Environmental roles and biological activity of domoic acid: A review

Algal Research 13 (2016) 94–101

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Environmental roles and biological activity of domoic acid: A review Kornelia Zabaglo ⁎, Ewelina Chrapusta, Beata Bober, Ariel Kaminski, Michal Adamski, Jan Bialczyk Department of Plant Physiology and Development, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland

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Article history: Received 7 July 2015 Received in revised form 2 November 2015 Accepted 25 November 2015 Available online xxxx Keywords: Diatom Domoic acid Amnesic shellfish poisoning Pseudo-nitzschia

a b s t r a c t Domoic acid (DA) is classified as a potent neurotoxin, an excitatory amino acid naturally produced by several diatom species belonging to the genus Pseudo-nitzschia. The molecule is excitotoxic in the vertebrate central nervous system, myocardium and other organs that contain glutamate receptors. The biggest risk of DA exposure for humans comes from the consumption of DA-contaminated shellfish. Algal blooms, including diatom blooms, are an excellent source of biomass for filter-feeding marine organisms, which makes the knowledge of DA occurrence quite relevant. In recent years, DA exposure has become more widespread due to the higher prevalence of toxigenic Pseudo-nitzschia blooms and increased human consumption of seafood. There is therefore an urgent need to update frequently the latest information on DA. Symptoms of having consumed high doses of DA are known but there are still significant gaps in knowledge of the health effects of chronic exposure to low levels of DA as well as of effective methods for removing DA from shellfish tissues. Here we summarize current knowledge about DA: its structure and biological activity, degradation in seawater, ecological and physiological roles, new producers, and risks of human exposure to high and low concentrations of this toxin. © 2015 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . 2. Structure and stability of domoic acid . . . . . . . . . . . 3. Producers of domoic acid . . . . . . . . . . . . . . . . 4. Degradation of domoic acid . . . . . . . . . . . . . . . 5. Food web transfer of domoic acid and human exposure risk . 6. Toxicology and symptoms of amnesic shellfish poisoning . . 7. Known or unrecognized ecological roles of domoic acid . . . 8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The increase in frequency and prevalence of periodic and sudden harmful algal blooms (HABs) in seawater has become a growing problem worldwide [1–5]. Marine HABs that produce phycotoxins are formed mainly by marine phytoplankton such as dinoflagellates and diatoms, which are capable of rapid growth in all geographical areas. These organisms produce a wide range of biologically active secondary metabolites, some of which have therapeutic potential [6] or toxic properties to humans and animals [7]. Algal blooms are an excellent source

⁎ Corresponding author. E-mail address: [email protected] (K. Zabaglo).

http://dx.doi.org/10.1016/j.algal.2015.11.020 2211-9264/© 2015 Elsevier B.V. All rights reserved.

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of biomass for filter-feeding marine organisms, which makes the knowledge of phycotoxin occurrence quite relevant. Such phycotoxins cause N60,000 marine mammal poisonings worldwide per year, with a mortality rate of 1.5% [8]. The bioaccumulation of these toxins in filterfeeding marine organisms, and their transfer to higher trophic levels, are a great threat to marine ecosystems, fisheries resources and human health [7,9]. The increased prevalence of phycotoxins also leads to large economic losses for finfish and shellfish farming [10]. Human poisonings induced by phycotoxins in shellfish or fish tissues are divided into the following six groups (types), based on their exerted effects: paralytic shellfish poisoning (PSP) [11], neurotoxic shellfish poisoning (NSP) [12], amnesic shellfish poisoning (ASP) [13–15], diarrhetic shellfish poisoning (DSP) [16], azaspiracid poisoning (AZP) [17] and ciguatera fish poisoning (CFP) [8,18,19].

