues. Toxicon 1983, 21, 817–824. [Google Scholar] [CrossRef]
  121. Tsumuraya, T.; Fujii, I.; Inoue, M.; Tatami, A.; Miyazaki, K.; Hirama, M. Production of monoclonal antibodies for sandwich immunoassay detection of ciguatoxin 51-hydroxyCTX3C. Toxicon 2006, 48, 287–294. [Google Scholar] [CrossRef] [PubMed]
  122. Tsumuraya, T.; Fujii, I.; Hirama, M. Production of monoclonal antibodies for sandwich immunoassay detection of Pacific ciguatoxins. Toxicon 2010, 56, 797–803. [Google Scholar] [CrossRef] [PubMed]
  123. Hokama, Y.; Takenaka, W.E.; Nishimura, K.L.; Ebesu, J.S.M.; Bourke, R.; Sullivan, P.K. A Simple Membrane Immunobead Assay for Detecting Ciguatoxin and Related Polyethers from Human Ciguatera Intoxication and Natural Reef Fishes. J. AOAC Int. 1998, 81, 727–736. [Google Scholar] [CrossRef] [Green Version]
  124. Campora, C.E.; Dierking, J.; Tamaru, C.S.; Hokama, Y.; Vincent, D. Detection of ciguatoxin in fish tissue using sandwich ELISA and neuroblastoma cell bioassay. J. Clin. Lab. Anal. 2008, 22, 246–253. [Google Scholar] [CrossRef] [PubMed]
  125. Zhang, Z.; Liu, Y.; Zhang, C.; Luan, W. Horseradish peroxidase and antibody labeled gold nanoparticle probe for amplified immunoassay of ciguatoxin in fish samples based on capillary electrophoresis with electrochemical detection. Toxicon 2015, 96, 89–95. [Google Scholar] [CrossRef]
  126. Hardison, D.R.; Holland, W.C.; McCall, J.R.; Bourdelais, A.J.; Baden, D.G.; Darius, H.T.; Chinain, M.; Tester, P.A.; Shea, D.; Flores Quintana, H.A.; et al. Fluorescent Receptor Binding Assay for Detecting Ciguatoxins in Fish. PLoS ONE 2016, 11, e0153348. [Google Scholar] [CrossRef]
  127. Caillaud, A.; De la Iglesia, P.; Darius, H.T.; Pauillac, S.; Aligizaki, K.; Fraga, S.; Chinain, M.; Diogène, J. Update on Methodologies Available for Ciguatoxin Determination: Perspectives to Confront the Onset of Ciguatera Fish Poisoning in Europe. Mar. Drugs 2010, 8, 1838–1907. [Google Scholar] [CrossRef]
  128. Paul, B.; Suzanne, D.; Anne, D. Quantitative Evaluation of Commercially Available Test Kit for Ciguatera in Fish. Food Nutr. Sci. 2011, 2, 594–598. [Google Scholar] [CrossRef] [Green Version]
  129. Yogi, K.; Oshiro, N.; Inafuku, Y.; Hirama, M.; Yasumoto, T. Detailed LC-MS/MS Analysis of Ciguatoxins Revealing Distinct Regional and Species Characteristics in Fish and Causative Alga from the Pacific. Anal. Chem. 2011, 83, 8886–8891. [Google Scholar] [CrossRef]
  130. Sibat, M.; Herrenknecht, C.; Darius, H.T.; Roué, M.; Chinain, M.; Hess, P. Detection of pacific ciguatoxins using liquid chromatography coupled to either low or high resolution mass spectrometry (LC-MS/MS). J. Chromatogr. A 2018, 1571, 16–28. [Google Scholar] [CrossRef]
  131. Oshiro, N.; Tomikawa, T.; Kuniyoshi, K.; Ishikawa, A.; Toyofuku, H.; Kojima, T.; Asakura, H. LC–MS/MS Analysis of Ciguatoxins Revealing the Regional and Species Distinction of Fish in the Tropical Western Pacific. J. Mar. Sci. Eng. 2021, 9, 299. [Google Scholar] [CrossRef]
  132. Inserra, M.; Lavrukhina, Y.; Jones, A.; Lewis, R.J.; Vetter, I. Ciguatoxin Detection Methods and High-Throughput Assays. In Analysis of Food Toxins and Toxicants; Wong, Y., Lewis, R.J., Eds.; John Wiley & Sons, Ltd.: Chichester, UK, 2017; pp. 469–488. ISBN 978-1-118-99268-5. [Google Scholar]
