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Review

Progresses of the Influencing Factors and Detection Methods of Domoic Acid

by
Aoao Yang
,
Haiguang Zhang
,
Yu Yang
and
Zhaoyu Jiang
*
College of Life Science, Linyi University, Linyi 276000, China
*
Author to whom correspondence should be addressed.
Processes 2023, 11(2), 592; https://doi.org/10.3390/pr11020592
Submission received: 7 January 2023 / Revised: 7 February 2023 / Accepted: 13 February 2023 / Published: 15 February 2023
Browse Figures
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Abstract

:
Domoic acid (DA) is a neurotoxin mainly produced by Pseudo-nitzschia diatom, which belongs to the genera Rhomboida. It can combine with the receptors of glutamate of neurotransmitters, then affecting the normal nerve signal transmission of the organism and causing nervous system disorders. However, as a natural marine drug, DA can also be used for pest prevention and control. Although the distribution of DA in the world has already been reported in the previous reviews, the time and location of its first discovery and the specific information are not complete. Therefore, the review systematically summarizes the first reported situation of DA in various countries (including species, discovery time, and collection location). Furthermore, we update and analyze the factors affecting DA production, including phytoplankton species, growth stages, bacteria, nutrient availability, trace metals, and so on. These factors may indirectly affect the growth environment or directly affect the physiological activities of the cells, then affect the production of DA. Given that DA is widely distributed in the environment, we summarize the main technical methods for the determination of DA, such as bioassay, high-performance liquid chromatography (HPLC), enzyme-linked immunosorbent assay (ELISA), biosensor, and so on, as well as the advantages and disadvantages of each method used so far, which adds more new knowledge in the literature about DA until now. Finally, the DA research forecast and its industrial applications were prospected to prevent its harm and fully explore its potential value.

1. Introduction

Domoic acid (DA) is a potent neurotoxin that is produced by some species of the diatom genus Pseudo-nitzschia (used to be called Nitzschia multiseries). The large-scale outbreak of harmful algal blooms will pose a serious threat to fishery production, marine ecological security, and the health of humans and marine organisms [1,2,3]. The first reported poisoning event caused by DA goes back to 1987 on Prince Edward Island, Canada, for people eating Mytilus edulis [4]. Previous studies have shown that DA exposure has toxic effects on an organism’s intestine of nematodes, behavior, and lifespan. Oral exposure to a few milligrams per kilogram of DA elicits gastrointestinal effects, whereas slightly higher doses cause neurological symptoms, memory impairment, and limbic system degeneration, such as hippocampal degeneration [5,6,7]. DA can accumulate in shellfish and finfish, such as bivalves and some crustaceans, under certain environmental conditions, thus causing poisoning events of aquatic organisms, which seriously threaten seafood safety [8,9,10,11,12].
Humans and wildlife alike can easily be exposed when consuming DA-contaminated seafood, especially for coastal dwelling populations. The excitotoxicity mechanism of DA involves a complex signal regulatory network, and a large number of related genes are upregulated or suppressed [5,7]. By over-activating glutamate receptors, DA causes intracellular calcium overload, resulting in dysfunction of mitochondria and endoplasmic reticulum, loss or loss of neurons in the hippocampus or amygdala of the brain, and various degenerative diseases, such as Alzheimer’s disease (Figure 1).
DA is an increasingly significant public health concern. Previous studies mentioned mainly summarized the structure and biological activity of DA, degradation of seawater, ecological and physiological effects, and risk of humans being exposed to DA [13], as well as species of the genera Pseudo-nitzschia and Nitzschia and their distribution [14]. In recent years, DA exposure has become more widespread due to drastic climate change, environmental pollution, and increased human activity [14]. Therefore, it is an urgent need to update the latest information on DA involving factors affecting DA production and the technical methods for DA detection. In this review, we characterize the physical and chemical properties, production mechanism, detection, and analysis of DA, which is encouraging for the research of DA and may prevent its harm and will help to make full use of its potential value.

