The plankton population in form of desirable bloom undertaken throughout the culture period as part of best pond management practice. Phytoplankton is used as a food stock for the production of zooplankton which are in turn used to feed cultured organisms. Living dinoflagellates are one of the most important components in phytoplankton. Many dinoflagellates are primary producers of food in the aquatic food webs. Dinoflagellates are an integral part of the first link in the aquatic food chain: the initial transfer of light energy to chemical energy photosynthesis.
The dinoflagellates along with other phytoplankton enter in to the aquaculture pond through water intake from adjacent tide water. Due to applied nutrients and water conditions, immediately the dinoflagellates proliferate its bloom in desire level or sometimes in heavy blooms which is harmful to pond condition.
These blooms appear in red-brown or red -green water coloration. Of the known species, about 60 are able to produce complex toxins. Dinoflagellates are a very successful group, at times to the detriment of the ecosystem.
When conditions are favorable, a population explosion or bloom may occur, sometimes resulting in contamination of fish and shellfish and posing a threat to human and animal health. The growth of dinoflagellates are regulated by several factors including water, temperature, solar irradiation, turbidity, and nutrient concentrations.
Acidic pond water is typically treated with calcium-based compounds aiming to raise the pH and promotes the growth of phytoplankton. Nutrients are supplied by the use of fertilizers and artificial feeds in which aquaculture ponds usually meet the ideal conditions for phytoplankton growth. These are tiny plants in plank tonic form live in sea water and obtain source of energy from sunlight during day.
In darkness the dinoflagagellates emit bright blue light luminescence in response to movement within water. This mechanism is regulated by activity of enzymes luciferases upon luminescent luciferins and requires oxygen. The dinoflagellates are making flash light during dark time and light became brightest after several hours of darkness. In their study, despite general morphological characters agreed with those reported for A.
Their phylogenetic analysis supported their identification as A. Previously A. The report of this toxin-producing species account to four PSTs producing dinoflagellates in the Brazilian coasts, where more studies are needed Menezes et al.
Molecular markers have been particularly useful for discerning Alexandrium species when morphological traits are not sufficient, to know the genetic diversity among populations, or to determine phylogenetic relationships among species geographically distant. In LAm the few genetic studies in Alexandrium species have allowed to corroborate taxonomic questions, biogeographic history, and changes in distribution patterns.
A classic study related with molecular phylogeny of Alexandrium genus in North America was published by Scholin et al. Alexandrium catenella and A. The molecular markers developed by these authors are still used to answer current taxonomic and phylogenetic issues Scholin et al.
Six years later, Uribe et al. Moreover, ESTs of A. Taking into account that bioluminescence proteins were among the most expressed genes in A. A remarkable variability at the genetic and physiological level among strains was observed.
Intraregional diversity of this species, partial sequences of the LSU gene, and ITS regions of rDNA, as well as toxicological and morphological analysis, have been evaluated.
However, a significant genetic diversity was observed between Chilean strains with ITS sequences. Although morphological variations within and between strains were observed, some features were absent, such as a ventral pore in the 1' plate, which was a distinctive characteristic in Chilean strains.
These approaches indicate a significant intraregional variability, however this genetic diversity does not agree with the supposed northward expansion along the west coast of South America.
Sequences from the ITS1, 5. Species-specific primers designed for real time PCR were a good molecular tool to detect this dinoflagellate in bivalves such as M. Interestingly, they did not find any close relationship to any of the A. According to the molecular information, they proposed that the isolates used for this study were probably transported from Uruguayan waters during coastal fronts in Argentina and Uruguay; they considered the possibility of further outbreaks from transported cells or resting cysts in Brazilian coasts Persich et al.
This hypothesis was proposed since the LSUrDNA sequences from South American isolates have enough differences from the North American modern populations that may indicate that these populations have been separated for a long time, and evolutionary processes have occurred Persich et al. Recently, Fabro et al. Their results showed some variations in morphological characteristics, but were consistent with classical descriptions of A.