K. Zabaglo et al. / Algal Research 13 (2016) 94–101

The primary aim of this review is to update and complete the information described in previous reviews on DA [10,20–24]. In recent years, DA exposure has become more widespread, accompanied by an increased frequency and intensity of toxic Pseudo-nitzschia blooms [10, 20]. One recent example is the major toxic bloom occurring during May to August 2015, along most of the west coast of North America [25]. This, plus the significant increase in global consumption of shellfish [26,27], entails the need for frequent updates on DA, in particular relating to its sources and human health risks. DA is the toxin responsible for ASP. The first documented episode of ASP occurred in eastern Canada in 1987, and was caused by the consumption of blue mussels (Mytilus edulis) containing the potent neurotoxin, DA. As a result of the poisoning, at least four people died and 143 were hospitalized. The symptoms of the poisoning included both gastrointestinal (vomiting and diarrhea) and neurologic effects (short-term memory loss, confusion, seizures, coma, and even death) [7]. The source of DA was the diatom Pseudo-nitzschia multiseries, which was the main food for mussels [13,28]. The impact of DA has also been observed among marine wildlife representing various trophic levels in the food web. This toxin was the cause of death or illnesses of many fish, seabirds, sea otters, sea lions and whales [8,10,29]. Therefore, DA and the organisms that produce this toxin have become the subject of intensive research, but information about DA is still incomplete [20]. Studies have shown previously unknown threats and novel syndromes caused by acute and chronic exposure to DA [30]. This review summarizes and encompasses 1) detailed structure and properties of DA; 2) the latest list of species able to produce DA; 3) possible ways of human exposure to DA; 4) degradation of DA in the environment; 5) available knowledge on the ecological roles of DA; 6) toxicology and new symptoms of amnesic shellfish poisoning; and 7) graphical mechanism of DA action in nerve cells. 2. Structure and stability of domoic acid DA belongs to the kainoid class of compounds [31]. The full structure of DA, which was confirmed following total synthesis, was first presented by Ohfune and Tomita [32]. DA is a water-soluble, crystalline, nonprotein amino acid with a molecular weight of 311 Da. It contains a proline ring, one imino group and three carboxyl groups (Fig. 1). The carboxyl groups are responsible for the high hydrophilicity and polarity of the molecule [33]. The chemical structure of DA is similar to that of another neurotoxin, kainic acid (KA), and to that of glutamic acid (Glu) (Fig. 1). DA has many derivatives, including iso-domoic acids (iso-DAs) (designated A through H) and 5′-epi-domoic acid [24,34]. Iso-DAs were first identified in the red alga Chondria armata [35]. Since the identification of Iso-DAs, the production of some of them has been confirmed in other marine diatoms, including Nitzschia navisvaringica [36], Pseudo-nitzschia australis [37] and Pseudo-nitzschia seriata [38]. Sometimes, a small amount of Iso-DAs is found in plankton cells and molluscan shellfish [31,39]. Iso-DAs also constitute degradation products of DA formed under exposure to UV radiation or heat [40,41] (see Section 4). Isomers are present in the environment at lower concentrations than DA. Moreover, the affinity of iso-DAs to the glutamate receptor is approximately 240 times lower than that of DA [39]. This lower affinity is related to the lack of the two conjugated

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Table 1 Physical and chemical properties of domoic acid [134,135]. IUPAC name Empirical formula Molecular weight Density Absorbance maximum Solubility in water Appearance Lethal dose

(2S,3S,4S)-2-carboxy-4-1-methyl-5(R)-carboxyl-1(Z)3(E)-hexadienyl pyrrolidine-3-acetic acid C15H21NO6 311.33 g mol−1 1.273 g cm−3 242 nm 8 mg mL−1 Finely crystalline white solid LD50 (intraperitoneal injection mouse) = 3.6 mg kg−1 LD50 (oral mouse) = 68 mg kg−1