2. The Discovery of DA and Its Physicochemical Properties

DA is a kind of neurotoxin that is mainly produced by Pseudo-nitzschia and can cause amnesic shellfish toxins (AST) or amnesic shellfish poisoning (ASP). It was first discovered by Takemoto and Diago from chondria armata domoi in Kagoshima Prefecture, Japan, in 1958, and then named after its Japanese name [15]. It was first isolated from Pseudo-nitzschia in Prince Edward Island, Canada, in 1987 [16]. As a strong neurotoxic substance, it can cause abdominal pain, diarrhea, and vomiting in mild cases and even coma and death in severe cases [17,18]. In recent years, new species (P. brasiliana) of Pseudo-nitzschia has been that can also produce DA [19]. So far, among the 54 species of Pseudo-nitzschia, 26 species have been confirmed to produce DA [14,20]. Table 1 shows the research history of DA from its discovery to its spread in the coastal countries of the world. Although DA poisoning cases have not been reported in some countries, such as China, DA produced by Pseudo-nitzschia has still been detected in some coastal areas, such as P. uniseriata and P. yuensis [20,21].
Domoic acid is chemically expressed as [2S-[2 α, 3 β, 4 β (1Z, 3E, 5R)]-2-carboxyl-4-(5-carboxyl-1-methyl-1,3-hexadiene)-3-pyrrolidine acetic acid, with a molecular formula of C15H21NO6 and a molecular weight of 311.34. The pure product of DA is a solid white powder with a melting point is 223~224 °C. It is soluble in water (8 mg mL−1) and slightly soluble in methanol (0.6 mg mL−1). In the ultraviolet region, its maximum absorption wavelength is 242 nm. DA can remain stable for about one year [21]. To a certain extent, the structure of DA is similar to that of excitatory amino acids glutamic acid and kainic acid. It can directly activate the kainate receptor and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor to mediate excitatory neurotoxicity and cause nerve tissue damage [41,52,53]. However, its toxic effect is 2–3 times higher than that of kainic acid and more than 100 times stronger than that of glutamic acid. In recent years, isodomoic acids A, B, C, D, E, and F have been discovered, which are homologous compounds of DA [54,55,56].

3. Factors Affecting DA Production

At present, preliminary results of the DA biosynthesis pathway have been obtained based on the functional annotation of genes in the DA transcriptome library [57]. The first step of DA biosynthesis may be that geranyl pyrophosphate (GPP) reacts with L-glutamic acid (Glu) to form N-geranyl-l-glutamic acid (l-NGG) under the catalysis of terpene cyclase. Then, the subsequent reaction takes place under the catalysis of a-ketoglutarate-dependent dioxygenase and cytochrome P450 [57]. However, the biological, physiological, and biochemical molecular mechanism of DA production is still unclear. It is worth mentioning that Pseudo-nitzschia of different or the same algal species with different strains have different interspecific and intraspecific toxin production capacities [58]. Based on the findings of existing research, the toxicity production and level of Pseudo-nitzschia species are closely related to the species/strains, physiological status, and related ecological and environmental factors (Figure 2; Table 2) [59,60,61].

3.1. Species and Life Stages of Algae

Different species or strains of Pseudo-nitzschia have varying abilities to produce DA at different life stages. Early studies found that P. multilocularis almost did not produce DA in the exponential growth phase, but in the stationary phase, it produced a significant quantity of DA [62]. Some species, on the contrary, such as P. vulgaris and P. australis, gradually increase cellular DA concentrations from the exponential growth period to the stationary period and finally discharge them into the water [33,63]. Moreover, compared with the nutrient limitation, the exponential growth period enables algae to produce the maximum net DA yield [63]. In the process of culturing four strains of Pseudo-nitzschia isolated from the field, it was found that DA was detected in all strains on the 25th day of culture (stationary period), and the amount of DA produced by P. australis strain PLY1St.52B was significantly higher than that of the other three strains [64]. It can be seen that under the same cultural environments, different species or strains of Pseudo-nitzschia have different abilities to produce DA. Even for the same species, DA production will also change with growth rate and cell morphology due to different growth environments [13,14,65].

3.2. Nutrients Supply

Many studies have shown that DA production of Pseudo-nitzschia significantly increases under a limited supply of nutrients [66,67]. Among the nutrients, silicon (Si), nitrogen (N), and phosphorus (P) had the most obvious effect on DA production by Pseudo-nitzschia.
Some studies have shown that P. seriata produced DA under limited P and Si availability, and DA production further increased when the algae were in the stationary period. Silicon deficiency was comparatively more prominent than P for enhancing DA production [68]. Through the analysis of transcriptome data, the gene expression activity of DA synthesis significantly upgraded under phosphorus deficiency [58]. This could be attributed to the fact that cells can preferentially promote the gene expression of toxin synthesis by reducing their own basic metabolic activity, thus promoting the production of DA [65]. DA production also increased when the N:P ratio was high (that is, the content of phosphorus was low) and silicon was not limited. Moreover, its production also increased when other basic metabolisms, such as carbon, nitrogen, phosphorus, silicon, and other absorption levels, were decreased [69].
The content and type of nitrogen source also affected DA production. Studies have shown that when nitrogen existed as a macroelement, the DA content of P. cuspidata in the exponential growth period was significantly higher than that in the stationary period [70]. When the content of the nitrogen source was the same, organic nitrogen promoted algae to increase DA production more than inorganic nitrogen. For example, compared with inorganic nitrogen sources, when urea was used as a nitrogen source, the amount of DA in the exponential growth period was significantly increased [71]. Martin-Jézéquel found that for P. multilocularis, under urea application as a nitrogen source, the DA production was the highest, but for P. australis, DA production reached the maximum when glutamate was added as a nitrogen source, confirming that the DA production was also dependent on the type of nitrogen source and algae species [72].