Using qPCR method, it was possible to corroborate the presence of A. This was the first report of A. Cruzat et al. The authors found 33 haplotypes, three of these highly frequent, increasing the genetic diversity from 2.
All sequences agreed with the morphological identification for A. Toxin profiles, morphology and phylogeny were also investigated by Salgado et al.
The phylogenetic reconstruction was performed with LSUrRNA sequences, showing a geographic distribution congruent with the selected strains. Therefore, they suggested the possibility of them being conspecific species, and pointed out the need of genetic studies on wild and cultured populations to confirm their taxonomic identity, given that the use of morphological characters as an only tool for identification has caused misidentifications.
Phylogenetic reconstruction showed a monophyletic clade, which included Brazilian and Asiatic strains, with enough genetic distance between them.
Moreover, based on their results they propose a fraterculus group A. Two strains isolated from Guanabara Bay formed a monophyletic clade with both molecular markers; suggesting it could be a new species of Alexandrium closely related to A.
In the Mexican Pacific coast A. Differences in cell densities and their distribution in water column were observed, and two explanations were proposed: A. Dinoflagellates are characterized by different ecological relationships.
A relationship that has acquired a great interest is the one established between bacteria and dinoflagellates. This interest relies since bacteria are capable of regulating the different HAB phases, in addition that they are considered to have a role in cell toxicity, growth, and other physiological aspects of dinoflagellates Hold et al.
Alexandrium strains from the southern coast of Chile grow in association with heterotrophic bacteria that mostly affect its growth by the synthesis of algicidal substances that promote cell lysis Vasquez et al. The proliferation of A. Also, this was the first time that bacteria of the genus Moraxella sp.
When the same bacteria, free of organic nutrients, were returned to the algal culture they displayed no detrimental effects on the dinoflagellate and recovered their symbiotic characteristics. Thus, bacterial-derived lytic activities are expressed only in the presence of high-nutrient media and it is likely that in situ environmental conditions modulate their expression Amaro et al. Another aspect to consider is the geographical distribution of strains, since despite isolating the bacteria from different regions, the associated bacteria community is similar, recording the presence of the genera Psychrobacter, Sulfitobacter, Aeromonas, Flavobacterium, Pseudomonas, Proteus and Moraxella in isolates of A.
Bacterial phagocytosis by Alexandrium has also been documented Silva, In total absence of bacteria, cell toxicity of A. In LAm, the three main marine dinoflagellate genera that produce PSTs are widely distributed and represent an important risk for human health, economic and ecological reasons.
PSTs have been also related to epizoic events, fish and aquaculture losses, though most of the times the impacts have not been calculated in economic terms. Despite these problems and risks, few countries have established and maintained monitoring programs, and losses due to PSTs are becoming an important public concern.
Few studies regarding P. Studies related to bloom dynamics, autoecology and toxins of G. Even though natural plankton samples have a low toxicity, and a profile dominated by the less toxic sulfocarbamoyl analogs, this profile can change in mollusks tissues due to their digestive metabolism and become highly toxic for consumers. Interestingly, autoecology studies have demonstrated that the cell toxin content is higher under in vitro conditions than in the natural environment, which can be partly explained by the higher nutrient concentrations used in culture media.
It has also been proposed that the toxin composition is not a conservative feature in G. It has also been demonstrated that under culture conditions, G.
Nevertheless, some variations exist, which have been related to strain origin, temperature, and culture age. Table 7. Abiotic factors during HABs of G. The distribution of P. This species is found in a broad salinity range from 7 to It has been suggested that it could be an invasive species in the northern boundary of its distribution GOLCA region. Data regarding toxicity and toxin profile of natural phytoplankton samples are scarce and contradictory, carbamoyl or sulfocarbamoyl analogs can dominate.
Toxin profiles in mollusks is also quite variable. It is clear that more research and close monitoring is needed for the understanding of the bloom ecology on this species. HABs of A. Deep water upwelling also trigger blooms and cyst beds play an important role in the initiation of blooms. Also, an important expansion in the northern limits of these species has been registered, but the reason for this remains to be understood.