  133. Tsumuraya, T.; Hirama, M. Rationally Designed Synthetic Haptens to Generate Anti-Ciguatoxin Monoclonal Antibodies, and Development of a Practical Sandwich ELISA to Detect Ciguatoxins. Toxins 2019, 11, 533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Vacarizas, J.; Benico, G.; Austero, N.; Azanza, R. Taxonomy and toxin production of Gambierdiscus carpenteri (Dinophyceae) in a tropical marine ecosystem: The first record from the Philippines. Mar. Pollut. Bull. 2018, 137, 430–443. [Google Scholar] [CrossRef] [PubMed]
  135. Liefer, J.D.; Richlen, M.L.; Smith, T.B.; DeBose, J.L.; Xu, Y.; Anderson, D.M.; Robertson, A. Asynchrony of Gambierdiscus spp. Abundance and Toxicity in the U.S. Virgin Islands: Implications for Monitoring and Management of Ciguatera. Toxins 2021, 13, 413. [Google Scholar] [CrossRef] [PubMed]
  136. Van Wagoner, R.M.; Satake, M.; Wright, J.L.C. Polyketide biosynthesis in dinoflagellates: What makes it different? Nat. Prod. Rep. 2014, 31, 1101. [Google Scholar] [CrossRef] [PubMed]
  137. Kohli, G.S.; John, U.; Van Dolah, F.M.; Murray, S.A. Evolutionary distinctiveness of fatty acid and polyketide synthesis in eukaryotes. ISME J. 2016, 10, 1877–1890. [Google Scholar] [CrossRef] [Green Version]
  138. Vilotijevic, I.; Jamison, T.F. Epoxide-Opening Cascades in the Synthesis of Polycyclic Polyether Natural Products. Angew. Chem. Int. Ed. 2009, 48, 5250–5281. [Google Scholar] [CrossRef] [Green Version]
  139. Kohli, G.S.; John, U.; Figueroa, R.I.; Rhodes, L.L.; Harwood, D.T.; Groth, M.; Bolch, C.J.S.; Murray, S.A. Polyketide synthesis genes associated with toxin production in two species of Gambierdiscus (Dinophyceae). BMC Genom. 2015, 16, 410. [Google Scholar] [CrossRef] [Green Version]
  140. Van Dolah, F.M.; Morey, J.S.; Milne, S.; Ung, A.; Anderson, P.E.; Chinain, M. Transcriptomic analysis of polyketide synthases in a highly ciguatoxic dinoflagellate, Gambierdiscus polynesiensis and low toxicity Gambierdiscus pacificus, from French Polynesia. PLoS ONE 2020, 15, e0231400. [Google Scholar] [CrossRef] [Green Version]
  141. Gwinn, J.K.; Robertson, A.; Kiene, R.P. Effect of Salinity on DMSP Production in Gambierdiscus belizeanus (Dinophyceae). J. Phycol. 2019, 55, 1401–1411. [Google Scholar] [CrossRef]
  142. Arnold, H.E.; Kerrison, P.; Steinke, M. Interacting effects of ocean acidification and warming on growth and DMS-production in the haptophyte coccolithophore Emiliania huxleyi. Glob. Change Biol. 2013, 19, 1007–1016. [Google Scholar] [CrossRef] [PubMed]
  143. Yang, G.; Li, C.; Sun, J. Influence of salinity and nitrogen content on production of dimethylsulfoniopropionate (DMSP) and dimethylsulfide (DMS) by Skeletonema costatum. Chin. J. Oceanol. Limnol. 2011, 29, 378–386. [Google Scholar] [CrossRef]
  144. McGann, L.E.; Walterson, M.L. Cryoprotection by dimethyl sulfoxide and dimethyl sulfone. Cryobiology 1987, 24, 11–16. [Google Scholar] [CrossRef]
  145. Sunda, W.; Kieber, D.J.; Kiene, R.P.; Huntsman, S. An antioxidant function for DMSP and DMS in marine algae. Nature 2002, 418, 317–320. [Google Scholar] [CrossRef] [PubMed]
  146. Ghiaroni, V.; Fuwa, H.; Inoue, M.; Sasaki, M.; Miyazaki, K.; Hirama, M.; Yasumoto, T.; Rossini, G.P.; Scalera, G.; Bigiani, A. Effect of Ciguatoxin 3C on Voltage-Gated Na+ and K+ Currents in Mouse Taste Cells. Chem. Senses 2006, 31, 673–680. [Google Scholar] [CrossRef]