3.3. Trace Metals

DA may be a kind of chelate of some trace metals such as iron (Fe) and copper (Cu). Pseudo-nitzschia can selectively combine with trace elements to produce DA. Thus, the concentration of trace elements is closely related to the production of DA in seawater [73].
Maldonado et al. studied the relationship between DA production and the iron and copper content of P. multilocularis and P. australis. They found that its production in intracellular and extracellular increased due to iron deficiency or copper toxicity during the exponential growth period [74]. However, its intracellular production was increased, accompanied by the increase in iron in P. multilocularis [14]. In addition to iron content, extracellular production of DA also varied with life stages, showing that there is a maximum DA production under iron deficiency in the exponential growth stage and decline stage, while the result is the opposite in the stationary stage [14]. This may happen due to the regulation of electron transfer reactions (such as photosynthesis and respiration) by Fe, which indirectly affects the production of DA [75]. Early studies have also found that a high concentration of lithium could significantly promote DA production by Pseudo-nitzschia [76]. This could be due to the smaller radius and higher polarity of lithium, which is easier to replace cations such as sodium and potassium ion, thus affecting the normal operation of the ion pump in the plasma membrane; moreover, lithium can combine with various ligands to form aggregates and play a role in cells [75,76].

3.4. Temperature and Irradiance

Temperature and irradiance are very important environmental and ecological factors. Their effects on DA may be worked by directly affecting the physiological activity of a single cell (such as enzyme activity) or indirectly affecting the algal’s density (such as growth rate). Therefore, the interaction of temperature and light can significantly affect the yield of DA during the cultivation of P. australis [77].
Under the same culture conditions, the effect of temperature on the toxicity of Pseudo-nitzschia varied with species. Generally, high temperature promotes DA production. DA production by the P. australis S7 strain was below the detection limit at temperatures <20 °C but increased exponentially from 23 to 30 °C [78]. It should be noted that this is not the case for all algae, as in the P. multilocularis strain PM4, the intracellular DA production at 27 °C was much lower than that at 18 °C in a specific temperature range [79]. This may be caused by different physiological and ecological reaction mechanisms in algae.
Irradiance can affect DA content by the change of photoperiod and light intensity. Early studies found that under a long photoperiod (18 h light: 6 h dark), DA production of P. tenuifolia significantly increased [80]. Although DA can be produced under weak irradiance, the yield of DA under strong light is much higher compared to weak light. Moreover, under strong light, DA production further increases with increasing light intensity [64,77]. The reason for the irradiance effect on DA production may be photosynthesis provides the energy required for DA production.

3.5. Bacteria

Single bacteria or bacterial communities can also affect the DA production process of Pseudo-nitzschia. In the study of P. multilocularis, it was found that the production of DA was closely related to the presence of bacteria [81,82]. Early studies showed that although algae treated with antibiotics grew well, their toxin production capacity would be 8–10 times lower than that of bacteria, and their DA production would be 2–95 times higher than a single strain of the added original bacteria. In other words, the presence of extracellular bacteria can effectively promote the production of DA [81]. Later research also confirmed this view; that is, in the presence of living bacteria, the production of DA by algae was significantly higher than that in a sterile environment [82].
However, there is not a single corresponding relationship between DA production and bacteria, and their toxigenicity differs with species of the diatom Pseudo-nitzschia. For example, the physiological activity of P. pseudodelicatissima is not toxic and does not affect the absence of original bacteria or the presence of foreign bacteria, and it never produces DA, while P. multiseries is toxic, growing rapidly under sterile conditions while growing slowly when co-cultured with foreign bacteria and producing a small amount of DA [83]. Research showed that the existence of DA affected the composition and structure of the bacterial community to a certain extent, and there is a mutual association between DA and bacteria [84]. Further studies are needed to find out the relationship between the genus of Pseudo-nitzschia and bacteria.