Seasonal differences in cell toxicity and in toxin analogs in A. Regarding toxin analysis in PSTs producers, an important factor to be considered is the different techniques used to extract and analyze toxins which have led to different and confusing results in some cases samples from the same species and region.
Different studies have used two acids hydrochloric acid or acetic acid in various concentrations, sometimes even using thermic processing of samples. Post-column and pre-column oxidations methods are used, with different drawbacks such as lack of separation of some analogs or the inability to detect some others, and even the appearance of phantom peaks that could be mistaken for toxin analogs.
Also, GC toxins are not yet considered in normal analysis and their presence is often neglected due to the longer retention times needed to elute them, and to the lack of commercial standards. It is clear that only a few countries in LAm have the sufficient technological and technical capacity to analyze paralytic toxins a factor that needs to be considered to support both research and monitoring programs in this region.
Other studies such as molecular biology, in silico analyses in order to assess toxicity, nutrient assimilation, trophic interactions, and bacterial community studies are still incipient in LAm, but given the great importance of PSTs producing species in LAm, undoubtedly they will continue to increase in the next few years.
This review evidences that studies have been concentrated in relatively few countries, species and topics. And in some regions studies are only supported for a few years by specific research groups. In general, there is equipment and technical limitation in the different regions of LAm. A regional HAB research program is needed in order to have a more complete understanding of the environmental conditions that favor the PST blooms in this region.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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PSP toxins are the most well known potent neurotoxins that specifically and selectively bind the sodium channels on excitable cells [ 27 ]. In , Hill postulated a plugging model for the binding of the sodium channel with saxitoxin [ 28 ].
In this model, the toxin molecular penetrates rather deeply inside the channel and plugs it, having formed an ion pair with an anionic site thought to be located near the bottom of the channel. However, this model could not explain the lack of anticipated steric interactions with other structurally unfolded toxins, the gonyautoxins. Later, Kao and Walker proposed a model which placed the toxin molecules on the outside edge of the channel with the guanidinium group on the top of the channel entrance [ 29 ].
Meanwhile Shimizu also suggested a three-point binding model involving two hydrogen bonds with the ketal OHs, and ion pairing of the guanidinium group with an anionic site on the outside surface of the membrane [ 30 ]. With the success of cloning of the sodium channel [ 31 ], more precise information regarding the toxin-binding mode has arisen from the molecular biological studies of the sodium channel.
The resulting widespread blockade prevents impulse-generation in peripheral nerves and skeletal muscles. Saxitoxin also affects skeletal muscle directly by blocking the muscle action potential without depolarizing cells, which abolishes peripheral nerve conduction but with no curare-like action at the neuromuscular junction. Surprisingly, selective pressure from the presence of STX in the natural environment can select for mutations in the ion selectivity filter that cause resistance to these toxins in the softshell clam Mya arenaria [ 32 ].
NSP is caused by the ingestion of shellfish exposed to blooms of the dinoflagellate Kerenia brevis formerly Gymnodinium breve [ 33 , 34 ].
This dinoflagellate species produces two types of lipid soluble toxins: hemolytic and neurotoxic [ 35 ], causing massive fish kills, bird deaths, and marine mammal mortalities [ 36 , 37 ]. The neurotoxic toxins are known as brevetoxins, which are a suite of ladder-like polycyclic ether toxins.
Brevetoxin congeners are of two types based on backbone structure: brevetoxin B backbone type 1; PbTx-2, 3, 5, 6, 8, 9 and brevetoxin A backbone type 2; PbTx-1, 7, 10 Figure 3.
Among them, PbTx-2T is the major brevetoxin produced by K. Massive fishes are killed due to neurotoxin exposure, with the possible contribution of the hemolytic fraction. Recently neurotoxins were also found in other fish-killing flagellate species, Chatonella marina , C. Structure and species of neurotoxic shellfish poisoning toxins from marine dinoflagellates [ 4 ].