double bonds between the 1′-2′ carbon atoms in the molecular structure of iso-DAs [42]. Therefore, iso-DAs are not a major threat to humans or animals, in contrast to the parent toxin [43]. Relevant physical and chemical properties of DA are summarized in Table 1. 3. Producers of domoic acid Originally, DA was isolated from the red seaweed C. armata and was used in Japan as an intestinal parasite remedy [6] and as an insecticidal compound [44]. Additionally, the ability to produce DA has been reported in other genera of marine diatoms, such as Amphora coffeaeformis [45] (although this finding has been disputed [46]), N. navis-varingica [47] and Nitzschia bizertensis [48] (Table 2). Pseudo-nitzschia is a cosmopolitan genus of pennate diatoms with at least one-third (19) of the species capable of DA synthesis, out of the 45 described to date [49]. P. multiseries [28], P. australis [50,51] and P. seriata [52] are recognized as major DA producers, which can produce even N 10 pg DA cell−1. Other species belonging to the genus Pseudo-nitzschia produce b1 pg DA cell−1 [10,53]. The occurrence of toxic Pseudo-nitzschia species has been reported in many coastal areas on all continents, except Antarctica [20]. In polar regions, DA production has been confirmed only in Greenland, by P. seriata, in amounts of 1.46–1.93 pg DA cell−1 [38]. Although toxic Pseudo-nitzschia species (e.g., P. australis [54], P. calliantha, P. galaxiae, P. multiseries, P. multistriata [55], P. pseudodelicatissima [56], P. pungens and P. seriata [10,52]) are found in European waters, neither mild cases of DA poisoning nor human deaths associated with DA have yet been reported [10,57]. The lack of DA poisoning may result from the low production of DA by the species present [58] or the lack of methods to detect the low concentrations of DA on the human body [30]. However, it cannot be assumed that mild cases of DA poisoning have not occurred [10]. 4. Degradation of domoic acid DA is stable for nine months in an aqueous acetonitrile solution at 20 °C [59] and for one year in an aqueous solution (pH 5–7) at 4 °C in the dark [20,60]. Long-term storage is best at −80 °C [60]. Decomposition is observed at high temperatures (N50 °C) [59], at extreme pH (pH 2 or 12) or during exposure to oxygen [60]. However, cooking shellfish products containing DA at 121 °C does not reduce its absolute concentration [61]. Any reduction in DA content in shellfish tissue during heating or freezing is caused by the translocation of hydrophilic toxin

Fig. 1. Structures of domoic acid, kainic acid and glutamic acid.

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Table 2 Primary producers of domoic acid. Species

References for toxicity

Red macroalgae Alsidium corallinum Amansia glomerata Chondria armata Chondria baileyana Digenea simplex Vidalia obtusiloba

[45,46] [136] [44] [137] [136] [136]

Diatoms Amphora coffeaeformis Nitzschia bizertensis Nitzschia navis-varingica Pseudo-nitzschia australis Pseudo-nitzschia brasiliana Pseudo-nitzschia caciantha Pseudo-nitzschia calliantha Pseudo-nitzschia cuspidata Pseudo-nitzschia delicatissima Pseudo-nitzschia fraudulenta Pseudo-nitzschia fukuyoi Pseudo-nitzschia galaxiae Pseudo-nitzschia cf. granii Pseudo-nitzschia kodamae Pseudo-nitzschia multiseries Pseudo-nitzschia multistriata Pseudo-nitzschia plurisecta Pseudo-nitzschia pseudodelicatissima Pseudo-nitzschia pungens Pseudo-nitzschia seriata Pseudo-nitzschia subpacifica Pseudo-nitzschia turgidula