3.6. Other Factors

The production of DA is not only affected by nutrients, light, and temperature but also by other substances and factors such as:
(1)
Clay and Germanic acid: In early studies, Yu et al. found that both clay minerals and Germanic acid could inhibit the production of DA by P. multilocularis. Germanic acid completely inhibited the production of DA when the Ge/Si ratio was 35 [85,86]. The reason may be that the high concentration of clay affects the photosynthesis and nutritional environment of cells and thus affects the production of DA, while Germanic acid may destroy or even interrupt the normal silicification in cells, destroying the respiration, nucleic acid synthesis, and protein compounds of algae, thus inhibiting DA production.
(2)
pH: Lundholm et al. found that DA produced by P. multilocularis in the late exponential period significantly increased with the increase in pH (9.3~9.8) in the laboratory [87]. In the field observation, the water body of P. multilocularis usually had higher pH (about 9 or even 10), which suggested that this water body might be polluted with lots of DA. The effect of pH on DA production may be realized by affecting enzyme process, carbon content, metal toxicity, or bacterial structure. pH in natural water is not easy to regulate and mainly depends on the water’s ecosystem self-healing. If it is a specific area, such as fish ponds, there are relevant methods of equilibrium pH. Therefore, pH can affect the production of DA, but whether DA will affect pH, in turn, needs further research.
(3)
pCO2: Increasing of pCO2 can promote the production of DA in two different Pseudo-nitzschia, especially under phosphorus [88] or silicon deficieny [89]. Even if the nutrients are enough, the intracellular DA production of some algae, such as P. multilocularis, increased due to the increased pCO2 [90]. The expression of intracellular DA synthesis gene upregulated with the increased pCO2 [57]. With global warming and ocean acidification, it is of great practical significance to study the impact of pCO2 on algae.
(4)
Predator: Several studies have shown that the toxicity of toxic diatoms such as P. seriata increased under the direct or indirect existence of calanoid copepods, indicating that toxic diatoms may resist predation by producing poison [91]. For zooplankton, there was no obvious selection tendency in the predation of toxic and nontoxic diatoms, and the predation of toxic diatoms had no obvious effect on itself. Therefore, zooplankton is more likely to act as a carrier to realize the transfer or transformation of DA indirectly in the marine food web by predating toxic diatoms [92,93].
Table
Table 2. Factors affecting the production of domoic acid (DA) by Pseudo-nitzschia spp.
Table 2. Factors affecting the production of domoic acid (DA) by Pseudo-nitzschia spp.
FactorsEffects on DA ProductionRelated SpeciesReference
Biotic factors
Strains/SpeciesDA production varies in different strainsP. australis[64]
Life stagesProduce lots of DA in stationary phase while noting on exponential growth phaseP. multilocularis[62]
Intracellular DA production increased from the exponential growth period to stationary periodP. vulgaris and P. australis[33,63]
BacteriaEffectively promote the production of DAP. multiseries[80,82]
PredatorDA production increased up to 3300% when exposed to grazing copepoditesP. seriata[94]
DA production induced in nontoxic speciesP. obtusa[94]
Abiotic factors
IrradianceDA production increases with increasing irradianceP. australis[77]
TemperatureDA production was below the detection limit at temperatures <20 °C, but increased exponentially from 23 to 30 °CP. australis[78]
The intracellular DA production at 27 °C was much lower than that at 18 °CP. multilocularis[79]
pHElevated pH induced production of domoic acid
DA production in the late exponential growth period increased significantly with pH (9.3–9.8) in the laboratory		P. multilocularis[87]
pCO2Increase due to the increased pCO2P. multilocularis[89]
NitrogenHigher DA production when grown on NO3− or NH4+ than on urea during exponential growthP. cuspidata[95]
Highest DA production on urea and NO3−P. multiseries[72]
DA production on urea >than on NO3−, NH4+P. multiseries[96]
Highest DA production on glutamate and NH4+P. australis[72]
Silicon (Si)DA production increased when stressed by Si limitation during the stationary phaseP. seriata[64]
Copper (Cu)increased due to the excessive copper during exponential growth periodP. multilocularis and P. australis[74]
Phosphorus (P)DA synthesis was significantly upregulated under phosphorus restrictionP.multiseries[57,65]
Iron (Fe)Increased due to the lack of iron or excessive copper during exponential growth periodP. multiseries and P. australis[74]
Intracellular DA production increased, accompanied by increase in ironP. multilocularis[14]
Lithium (Li)Significantly promote DA productionP.multiseries[76]
SalinityDA production rates varied significantly
with salinity; they were low and similar at salinities of 5–15 (2.56–3.12 ng mL−1 day−1) and increased with increasing salinity, highest in 35		P. pungens[97]
Clay (halloysite)Inhibit the production of DAPsuedonitzschia pungens f. multiseries[85]
Germanic acidCompletely inhibit the production of DA when the Ge/Si ratio was 35P. pungens[86]

4. Detection Methods of DA

Detection methods can be divided into algae DA concentration, water DA concentration, and shellfish DA concentration determination according to the detecting subject. Each detection method, biological, chemical, and physical, has its own advantages and limitations. In this paper, the main detection and analysis methods are introduced. Table 3 summarizes the current main methods for DA detection.