Pathogenic dose for humans is in the order of mouse units. The symptoms of NSP include nausea, tingling and numbness of the perioral area, loss of motor control, and severe muscular pain [ 43 , 44 ].
This action differs from that of PSP toxins which block the sodium channel and prevent sodium ions from passing through the membranes of nerve cells. The toxin appears to produce its sensory symptoms by transforming fast sodium channels into slower ones, which results in persistent activation and repetitive firing [ 50 ]. It was reported that brevetoxin could combine with a separate site on the gates of the sodium channel, causing the release of neurotransmitters from autonomic nerve endings.
In particular, this can release acetylcholine, leading to smooth tracheal contraction, as well as massive mast cell degranulation [ 51 ]. Recently, LePage et al. An early investigation also reported that conformational variation of brevetoxins induces a significant change in the gross shape of the molecule, which results in the loss of binding affinity and toxicity of the brevetoxins [ 46 ]. CFP, which is the most commonly reported marine toxin disease in the world, is caused by consumption of contaminated coral reef fishes such as barracuda, grouper, and snapper [ 53 , 54 ].
It is estimated that approximately 25, people are affected annually by ciguatoxins and CFP is regarded as a world health problem [ 54 ]. The origin of ciguatera toxins has been identified in a dinoflagellate species, Gambierdiscus toxicus , which originally produces maitotoxins MTXs , the lipophilic precursors of ciguatoxin [ 55 ]. These precursors are biotransformed to ciguatoxins by herbivorous fishes and invertebrates grazing on G.
The ciguatoxins are a family of heat-stable, lipid-soluble, highly oxygenated, cyclic polyether molecules with a structural framework reminiscent of the brevetoxins [ 57 — 60 ], and more than 20 toxins may be involved in CFP Figure 4 [ 53 ].
Structure and species of ciguatoxins from the dinoflagellate G. They produce more than ciguateric symptoms, classified into four categories: gastrointestinal, neurological, cardiovascular and general symptoms [ 54 , 61 ].
It should be emphasized that the symptoms of ciguatera vary in different oceans: in the Pacific Ocean neurological symptoms predominate, while in the Caribbean Sea the gastrointestinal symptoms dominate due to the difference in toxin composition. Ciguatoxin and maitotoxin are the two most common toxins associated with CFP, and they are the most lethal natural substances known.
Pharmacological studies have revealed that CTXs activate the voltage-sensitive sodium channel at nM to pM concentrations [ 61 ]. In mice, ciguatoxin is lethal at 0. Oral intake of as little as 0. However, the affinity of ciguatoxins is higher than that of brevetoxins and, thus, the affinity of CTX-1 for voltage dependent sodium channels is around 30 times higher than that of brevetoxin.
With neurophysiological testing, significant slowing of sensory and motor nerve conduction velocities, and F wave latencies has been demonstrated [ 62 , 64 , 65 ]. This observation may be related to nodal swelling and internodal length and volume increase, all of which have been confirmed with in vitro CTX exposure [ 63 , 66 ]. Calcium is the intracellular trigger for muscle contraction. Although much of the increased calcium is buffered by the sarcoplasmic reticulum, it is likely that locally increased calcium concentrations increase the force of cardiac muscle contraction as is observed in ciguatoxin poisoning.
A similar mechanism of ciguatoxin-induced intracellular transport of calcium occurs in intestinal epithelial cells. The increased concentration of intracellular calcium induced by ciguatoxin acts as a second messenger in the cell, which disrupts important ion-exchange systems, resulting in fluid secretion and symptoms of diarrhea [ 67 ]. Maitotoxin, another important neurotoxin involved in CFP, is a water soluble, ladder-shaped polycyclic molecule with numerous hydroxyl groups and sulfate groups Figure 5.
However, the primary target of MTX still remains undefined and the molecular mechanism of action is not clear. It is postulated that MTX might cause a shift in voltage-dependence of gating that favors opening of voltage-gated calcium channels at resting membrane potentials. However, MTX activates voltage-gated calcium channels indirectly via membrane depolarization as a consequence of activating a nonselective cation current [ 69 ].