  147. Hidalgo, J.; Liberona, J.L.; Molgó, J.; Jaimovich, E. Pacific ciguatoxin-1b effect over Na+ and K+ currents, inositol 1,4,5-triphosphate content and intracellular Ca2+ signals in cultured rat myotubes: Effects of Pacific CTX-1b on rat myotubes. Med. J. Aust. 2002, 137, 1055–1062. [Google Scholar] [CrossRef] [Green Version]
  148. Lombet, A.; Bidard, J.-N.; Lazdunski, M. Ciguatoxin and brevetoxins share a common receptor site on the neuronal voltage-dependent Na+ channel. FEBS Lett. 1987, 219, 355–359. [Google Scholar] [CrossRef] [Green Version]
  149. Tanyag, B.E.; Perelonia, K.B.S.; Cambia, F.D.; Montojo, U.M. Screening of Ciguatoxins in the Philippines by Animal Assay: Symptoms, Levels, and Distribution in Fish Tissue. TPJF 2021, 28, 87–95. [Google Scholar] [CrossRef]
  150. Vetter, I.; Touska, F.; Hess, A.; Hinsbey, R.; Sattler, S.; Lampert, A.; Sergejeva, M.; Sharov, A.; Collins, L.S.; Eberhardt, M.; et al. Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling: How ciguatoxins cause burning pain from cooling. EMBO J. 2012, 31, 3795–3808. [Google Scholar] [CrossRef] [Green Version]
  151. Pearn, J.H. Chronic fatigue syndrome: Chronic ciguatera poisoning as a differential diagnosis. Med. J. Aust. 1997, 166, 309–310. [Google Scholar] [CrossRef]
  152. Arulanandam, C.D.; Dharmara, R.; Ragothaman, P.; Vincent, S.G.P. Use of Marine biotoxins to modulate the tyrosine kinase domain of the human epidermal growth factor receptor. ChemRxiv 2021. [Google Scholar] [CrossRef]
  153. Ryan, J.C.; Morey, J.S.; Bottein, M.-Y.D.; Ramsdell, J.S.; Van Dolah, F.M. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response. BMC Neurosci. 2010, 11, 107. [Google Scholar] [CrossRef] [Green Version]
  154. Rubiolo, J.; Vale, C.; Boente-Juncal, A.; Hirama, M.; Yamashita, S.; Camiña, M.; Vieytes, M.; Botana, L. Transcriptomic Analysis of Ciguatoxin-Induced Changes in Gene Expression in Primary Cultures of Mice Cortical Neurons. Toxins 2018, 10, 192. [Google Scholar] [CrossRef] [Green Version]
  155. Ryan, J.C.; Wu, Q.; Shoemaker, R.C. Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin. BMC Med. Genom. 2015, 8, 15. [Google Scholar] [CrossRef] [Green Version]
  156. Guillotin, S.; Delcourt, N. Marine Neurotoxins’ Effects on Environmental and Human Health: An OMICS Overview. Mar. Drugs 2021, 20, 18. [Google Scholar] [CrossRef]
  157. Ogura, A.; Ohizumi, Y.; Yasumoto, T.; Kasei, M. Calcium-dependent depolarization induced by a marine toxin, maitotoxin, in a neuronal cell. Jpn. J. Pharmacol. 1984, 36, 315. [Google Scholar] [CrossRef]
  158. Gusovsky, F.; Bitran, J.A.; Yasumoto, T.; Daly, J.W. Mechanism of maitotoxin-stimulated phosphoinositide breakdown in HL-60 cells. J. Pharmacol. Exp. Ther. 1990, 252, 466–473. [Google Scholar]
  159. Ohizumi, Y.; Yasumoto, T. Contraction and increase in tissue calcium content induced by maitotoxin, the most potent known marine toxin, in intestinal smooth muscle. Br. J. Pharmacol. 1983, 79, 3–5. [Google Scholar] [CrossRef]
Toxins 14 00485 g001 550