[45,46] [48] [47,138] [51] [139,140] [141] [142] [143] [144,145] [146] [147] [148] [128] [149] [28] [55] [150] [142,151] [140,144] [52] [150] [144]

between different tissues or from the body to the surrounding solution, rather than its degradation [62]. The decomposition of DA has been reported after exposure to aqueous methanol. The concentration of toxin extracted from king scallops (Pecten maximus) stored in aqueous methanol was reduced to 45% over 2 weeks [63]. The most important factor controlling the biogeochemical cycling and ultimate fate of DA in seawater is photochemical degradation. Photodegradation of DA molecules is observed in natural and artificial seawater and in deionized water [64]. Wright et al. [31] showed that the exposure of DA to high-energy ultraviolet radiation (253.7 nm) causes its rapid degradation in seawater. Under normal light conditions, which are usually used for Pseudo-nitzschia growth studies in the laboratory, the concentration of DA decreased by 68% in cell-free growth media within 12 days [65]. Bouillon et al. [66] demonstrated a loss of DA (from 84 to 18 nmol L−1) in light-exposed cells over a 10-h incubation period, but not in the dark controls. The photodegradation of DA via sunlight-mediated reactions depends on water depth and is limited to the upper few meters or centimeters [66]. The maximum degradation of toxin is observed at a wavelength of ~330 nm. These results revealed that, at the sea surface, UV-B removes N 9% and UV-A removes N 90% of the DA. Of the total dissolved DA, 1.7% to 3.5% is photochemically removed in the upper layer of water (5 m depth) each day. An increase in DA photodegradation is also correlated with temperature. The DA photodegradation rate coefficient increases from 0.12 h− 1 at 5 °C to 0.15 h−1 at 20 °C [66]. Additionally, Fisher et al. [67] found that iron and dissolved organic matter indirectly stimulate DA photodegradation. In contrast, Bouillon et al. [66] demonstrated that the addition of humic material, dissolved oxygen and iron or copper does not affect the rate of this process. The photochemical degradation of DA increases after the addition of Fe(III) only in deionized water, and a similar effect was not found in seawater [64,66]. Photodegradation is not the only way to eliminate DA in seawater. Studies have shown that bacteria also have the ability to degrade DA, but the rate of biodegradation, depends on their origin. Hagström

et al. [68] noticed that only bacteria from the location of the P. multiseries bloom were able to degrade DA. Similarly, Stewart [69] demonstrated that bacteria of the genera Alteromonas and Moraxella isolated from a P. multiseries culture were able to degrade pure DA when added to the medium. Stewart et al. [70] also noted that some bacteria, such as Alteromonas and Pseudomonas isolated from blue mussels (M. edulis) and softshell clams (Mya arenaria), are able to biodegrade extracellular DA in water. It is believed that these bacteria enable the rapid depuration of DA from the body of molluscan shellfish [70]. Toxin levels in anchovies and sand crabs, which accumulate DA during toxic Pseudo-nitzschia blooms, are not detectable a week after the disappearance of the bloom [71]. Sea scallops (Placopecten magellanicus) and red mussels (Modiolus modiolus) have a significantly slower rate of DA depuration, due to the temporary occurrence of bacteria with this capability [70].