Recently, Kakizaki et al. Structure of maitotoxin from the dinoflagellate G. Azaspiracid poisoning AZP , first reported from the Netherlands but later becoming a continuing problem in Europe [ 71 ], is a newly identified marine toxin disease. It is caused by consumption of contaminated shellfish associated with the dinoflagellate Protoperidinium crassipes , which can produce high intracellular concentrations of azaspiracid AZA1 , a lipophilic, polyether toxin.
AZAs differ significantly from other dinoflagellate toxins, in that they have unique structural features characterized by a tri-spiro assembly, an azazpiro ring fused with a 2,9-dinoxabicyclo[3.
Structure and species of azaspiracid poisoning toxins from marine dinoflagellates [ ]. The symptoms of AZP include nausea, vomiting, severe diarrhea and stomach cramps. Neurotoxic symptoms were also observed [ 72 , 75 , 76 ].
However, the extremely limited availability of the pure toxins has impeded the necessary investigations of AZP. Some experiments carried out with mice showed that AZP, unlike okadaic acid OA and its analog, dinophysistoxin-1, which need an initiator [ 77 ], can cause lung tumor formation during repeated administration or after withdrawal of AZP without the combined use of any initiator [ 78 ]. Also the toxin can cause necrosis in the lamina propria of the small intestine and in lymphoid tissues such as the thymus, spleen and Peyer's patches [ 78 ].
The action mechanism of AZAs is unknown at present. YTX and it analogues, which are disulphated polyether compounds of increasing occurrence in seafood, were originally isolated from the scallop Patinopecten yessoensis , collected at Mutsu Bay, Japan [ 79 ].
YTXs were produced by three dinoflagellate species, Protoceratium reticulatum , Lingulodinium polyedrum and Gonyaulax spinifera [ 80 — 83 ]. Structure and species of yessotoxins from marine dinoflagellates [ ]. However, YTXs are proved to be not diarrheogenic compared to OA and its derivatives, the DTXs, which cause intestinal fluid accumulation or inhibition of protein phosphatase 2A. Terao et al. YTX caused motor discoordination in the mouse before death due to cerebellar cortical alterations [ 90 , 92 , 93 ].
Histopathological study revealed that YTX provoked alterations in the Purkinje cells of the cerebellum, including cytological damage to the neuronal cell body and change in the neurotubule and neurofilament immunoreactivity [ 93 ].
Recently it was demonstrated that YTX is a potent neurotoxin to neuronal cells. However, the action site and the mechanism are unknown [ 94 ]. YTX was observed to induce a two-fold increase in cytosolic calcium in cerebellar neurons that was prevented by the voltage-sensitive calcium channel antagonists nifedipine and verapamil.
Previous studies also showed that YTX activated nifedipine-sensitive calcium channels in human lymphocytes [ 95 ], and YTX was postulated to activate non-capacitative calcium entry and inhibit capacitive calcium entry by emptying of internal calcium stores. PTX is a polyhydroxylated compound that shows remarkable biological activity at an extremely low concentration [ 96 ].
This toxin was first isolated from the soft coral Palythoa toxica and subsequently from many other organisms such as seaweeds and shellfish. Recently, palytoxin was also found in a benthic dinoflagellate, Ostrepsis siamensis , which caused blooms along the coast of Europe [ 97 — ], extensive death of edible mollusks and echinoderms [ 99 , ] and human illnesses [ 98 , 99 ].
Cases of death resulting from PTX have been reported to be due to consumption of contaminated crabs in the Philippines [ ], sea urchins in Brazil [ ] and fish in Japan [ — ]. PTX has become of worldwide concern due to its potential impact on animals including humans. PTX is a large, very complex molecule with both lipophilic and hydrophilic regions, and has the longest chain of continuous carbon atoms in any known natural product Figure 8.
Recently several analogues, ostreocin-D hydroxy-3, didemethyl-9,dideoxypalytoxin and mascarenotoxins were identified in O. PTX is regarded as one of the most potent toxins so far known [ ], the LD 50 s 24 h after intravenous injection vary from 0.