Figure 1. Schematic diagram of the identification of different species of Gambierdiscus according to their morphology. Because of the wide variability in Gambierdiscus cell size, the size of the line drawings does not reflect the true differences in cell sizes. The line drawings in the figure are modified from: G. jejuensis [33], G. honu [34], G. excentricus [35], G. toxicus [30], G. australes [30], G. belizeanus [30], G. pacificus [30], G. caribaeus [30], G. carolinianus [30], G. carpenteri [30], G. polynesiensis [30], G. silvae [36], G. cheloniae [37], G. balechii [38], G. lapillus [39], and G. scabrosus [40].
Figure 1. Schematic diagram of the identification of different species of Gambierdiscus according to their morphology. Because of the wide variability in Gambierdiscus cell size, the size of the line drawings does not reflect the true differences in cell sizes. The line drawings in the figure are modified from: G. jejuensis [33], G. honu [34], G. excentricus [35], G. toxicus [30], G. australes [30], G. belizeanus [30], G. pacificus [30], G. caribaeus [30], G. carolinianus [30], G. carpenteri [30], G. polynesiensis [30], G. silvae [36], G. cheloniae [37], G. balechii [38], G. lapillus [39], and G. scabrosus [40].
Toxins 14 00485 g001
Toxins 14 00485 g002 550
Figure 2. Phylogenetic trees of Gambierdiscus. Maximum likelihood phylogenetic trees were constructed based on the LSU D8–D10 rRNA, LSU D1–D3 rRNA, and SSU rRNA genes of Gambierdiscus. Different colors are used to label different species, the branching points of Gambierdiscus and Fukuyoa are marked with red plots, and the first branching point of Gambierdiscus is marked with blue plots (the distance between the red and blue plots in the SSU tree is greater than that in the LSU trees).
Figure 2. Phylogenetic trees of Gambierdiscus. Maximum likelihood phylogenetic trees were constructed based on the LSU D8–D10 rRNA, LSU D1–D3 rRNA, and SSU rRNA genes of Gambierdiscus. Different colors are used to label different species, the branching points of Gambierdiscus and Fukuyoa are marked with red plots, and the first branching point of Gambierdiscus is marked with blue plots (the distance between the red and blue plots in the SSU tree is greater than that in the LSU trees).
Toxins 14 00485 g002
Toxins 14 00485 g003 550
Figure 3. Global distribution of ciguatera food poisoning (CFP) records and Gambierdiscus spp. The locations where Gambierdiscus are present are classified into six regions (A–G), and the pie charts in the phylogenetic tree show the probability of the locations at each node. The colors of the point on the right side of the phylogenetic tree are used to distinguish different Gambierdiscus species in the global ocean. Distribution information is obtained from the Ocean Biodiversity Information System and the IOC Harmful Algal Bloom Programme (Searched on 23 August 2021) [43,53,54].
Figure 3. Global distribution of ciguatera food poisoning (CFP) records and Gambierdiscus spp. The locations where Gambierdiscus are present are classified into six regions (A–G), and the pie charts in the phylogenetic tree show the probability of the locations at each node. The colors of the point on the right side of the phylogenetic tree are used to distinguish different Gambierdiscus species in the global ocean. Distribution information is obtained from the Ocean Biodiversity Information System and the IOC Harmful Algal Bloom Programme (Searched on 23 August 2021) [43,53,54].