4.1. Bioassay Methods

Mouse bioassay (MBA) is a classical method for most marine toxins, except for domoic acid. It mainly uses mice of a certain age, size, and weight to detect the toxicity of algal toxins and finally uses half-lethal doses to evaluate the toxicity. This method was first used for DA detection in 1987 [4]. However, subsequently, it was found that there were many uncertain factors (such as the size of experimental animals, physiological state, operation technology, and experimental time) in using this method, and the detection limit was high (suitable for DA concentration >20 μg·g−1). This method has been gradually replaced by new detection methods due to some other defects such as poor repeatability, long operation time, and inability to distinguish toxins types, but it still plays an irreplaceable role in toxicology research [98]. Besides the mouse model, zebrafish (Danio rerio) as a translational model is also used extensively for toxicological studies. The contemporary Bibliography is replete with studies of “fish embryo toxicity tests” for the study of environmental contaminants (pollutants, drugs, and toxins) in which zebrafish larvae are used as indicators of toxicity. For example, dexamethasone sodium phosphate (DEX) exposure could affect the survival and hatching rate, morphology score, and body length in zebrafish larvae, especially disturbing the antioxidant defense system [110]. Several mycotoxins, such as Aflatoxin B1 (AFB1) and Fumonisin B1 (FB1), both exerted negative effects on zebrafish (Danio rerio) embryos [111].

4.2. High-Performance Liquid Chromatography (HPLC)

Although the use of HPLC requires special instruments and the cost is relatively high, HPLC is recognized as the most effective method among detection methods such as liquid chromatography, thin layer chromatography, capillary electrophoresis, amino acid analysis, receptor analysis, and many other methods, due to its rapid detection, suitable repeatability, high accuracy [112]. Among shellfish toxins analyzed by HPLC, DA analysis is the most successful one, which has been listed as the national standard method in many countries. According to Chinese national standards, the content of DA in marine bivalves and their products (excluding salted products) should be detected by reverse-phase high-performance liquid chromatography (RP-HPLC) with a detection limit of 1.0 μg.
Combined with HPLC, a series of new detection methods have been developed, such as high-performance liquid chromatography ultraviolet detection (HPLC-UV), high-performance liquid chromatography fluorescence detection (HPLC-FLD), high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and high-performance liquid chromatography electrospray ion trap mass spectrometry (HPLC/ESI-IT-MS) and so on (see Table 3), to determine residues of residues in shellfish in the past 20 years [9,10,11,12,112]. Subsequently, some optimized LC-MS techniques were applied to DA detection. For example, solid solvent extraction combined with LC-MS technology can be used to detect DA at a trace level (<1 pg·mL−1) [102]. DA of 5 μg·g−1 can be detected in fresh scallops tissue samples by laser ablation electrospray ionization high-resolution mass spectrometry (LAESI-HRMS), which is a quarter of the detection limit [103]. In contrast, the detection limit of DA in urine can reach 0.12 ng·mL−1 by liquid chromatography high-resolution mass spectrometry (LC-HRMS) [104].
As the most mature technology for DA detection, HPLC is generally stable and sensitive for the determination of samples. It is less affected by operational and environmental factors. HPLC technology has the advantages of stable sample determination, high sensitivity, and less affected by the operation and environmental factors, but it has weaknesses in efficiency, quantity, and cost of determination.