Toxic symptoms include fever inaction, ataxia, drowsiness, and weakness of limbs followed by death. Over the past few decades much effort has been devoted to define the action mechanisms of PTXs, however these have not been identified. Pharmacological and electrophysiological studies have demonstrated that PTXs act as a haemolysin and alter the function of excitable cells.
It also induces contractions of striated and smooth muscle cells. This paper briefly outlines the origin, structure, symptoms and molecular action mechanisms of neurotoxins produced by marine dinoflagellates. These toxins vary in chemical structure and mechanism of action, and produce very distinct biological effects, which provides a potential application of these toxins in pharmacology and toxicology. However, some of them have not been well studied due to the limited supply of pure toxins and their molecular action mechanisms are unknown.
Moreover, novel species of neurotoxins produced by dinoflagellates have been found and identified, which provide a challenge for the characterization of their toxin mechanisms and their effects on marine organisms and humans. Further work using the cell-based approach is needed to determine the precise mode of action of these novel neurotoxins from marine dinoflagellates. The authors thank Prof.
John Hodgkiss for helping to revise the manuscript. National Center for Biotechnology Information , U. Journal List Mar Drugs v. Mar Drugs. Published online Jun Da-Zhi Wang. Author information Article notes Copyright and License information Disclaimer. China, Tel. This article has been cited by other articles in PMC. Abstract Dinoflagellates are not only important marine primary producers and grazers, but also the major causative agents of harmful algal blooms. Keywords: Dinoflagellates, neurotoxins, voltage-gated ion channels, molecular action mechanism, paralytic shellfish poisoning, neurotoxic shellfish poisoning, ciguatera fish poisoning, azaspiracid poisoning, yessotoxin, palytoxin.
Introduction Over the past few decades, the occurrence of harmful algal blooms HABs has increased both in frequency and in geographic distribution in many regions of the world. Open in a separate window. Figure 1. Table 1 Seafood poisonings caused by neurotoxins identified from marine dinoflagellate species.
PSP Saxitoxins and gonyautoxins Alexandrium spp. Voltage-gated ion channels and neurotoxins It is known that most dinoflagellate toxins are neurotoxins, which interact with the specific receptors associated with neurotransmitter receptors, or voltage-sensitive ion channels Figure 1 , resulting in the observed neurotoxicity [ 12 ].
Paralytic shellfish poisoning PSP PSP is a worldwide marine toxin disease with both neurologic and gastrointestinal symptoms, which is caused by the consumption of shellfish contaminated by toxic dinoflagellates [ 21 ]. Figure 2. Figure 3. Ciguatera Fish Poisoning CFP CFP, which is the most commonly reported marine toxin disease in the world, is caused by consumption of contaminated coral reef fishes such as barracuda, grouper, and snapper [ 53 , 54 ].
Figure 4. Figure 5. Azaspiracid Shellfish Poisoning AZP Azaspiracid poisoning AZP , first reported from the Netherlands but later becoming a continuing problem in Europe [ 71 ], is a newly identified marine toxin disease. Figure 6. Yessotoxin YTX YTX and it analogues, which are disulphated polyether compounds of increasing occurrence in seafood, were originally isolated from the scallop Patinopecten yessoensis , collected at Mutsu Bay, Japan [ 79 ]. Figure 7. Palytoxin PTX PTX is a polyhydroxylated compound that shows remarkable biological activity at an extremely low concentration [ 96 ].
Figure 8. Summary This paper briefly outlines the origin, structure, symptoms and molecular action mechanisms of neurotoxins produced by marine dinoflagellates. Acknowledgements The authors thank Prof.
References and Notes 1. Anderson DM. Toxic algal blooms and red tides: a global perspective. Elsevier; New York: Smayda TJ. Novel and nuisance phytoplankton blooms in the sea: evidence for a global epidemic.
Toxic Marine Phytoplankton. Hallegraeff GM. Harmful algal blooms: a Global review.
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