5. Food web transfer of domoic acid and human exposure risk In marine waters, the presence of extracellular DA is not a risk because DA does not accumulate in the water column, due to photodegradation [66] or biodegradation [68–70]. Small amounts of DA released into the water column are rapidly diluted to concentrations that are not life-threatening [72]. However, the absorption of DA onto sediments may have a long-lasting impact on the benthic food chain [10]. During toxic Pseudo-nitzschia blooms, DA is accumulated by zooplankton, molluscan shellfish, crustaceans, echinoderms and worms, demonstrating its stable transfer through the marine food web [73– 77]. DA bioaccumulation in the marine food chain has been also observed in fish, seabirds [78] and marine mammals that feed on contaminated food [23,29,79–81]. The main path for DA intoxication for people is via the consumption of contaminated food products (e.g., squid, scallops, mussels, razor clams) [10,82]. The consumption of blue mussels (M. edulis) containing up to 900 μg DA g−1 was the cause of human poisoning in Canada in 1987 [28]. During toxic Pseudo-nitzschia blooms, DA is routinely detected in seafood products [83]. After the incident in Canada, the regulatory limit for toxin concentration was set at 20 μg DA g− 1 wet weight shellfish tissue, and this limit has been adopted internationally [84]. EFSA [57] showed that an average of 59% of scallops tested contained DA at level higher than the EU regulatory limit [10,57,85]. McHuron et al. [80] documented that free-ranging and stranded harbor seals inhabiting the coast of California were exposed to the toxin. DA was found in 65% of the urine samples, and it was also detected in feces, stomach contents, milk, amniotic fluid, fetal meconium and fetal urine [80]. DA was also identified in the milk of naturally exposed California sea lions [86]. Indeed, young mammals are mostly exposed to DA in utero and during lactation. Maucher et al. [87] showed that the elimination of DA from the body takes longer for pregnant than for non-pregnant rats. DA is retained in the amniotic fluid and in the brain of pups. Consumption by pregnant women of seafood contaminated with DA could affect the neurodevelopment of their fetus [80,86,88]. Sensitivity to DA toxicity also depends on the age and sex of the organism. The symptoms induced by DA may be more severe in men than in women. Wetmore and Nance [89] noticed greater cell loss in adult male rats than in female rats after administration of DA into the lateral septal area. Baron et al. [90] reported that DA-induced behavioral responses in rats are quicker in females than in males. Acute toxicity was shown in 2/7 male rats and 0/8 female rats dosed with 1.8 mg DA kg−1. Thus, it could be argued that male rats are more susceptible to neurotoxicity than female rats, whereas female rats are affected more quickly than male rats [90]. Studies have also shown a higher vulnerability to DA in rats during early postnatal development [91,92]. Data from the 1987 incident in Canada show a higher sensitivity to the neurotoxicity of DA in elderly people [7]. Also people with compromised health, pregnant women, infants and children are more susceptible to DA poisoning [7,91,94].

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6. Toxicology and symptoms of amnesic shellfish poisoning DA is classified as a potent neurotoxin [95]. This toxin is an excitatory amino acid with a high affinity for the propanoic acid receptors (AMPA) and kainate subclasses of glutamate receptors that are present in the central nervous system (CNS) and myocardium [95–97]. The geometry of two conjugated double bonds (between the 1′-2′ carbon atoms) in the side chain affects the toxicity of the entire molecule and its interaction at glutamate receptors [42]. Indirectly, DA also causes the activation of N-methyl-D-aspartate (NMDA) receptors (Fig. 2). DA forms bonds with glutamate receptors that are three times more powerful than its KA analog and up to 100 times more powerful than Glu itself [14,15,98]. The binding of DA to kainate and AMPA receptors causes the intracellular accumulation of Ca2+. Activation of the NMDA receptors results in an uncontrolled influx of both Ca2+ and Na+ into the neurons. In contrast to glutamic acid, DA induces long-lasting depolarization [93]. Intraneuronal accumulation of excess Ca2+ leads to neuronal swelling, production of reactive oxygen species (ROS), neurological dysfunction, DNA damage, lipid peroxidation, energy depletion, mitochondrial damage and cell death [93,99]. The most susceptible region of the CNS to DA toxicity is the hippocampus, particularly the CA3 and CA1 regions [100]. DA is approximately 31 times more toxic to vertebrates when it is administered intraperitoneally than when it is administered orally [95, 101]. Additionally, the pure toxin is less neurotoxic than the shellfish extract, which may contain not only DA but also other toxic substances or it may be to synergies between DA and other compounds in the tissues [20,95]. The DA dose causing mouse deaths via intraperitoneal injection is 3.6 mg DA kg−1 body weight, whereas the dose of DA causing death via oral injection is ~ 70 mg DA kg−1 body weight (Table 1) [14,15]. The intoxication symptoms depend on the amount of toxin ingested and the health status of the poisoned person (see Section 5). Within 24 h after consuming mussels in 1987 in Canada, gastrointestinal symptoms (vomiting, diarrhea, abdominal cramps) occurred, and neurological effects (confusion, loss of memory, disorientation, seizures, coma) appeared within 48 h after intoxication [7]. Neuronal necrosis

Fig. 2. Mechanism of domoic-acid-induced neurotoxicity in nerve cells; the abbreviations and descriptions are in the text.

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and astrocytosis in the hippocampus were found in the brains of four people who died after this incident [102]. Symptoms, e.g., unstable blood pressure and cardiac arrhythmias, were also observed in people suffering from ASP, indicating DA-induced cardiotoxicity [7,93,102]. The cardiotoxic activity of DA has also been confirmed by the extensive heart damage observed in sea lions [103] and zebrafish [104] that died as a result of DA poisoning. In vitro studies have shown that stimulation of NMDA receptors in the cardiomyocyte may lead to apoptosis via Ca2+ and ROS [105]. Poisoning syndromes suggest that DA may adversely affect not only the heart but also other tissues and organs [93]. Information on the effects of DA on the kidneys is limited. Studies in rodents have shown that renal excretion is the exclusive route of systemic DA elimination [106,107]. Funk et al. [108] showed that the DA concentration in the kidney is 4-fold higher than in the liver, heart and hippocampus 30 min after injection. Oral dose toxicity studies have shown that humans are more sensitive to DA and that symptoms of poisoning occur at doses much lower than in mice, rats and monkeys. A dose (from C. armata) of 0.4–0.8 mg DA kg−1 body weight given to Japanese children did not cause adverse effects, but it did kill intestinal parasites, as intended [6]. During the incident in Canada, oral doses of 0.2–0.3 mg DA kg−1 body weight did not induce visible effects in humans, but 1.9– 4.9 mg DA kg−1 body weight resulted in confusion and disorientation [7,15]. In contrast, the oral dose of 28 mg DA kg− 1 body weight did not show any visible changes in mice [109]. Therefore, the establishment of safe exposure levels of DA for humans or other mammals is difficult [110,111]. DA is poorly absorbed in the gastrointestinal tract, and its half-life in most tissues is ca. 24 h. The toxin is excreted in the urine and feces in a chemically unchanged form. DA is quickly removed from systemic circulation, thus preventing easy transfer across the blood–brain barrier [109,112,113]. The direct effects of consuming a high dose of DA are known, but the health effects of chronic exposure to low levels of DA remain obscure [21]. Hiolski et al. [114] demonstrated that the transcription of genes involved in the proper functioning of the nervous system and neurodevelopmental processes, as well as the function of mitochondria, were significantly impaired by chronic asymptomatic exposure to low levels of DA. Impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive exposure to low levels of DA has a fundamental impact at the cellular level, which can contribute to chronic health consequences [114]. Consumption of small doses of DA (5 to 20 μg DA kg− 1 body weight), which maintains its concentration at low levels in the blood plasma, causes severe kidney damage [106]. This was reflected in a reduction in body weight and ultrastructural changes of nephrons manifested by their vacuolization. The chronic syndrome was observed in sea lions, even in the absence of DA-producing algal blooms, suggesting that sub-lethal DA exposure leads to lasting neurological effects in mammalian species [115]. Moreover Lefebvre et al. [30] demonstrated that chronic exposure in zebrafish caused increased neurological sensitivity to DA. Existing methods to determine the DA content in the body based on behavioral observations, post-mortem histological examination of brain tissue, and testing of bodily fluids, stomach contents and feces are not effective in assessing chronic exposure to low levels of toxin [116,117]. A breakthrough discovery in this field appears to be the DA-specific antibody response, which is a signature of chronic, low-level DA exposure [30]. DA-specific antibodies have been identified initially in the zebrafish exposure model and confirmed in naturally exposed populations of wild sea lions. The discovery that exposure to low levels of DA causes a detectable antibody response may assist in the further development of diagnostic tests to assess the chronic DA exposure in humans and wildlife [30]. To date, there is no antidote for ASP [20]. The emergence of novel toxicological syndromes of chronic exposure to low doses of DA may suggest the need to reduce the permissible limit of its content in the tissues of consumed finfish and shellfish. Determining the lower limit of DA toxicity in acute and chronic exposure

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is essential to understanding the potential risk for human health and life [30,118]. 7. Known or unrecognized ecological roles of domoic acid The physiological and ecological roles of DA have not yet been fully elucidated. Several hypotheses explain the potential role of DA synthesis, but they require further study. One suggests that the toxin molecule could serve as an osmolyte under increasing salinity [119]. Doucette et al. [120] noticed the intensification of DA production with increasing salinity, although they found no evidence that DA functions as an osmolyte. Another hypothesis postulates that DA may act as a “grazing deterrent” [121]. Tammilehto et al. [122] studied the effect of the copepods Calanus hyperboreus and Calanus firmarchicus on the toxicity of Pseudo-nitzschia seriata. The presence of copepods increased the toxicity of P. seriata, suggesting that DA production may be related to a defense against grazing and that the occurrence of zooplankton may be one of the factors affecting the toxicity of Pseudo-nitzschia blooms in the sea. This effect was observed even without direct contact of these organisms, as when they were separated by a membrane. In this case, DA production was induced by potential waterborne cues from the copepods or changes in water chemistry [122]. The increase of P. seriata toxicity in the presence of copepods was also noted by Harðardóttir et al. [123]. In contrast, Olson et al. [124] suggested that the impact of copepod grazing on Pseudo-nitzschia populations is negligible. One of the most common hypotheses is that DA can stimulate changes in the dynamics and composition of phytoplankton, thus allowing diatoms to gain an ecological advantage. Xu et al. [125] demonstrated the ability of P. pungens and P. multiseries to produce extracellular compounds capable of lysing and/or inhibiting the growth of co-occurring phytoplankton. Both P. pungens and P. multiseries produced DA, but the observed allelopathic effect of Pseudo-nitzschia was unlikely related to the toxin. Rather, other yet-unidentified compounds, classified as allelochemicals, which act directly on target species, may be responsible for this. Furthermore, Lundholm et al. [126] showed that the addition of DA-producing P. multiseries to cultures of other phytoplankton species (Chrysochromulina ericina, Heterocapsa triquetra, Eutreptiella gymnastica, Rhodomonas marina) had no allelopathic effect. Likewise, Prince et al. [127] demonstrated that DA addition had little effect on the growth of the diatom Skeletonema marinoi in monocultures. However, when S. marinoi was co-cultured with Pseudo-nitzschia delicatissima, DA caused an increase in P. delicatissima cell number by 17% and a decrease in S. marinoi cell number by 38%, after 22 days of cultivation, compared to DA-free cultures. These results were observed only under ironreplete conditions and did not recur in iron-deficient conditions. This provides evidence that DA can improve the competitive ability of Pseudo-nitzschia species, and that iron may play a key role in this process [127]. Trick et al. [128] observed changes caused by the addition of DA and iron to samples of natural phytoplankton communities in subarctic Pacific surface waters. The addition of iron stimulated the growth of toxigenic Pseudo-nitzschia spp., while limiting the biomass of other phytoplankton and cell abundance of other diatoms. The production and release of DA in a response to iron addition thus apparently provided Pseudo-nitzschia a competitive advantage over other phytoplankton. Similarly, the addition of dissolved DA altered phytoplankton community structure to benefit Pseudo-nitzschia spp., apparently by increasing the relative availability of the ambient organically dissolved iron, rather than by the impact of DA itself. Studies have also indicated the role of DA as a binding ligand for trace metals. DA released into the water column is an effective chelator for Cu(II) and Fe(III), which increases the bioavailability of iron and decreases the toxicity of copper [128,129]. Bound trace metal ions are not directly bioavailable to phytoplankton. Thus, DA may be involved in a high-affinity iron uptake system [129,130]. Bates et al. [131] documented that short, old cells that have undergone many generations of vegetative division produce less DA than

large, new cells formed after sexual reproduction. However, this toxin has not been found to play a role in sexual reproduction [131,132]. A final hypothesis is that DA may serve as a mechanism to eliminate excess photosynthetic energy when the cells are no longer capable of optimal growth. Support for this is that the highest production of DA was when ATP and NADPH from photophosphorylation were not used in primary metabolism [133]. Each of these hypotheses requires thorough research, as none has yet to be proven conclusively. It is well known that DA synthesis is stimulated by various factors, suggesting that it is useful for, but not essential to, the vegetative growth of Pseudo-nitzschia, especially because many species and strains of Pseudo-nitzschia do not produce any detectable DA [10,20]. 8. Conclusions The increase in frequency, intensity and geographical distribution of DA-producing diatom blooms has become a growing problem worldwide. Human health is threatened by consuming DA-contaminated organisms. At the same time, the consumption of shellfish and therefore its demand, is growing steadily globally [27]. Therefore, knowledge about the risk of human exposure to DA should be disseminated widely and made more accessible to both physicians and to the lay person. There is still little information about the effects of long-term exposure to low levels of DA. Previous studies suggest that the accepted limit for DA consumption regularly causes undesirable changes at the cellular level. Effective methods for removing DA from shellfish tissues are also unknown. Consequently, there is an urgent need for continued, but improved, effective monitoring of the occurrence of DA-producing diatoms in seawater, especially around aquaculture sites. Food contaminated with DA cannot be consumed, thus causing financial hardship to harvesters. Current as well as novel research using advanced technology may allow for a better prediction of DA-producing diatom blooms, as well as for a more complete assessment of the impact of DA on human health. Acknowledgments We thank Dr. Stephen S. Bates (Fisheries and Oceans Canada) for his constructive helpful comments that improved the paper. The Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University is a partner of the Leading National Research Center (KNOW), supported by the Ministry of Science and Higher Education. References [1] H.P. Van Egmond, G.J.A. Speijers, Natural toxins II. Phycotoxins, in: K. Van der Heijden, M. Younes, L. Fishbein, S. Miller (Eds.), International Food Safety Handbook. Science, International Regulation and Control, Marcel Dekker Inc., New York 1999, pp. 357–368. [2] M.L. Parsons, Q. Dortch, R.E. Turner, Sedimentological evidence of an increase in Pseudo-nitzschia (Bacillariophyceae) abundance in response to coastal eutrophication, Limnol. Oceanogr. 47 (2002) 551–558. [3] G.M. Hallegraeff, A review of harmful algal blooms and their apparent global increase, Phycologia 32 (1993) 79–99. [4] D.M. Anderson, A.D. Cembella, G.M. Hallegraeff, Progress in understanding harmful algal blooms: paradigm shifts and new technologies for research, monitoring, and management, Ann. Rev. Mar. Sci. 4 (2012) 143–176. [5] D. Anderson, HABs in a changing world: a perspective on harmful algal blooms, their impacts, and research and management in a dynamic era of climatic and environmental change, in: H.G. Kim, B. Reguera, G.M. Hallegraeff, C.K. Lee, M.S. Han, J.K. Choi (Eds.), Harmful Algae 2012, Proceedings of the 15th International Conference on Harmful Algae, International Society for the Study of Harmful Algae, Busan, Korea 2014, pp. 3–17. [6] K. Daigo, Studies on the constituents of Chondria armata. II. Isolation of an anthelmintical constituent, J. Pharm. Soc. Jpn. 79 (1959) 353–356. [7] T.M. Perl, L. Bédard, T. Kosatsky, J.C. Hockin, E. Todd, R.S. Remis, An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid, N. Engl. J. Med. 322 (1990) 1775–1780. [8] F.M. Van Dolah, Marine algal toxins: origins, health effects, and their increased occurrence, Environ. Health Perspect. 108 (2000) 133–141.

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