4.3. Enzyme-Linked Immunosorbent Assay (ELISA)

ELISA is a kind of analytical method that uses the principle of specific binding between enzyme-linked antigens and antibodies. Now, it has become the most widely used immunological detection technology because of its convenience, high specificity, low detection limit, easy qualitative and quantitative, and no need for special equipment.
DA was detected and quantitatively analyzed by specific antibodies against shellfish toxin when using ELISA. The detection limits of DA could reach 0.02 [105], 0.15 [113], and 0.15 [114] ng·mL−1 when using direct competition of polyclonal antibody, indirect competition of polyclonal antibody, and indirect competition of monoclonal antibody, respectively.
ELISA has high sensitivity and can be used for rapid DA detection. At present, a variety of ELISA methods and kits for DA detection have been developed [105,115,116,117,118]. Among them, the development of colloidal gold technology has grown rapidly. This technique is to develop a colloidal gold immunochromatographic strip by using competitive immune reaction and labeled monoclonal antibodies to detect DA. Tsao et al. used monoclonal antibodies from hybridoma cell line 9F1F11 to prepare a colloidal gold immunochromatographic strip (ICS). The detection time of DA was reduced to less than 10 min, and the sensitivity was increased to 5 ng·mL−1. The rapid and batch detection of DA was realized [107].
Some improved ELISA techniques have emerged and highlighted their own advantages, such as capillary electrophoresis-based enzyme immunoassay (CEEIA), which can detect DA in shellfish samples within 5 min by electrochemical method, and the sensitivity is 16 times higher than that of traditional ELISA [106]. In addition, a multi-functional detection technology-flow cytometry microsphere array, which combines three immunological methods (solid-phase microsphere method, flow cytometry, and Luminex xMAP Technology), has also been applied to the detection of DA, and the half inhibitory concentration (IC50) can reach (1.9 ± 0.1) ng·mL−1 [119].
Although the ELISA method has many advantages in use, the expensive DA standards, professional microplate instruments, small molecular weight of DA, difficulties in the preparation of immune antigen, and field operation all limited its application in DA analysis to a certain extent.

4.4. Other Detection Methods

In addition to the commonly used methods such as HPLC and ELISA, other detection methods, such as biosensors, capillary electrophoresis, and neural receptor binding detection, have also been applied to detect DA.
Biosensor is a kind of easy and cheap DA detection and quantification technology. This technology can transform biological reaction information into electrical signals, then output those quantitatively processed electrical signals so as to determine substances’ concentration. In the past 20 years, various biosensor has been widely used in the detection of chemical pollutants or pathogens [120,121]. For example, when using surface plasmon resonance (SPR) technology to detect DA in food, the semi-inhibitory concentration can reach 4.8–6.9 ng·L−1 and 2.3–6.0 ng·L−1, respectively, when using monoclonal antibody and polyclonal antibody [122].
Capillary electrophoresis (CE) is one of the earlier methods applied to separate and detect marine biotoxins because of its simplicity to use, low cost, and portability. CE is based on the principle that differently charged particles have different migration rates in the electric field, then separate the objects [123]. The detection limit can reach 1.5 μg/L by a coupled capillary isotachophoresis–capillary zone electrophoresis (cITP-CZE) method for the determination of domoic acid in shellfish [109].
With the development of technology, other new DA detection methods, such as pure or amino-functionalized Ag nanoparticles and surface-enhanced Raman scattering (SERS), are emerging, which gradually realized the rapid and accurate detection of DA in different situations [108]. However, the sensitivity and accuracy of the above methods are far less than those of chromatography and immunology, so the application scope is still limited.
The detection methods of DA production shall be improved. With the development of research, more toxic algae and their toxins are expected to be discovered and studied. At present, there are many methods to detect DA, but there are still some limitations in their use. HPLC has the advantages of rapid detection, suitable repeatability, and high accuracy, which is recognized as the most effective method. However, in recent years, ELISA kits have attracted more and more attention for the merits of being easy to carry and can be used for on-site monitoring, and some rapid detection strips are also becoming a new research direction. We can grasp the geographical distribution of DA through the detection of DA and establish appropriate models to predict the generation and migration of DA in the ecosystem so as to prevent potential DA disasters.

5. Conclusions

As a neurotoxin, on the one hand, DA pose a potential threat to aquatic organisms and human, while, on the other hand, it has a significant insecticidal and bactericidal role. Therefore, the research on DA has very important practical significance. At present, globally, a new Pseudo-nitzschia has been found, but the research on DA and Pseudo-nitzschia is still very limited. In addition to summarizing the distribution, species composition, and toxin production of Pseudo-nitzschia in various sea areas, the authors think the following three aspects need further scientific research.
The research on the DA production mechanism must be strengthened to understand the effects of specific environmental and biological factors on its production and distribution. At present, the up and down-regulated related to DA production, enzymes involved in DA synthesis, and possible mechanisms have been found by using advanced molecular biology and genetic methods [57,124,125]. On this basis, the use of enzyme inhibitors, gene knockout, or gene silencing techniques may increase or inhibit the production of DA in algae. In addition, the research can be carried out in the genus Pseudo-nitzschia rather than just for a certain species so as to ensure the universality of the previous findings.
Although there are many DA detection methods and corresponding products, the detection methods need further improvement. Through the update of technology or the combination of multiple methods, DA detection will be much simpler, faster, and more efficient. The application prospect of DA needs to be further explored. As a natural marine drug, DA has obvious advantages over organic synthetic chemicals; for example, it can be used as a useful reagent for neurophysiological research. People could make full use of its biological activity, such as the insecticidal ability of DA, and develop and utilize insecticides [126]. Autism spectrum disorder (ASD) features deficits in social interaction and communication and includes repetitive behaviors and circumscribed interests. Research has shown that the behaviors and neuropathology resulting from prenatal exposure to DA are strikingly similar to those in ASD. In addition, the geographic distribution of ASD suggests the possibility that exposure to toxic chemicals in seafood might contribute to the prevalence of some forms of autism. Infant rats exposed to DA express long-term social withdrawal in adults [127]. Therefore, more fully monitor of DA is needed for coastal human and non-human mammalian populations. Product development based on the characteristics of DA is an effective way to develop a green industry. In view of this, we can use gene recombination and other means to screen and cultivate high DA-producing strains so as to carry out the scientific and controllable production and application of DA.

Author Contributions

A.Y., H.Z. and Z.J. contributed to the planning of the main ideas and visualization; A.Y. and Y.Y. were responsible first draft manuscript; A.Y., H.Z. and Z.J. were responsible for the revision and final version. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Shandong Provincial Natural Science Foundation of China (ZR2018PC003) and Linyi University Ph.D. Fund for Scientific Start-up (LYDX2018BS036, LYDX2018BS031, and LYDX2019BS028) and College Students’ Innovative Training Program (X202010452124, X202210452475, and X202210452103).

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Processes 11 00592 g001 550
Figure 1. The mechanism of excitatory neurotoxicity of DA.
Figure 1. The mechanism of excitatory neurotoxicity of DA.
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Processes 11 00592 g002 550
Figure 2. Factors affecting the production of DA.
Figure 2. Factors affecting the production of DA.
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Table
Table 1. Geographical distribution of domoic acid accord to the early reports.
Table 1. Geographical distribution of domoic acid accord to the early reports.
CountrySampling DateSampling AreaSpecimenReferences
Japan1957Tropical and sub-tropical watersChrondria armata[15]
Natori estuary, Ishigaki Island, Okinawa [22]
American1961Capitola, California
1991Monterey Bay, California
Washington State beaches		Pseudo-nitzschia australis[23,24]
Florida (Gulf of Mexico) [25]
Canada1987Estuaries on the eastern coast of Prince Edward IslandPseudo-Nitzschia pungens[16,26]
Mexico1992Gulf of MexicoNitzschia pungens f. multiseries[27]
Portugal1995Not mentionedNot mentioned[28]
Spain1996Ria de Vigo, GaliciaPseudo-nitzschia multiseries[29]
New Zealand1992/1993Not mentioned [30]
Vietnam1997Do SonNitzschia navis-varingica[31]
France1998CoÃtes d’Armor (English
Channel)		P. pseudodelicatissima[32]
Ireland1999Southwest IrelandPseudo-nitzschia australis[33]
Scotland1999wild and cultivated molluscs waters in ScottishPseudo-nitzschia
maximus (mainly)		[34]
Italy2000the Gulf of Naples
(Mediterranean Sea)		Pseudo-nitzschia multiseries[35]
China2001The Bohai Sea and the lakes rivers polluted by algae in the SouthPseudo-nitzschia simulans[36,37]
Greece2002Greek coasts along Thermaikos Gulfgenus Pseudo-nitzschia (P. pungens f.pungens, P. pseudodelicatissima)[38]
Namibia2004Inshore and offshore stationsP. australis and P. pungens[39]
Philippines2004Manila Bay, San Pedro Bay, South SulawesiPseudo-Nitzschia pungens[40]
Croatia2006the Croatian coast of the Adriatic SeaPseudo-nitzschia spp.[41]
Morroco2007M’diq Bay, west Mediterranean coast of MoroccoP. multistriata, P.cuspidata, P. galaxiae,
P. multiseries, P. pseudodelicatissima, P. pungens var. aveirensis,
P. Calliantha, P. fraudulenta.		[42]
Tunisia2008Bizerte Lagoon [43]
Thailand200612°38′ N, 100°53′ EPseudo-nitzschia multiseries[44]
Chile2004–2006Bahı’a Inglesa (27°7′ S, 70°52′ W) and Bahı’a Tongoy (30°15′ S, 71°20′ W)Pseudo-nitzschia species (P. Australis, P. calliantha, P. subfraudulenta)[45]
Turkey2010Sea of MarmaraP. delicatissima, P. fraudulenta, and P. pungens[11]
Bulgaria2011North Black SeaPseudo-nitzschia[46]
Australia2012Tasmania, Victoria, South Australia, Western Australia, New South WalesPseudo-nitzschia delicatissima, P. multiseries, and P. australis[47]
Indonesia2010Panyula in South Sulawesi, Jakarta Bay, Lampung Bay, and Sangihe IslandPseudo-nitzschia strains[48,49]
Tunisia2014Bizerte LagoonNitzschia bizertensis sp. nov.[50]
Malaysia2015Johor, Negeri Sembilan, KelantanNitzschia navis-varingica[51]
Table
Table 3. Characteristics of main DA detection methods.
Table 3. Characteristics of main DA detection methods.
MethodsDetection LimitationMeritsLimitationsReference
Bioassay
Mouse bioassay>20 μg·g−1Universal detection, easy to perform, cheapEthical pressure; poor repeatability; interference of extracts and salts; long operation time and inability to distinguish toxins types; high detection limit; error % high[98]
Receptor bioassay0.001 ng·g−1SensitiveDifficult to obtain the receptor[99]
HPLC Needs standards, needs toxicology information for each toxin
HPLC-UV20 ng·mL−1High versatility, high sensitivity, easy to use, simple maintenance, low equipment cost, can detect a large number of samplesLow sensitivity to compounds with poor UV absorption[9]
HPLC-UV&SPE0.04 ng·mL−1High sensitivity, automatic analysis, suitable precision (<5%)Special instrument, professional operation[100]
HPLC-FLD0.2 ng·mL−1
(1.5 pg·mL−1 for seawater)		High sensitivity, automatic analysis, less clutter interferenceMost of the derivatization reagents are expensive and unstable, and the reagent’s deterioration may lead to toxin’s incomplete derivatization[11]
HPLC-MS/MS0.02 ng·mL−1No need for derivative reagent and toxin standard, wide detection range, high sensitivity, fast speed, and the operation is simpleThe equipment requirements are high, and can not be used for a large number of grass-roots day-to-day monitoring[9]
HPLC/ESI-IT-MS0.02 ng·mL−1High sensitivity, high selectivity, can carry on the mass examination. Can provide chemical structure informationHigh requirements for sample pretreatment[101]
LC-MS<1 pg·mL−1Allows quantification sensitiveSlow, complex, expensive, needs standards[102]
LAESI-HRMS0.24 μg·g−1Realized high-throughput screening or quantitation of DA in a variety of shellfish matricesLow accuracy, suit to screening than direct quantitation[103]
LC-HRMS0.12 ng·mL−1Less solvent consumption, low cost, the absence of the evaporation step, and short time requirement.High requirements for pH, the number of aspirating/dispensing cycles, and the type and volume of eluent[104]
ELISA
ELISA0.02 ng·mL−1High sensitivity, easy to useUnable to detect all individuals.
Expensive DA standards, professional microplate instruments, small molecular weight of DA, difficulties in preparation of immune antigen 		[105]
CEEIA0.02 ng·mL−1Rapid detection and high sensitivity[106]
ICS5 ng·mL−1Fast, sensitive, quantitative,
easy to use		Need enough toxin to obtain antibody
Expensive		[107]
Other methods
cITP-CZE1.5 ng·mL−1Simple to use, low cost, and portability. High sensitivityHigh requirement for pH value, poor repeatability[108]
SERS0.1 μg·mL−1 (in pure water)
0.01μg·mL−1 (in seawater)		Lower limit of detection, rapid detection of DA in different situationsSensitivity and accuracy are far less than those of HPLC and ELISA[109]
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Yang, A.; Zhang, H.; Yang, Y.; Jiang, Z. Progresses of the Influencing Factors and Detection Methods of Domoic Acid. Processes 2023, 11, 592. https://doi.org/10.3390/pr11020592

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Yang A, Zhang H, Yang Y, Jiang Z. Progresses of the Influencing Factors and Detection Methods of Domoic Acid. Processes. 2023; 11(2):592. https://doi.org/10.3390/pr11020592

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Yang, Aoao, Haiguang Zhang, Yu Yang, and Zhaoyu Jiang. 2023. "Progresses of the Influencing Factors and Detection Methods of Domoic Acid" Processes 11, no. 2: 592. https://doi.org/10.3390/pr11020592

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