Toxins 14 00485 g003
Toxins 14 00485 g004 550
Figure 4. The predicted 2D and 3D structures of Pacific ciguatoxin 1, maitotoxin, and other products of Gambierdiscus spp. The framed part indicates the CTX-like moiety, which is the hydrophobic part of the molecule.
Figure 4. The predicted 2D and 3D structures of Pacific ciguatoxin 1, maitotoxin, and other products of Gambierdiscus spp. The framed part indicates the CTX-like moiety, which is the hydrophobic part of the molecule.
Toxins 14 00485 g004
Table
Table 1. Reported polyether compounds in Gambierdiscus.
Table 1. Reported polyether compounds in Gambierdiscus.
SpeciesCiguatoxins (CTXs)Maitotoxins (MTXs)OthersReferences
Gambierdiscus australesCTX1B, P-CTX-3CMTX, MTX-3P-Gambierone analogue, putative gambieroxide[7,82,83]
Gambierdiscus balechii gambierone[84]
Gambierdiscus belizeanus MTX-3 [85]
Gambierdiscus cheloniae MTX-3gambierone[6,86]
Gambierdiscus excentricus MTX-4 [83]
Gambierdiscus honu MTX-3 [6,34]
Gambierdiscus pacificus51-hydroxyCTX-3C, 2,3-dihydroxyCTX-3CMTX-3 [6,87]
Gambierdiscus polynesiensisP-CTX-4A, P-CTX-4B, P-CTX-3C, M-seco-CTX-3C, 49-epiCTX-3CMTX-1, MTX-3 [31]
Gambierdiscus toxicusP-CTX-3C, 2,3-dihydroxy P-CTX-3C, P-CTX-4A/B Gambieric acids, gambierol, gambieroxide[88,89,90]
Table
Table 2. Examples of CTX detection methods and their characteristics.
Table 2. Examples of CTX detection methods and their characteristics.
Detection MethodsAdvantagesShortcomingsCommercialized Kits
Mouse bioassayEasy to useExpensive, lacks specificity, not sensitive enough, and ethical concerns
Mouse neuroblastoma cell-based assay (CBA-N2a)AutomatableExpensive, time-consuming, requires specific instruments, and lacks specificity [132]
RadioimmunoassaySensitiveExpensive, time-consuming, and requires specific instruments
Fluorescent receptor binding assayFastDetection limit is higher than for the CBA-N2a [126]SeaTox® F-RBA [126]
Enzyme immunoassayEasy to useCross-reaction with other polyether compounds [25]Ciguatect™ [127]
Antibody-based immunoassaysSensitive, field applicationCross-reaction with okadaic acid [121]
Membrane immunobead assaySpecificityVariation in signal strength [128]Cigua Check® [128]
Enzyme-linked immunosorbent assay (ELISA)Sensitive, low detection limitNeed laboratory conditions, require anti-CTX antibodiesCTX-ELISATM 1B [133]
Capillary electrophoresis-based immunoassayFaster than ELISANeed laboratory conditions, require anti-CTX antibodies
Electrochemical immunosensorsLow cost, integrable
LC–MS/MSSensitive, selectiveLack of reference toxins, cannot be used in the field
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Wang, D.-Z.; Xin, Y.-H.; Wang, M.-H. Gambierdiscus and Its Associated Toxins: A Minireview. Toxins 2022, 14, 485. https://doi.org/10.3390/toxins14070485

AMA Style

Wang D-Z, Xin Y-H, Wang M-H. Gambierdiscus and Its Associated Toxins: A Minireview. Toxins. 2022; 14(7):485. https://doi.org/10.3390/toxins14070485

Chicago/Turabian Style

Wang, Da-Zhi, Ye-Hong Xin, and Ming-Hua Wang. 2022. "Gambierdiscus and Its Associated Toxins: A Minireview" Toxins 14, no. 7: 485. https://doi.org/10.3390/toxins14070485

APA Style

Wang, D. -Z., Xin, Y. -H., & Wang, M. -H. (2022). Gambierdiscus and Its Associated Toxins: A Minireview. Toxins, 14(7), 485. https://doi.org/10.3390/toxins14070485

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop