Review of Cyanotoxicity Studies Based on Cell Cultures

Sazdova, Iliyana; Keremidarska-Markova, Milena; Chichova, Mariela; Uzunov, Blagoy; Nikolaev, Georgi; Mladenov, Mitko; Schubert, Rudolf; Stoyneva-Gärtner, Maya; Gagov, Hristo S.

doi:https://doi.org/10.1155/2022/5647178

Journal of Toxicology

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Abstract Introduction Limitations Conclusion Conflicts of Interest Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 5647178 | https://doi.org/10.1155/2022/5647178

Review of Cyanotoxicity Studies Based on Cell Cultures

Iliyana Sazdova,¹Milena Keremidarska-Markova,¹Mariela Chichova,¹Blagoy Uzunov,²Georgi Nikolaev,³Mitko Mladenov,⁴Rudolf Schubert,⁵Maya Stoyneva-Gärtner,²and Hristo S. Gagov¹

Academic Editor: You-Cheng Hseu

Received08 Jan 2022

Revised28 Feb 2022

Accepted25 Mar 2022

Published25 Apr 2022

Abstract

Cyanotoxins (CTs) are a large and diverse group of toxins produced by the peculiar photosynthetic prokaryotes of the domain Cyanoprokaryota. Toxin-producing aquatic cyanoprokaryotes can develop in mass, causing “water blooms” or “cyanoblooms,” which may lead to environmental disaster—water poisoning, extinction of aquatic life, and even to human death. CT studies on single cells and cells in culture are an important stage of toxicological studies with increasing impact for their further use for scientific and clinical purposes, and for policies of environmental protection. The higher cost of animal use and continuous resistance to the use of animals for scientific and toxicological studies lead to a progressive increase of cell lines use. This review aims to present (1) the important results of the effects of CT on human and animal cell lines, (2) the methods and concentrations used to obtain these results, (3) the studied cell lines and their tissues of origin, and (4) the intracellular targets of CT. CTs reviewed are presented in alphabetical order as follows: aeruginosins, anatoxins, BMAA (β-N-methylamino-L-alanine), cylindrospermopsins, depsipeptides, lipopolysaccharides, lyngbyatoxins, microcystins, nodularins, cyanobacterial retinoids, and saxitoxins. The presence of all these data in a review allows in one look to advance the research on CT using cell cultures by facilitating the selection of the most appropriate methods, conditions, and cell lines for future toxicological, pharmacological, and physiological studies.

1. Introduction

Cyanotoxins (CTs) are a large and diverse group of toxins produced by the peculiar photosynthetic prokaryotes of the domain Eubacteria, commonly known as cyanobacteria or blue-green algae, and since 1999 named Cyanoprokaryota [1, 2]. Some aquatic cyanoprokaryotes can develop in mass, causing so-called “water blooms” or “cyanoblooms” [3]. When such blooms are formed by toxin-producing cyanoprokaryotic algae, they are considered harmful and are usually abbreviated as CyanoHABs. The toxic substances are transported through the food webs and may reach people and animals by drinking water, or through other exposure routes, which include recreational activities or consumption of so-called “sea-food”, which includes both freshwater and marine organisms [3–5]. The excretion of toxic compounds may lead to environmental disasters—water poisoning, extinction of aquatic life, and even to human death [3–5]. Current climate changes and anthropogenic press can intensify and increase the frequency of these hazardous ecological events [3, 6]. Although most research addresses aquatic toxin producers, there is a growing body of evidence on such producers from aeroterrestrial and extreme habitats, and among airborne algae as well, with a considerable number of detected toxins and outlining of additional exposure route through consumption of crops, which have been irrigated by contaminated water [7, 8].

Different approaches have been applied to classify CT, two of which are the most common: by the target of their action, or by chemical composition. By target, CT are classified as hepatotoxins, neurotoxins, dermatoxins, and cytotoxins, whereas chemically they are divided in peptides, alkaloids, phosphorylated cyclic N-hydroxyguanine, diaminoacids, and lipopolysaccharides, the last widely recognized as endotoxins. Prolonged use of drinking water, contaminated with low-doses CTs, may have also carcinogenic effect [6]. Thus, microcystin-LR (MC-LR), the most toxic MC, is considered to express tumor promoting effect mainly by violating phosphorylation-dependent regulations of cellular proteins [new 9 Brozman et al., 2020]. The pleiotropic downstream mechanisms link MC-LR-dependent inhibition of eucaryotic protein phosphatases (PPs) PP1, PP2A, phospho-PP4, and phospho-PP5 [2] to tumor promotion and neoplastic transformation by cell growth induction, reactive oxygen species (ROS) generation, oxidative stress, mitochondrial DNA impairment, and by the transformation of cell phenotype [9]. Chronic proinflammatory effect of MC-LR alone or a combination with another CT-like cylindrospermopsin (CYN) may additionally stimulate the neoplastic transformation and tumor progression [6, 10].

Cell cultures are very convenient for toxicological studies. They allow to reveal the mechanisms of cytotoxic effects, the affected tissues, intracellular targets, and ways to minimize cytotoxicity [11]. The use of human cell lines in toxicological studies is a fast and effective way to investigate the damaging effects of toxins in humans and to identify the most sensitive tissues.

Although different methods are developed for testing of toxins in cell- and animal-based studies, during the last years, the trials on the use of animals have significantly decreased. This is caused by the high cost of these types of clinical trials and increasing resistance to the use of animals for scientific studies. Therefore, the significance and use of cell lines is gradually increasing.

This review aims to present (1) the important results of the effects of CT on human and animal cell lines; (2) the methods and concentrations used to obtain these results, (3) the studied cell lines, and (4) the intracellular targets of CT. The presence of all these data in a review allows in one look to advance the toxicological and pharmacological studies of CT using cell cultures by facilitating the selection of the most appropriate methods, conditions, and cell lines.

2. Cyanotoxicity on Cell and Cell Cultures

2.1. Cytotoxicity of Aeruginosins (Table 1)

Aeruginosin CT contains as a basic structure 2-carboxy-6-hydroxyoctahydroindol that are serine protease inhibitors [12]. They inhibit trypsin-like serine proteases and for this activity are important in the search for new anticoagulants [13].

2.2. Cytotoxicity of Anatoxins (Table 2)

Anatoxins-a are two types of low molecular bicyclic amino alkaloids: anatoxin-a (ANTX) and homoanatoxin-a (hANTX). The best known of them is ANTX, which was the first to be identified as a low molecular alkaloid (165 Da). hANTX is a homologue of anatoxin-a with molecular weight 179 Da and has propionyl instead of an acetyl group at C-2. ANTX and anatoxin-a (S) (ANTX(S)) are neurotoxins. ANTX binds competitively to acetylcholine receptors, while anatoxin-a (S) inhibits acetylcholine esterase [2].

2.3. Cytotoxicity of BMAA (Table 3)

β-N-methylamino-L-alanine (BMAA) is an environmental nonprotein and toxic amino acid that may harm nervous system via oxidative stress, binding to neuromelanin, forming high toxic metabolites like formaldehyde or inhibiting enzyme activity of glutathione reductase, β-amilase, catalase, and RNase H, and in this way to provoke sporadic neurodegenerative development, such as Alzheimer's disease and amyotrophic lateral sclerosis [20, 27, 28]. In addition, BMAA generates a carbamate, which is neurotoxin because it acts as ionotropic and metabotropic glutamate receptors agonist [21] and references therein.

2.4. Cytotoxicity of CYN (Table 4)

CYN is a cyclic quinidine alkaloid combined with hydroxymethyl uracil [49]. It has two epimers, which are equally toxic and are differentiated by the hydroxyl bridge CYN and 7-epi-CYN, and an additional variant 7-deoxy-CYN occurs in natural waters [49]. CYN has been classified mainly as hepatotoxin, but it has also neurotoxic and genotoxic effects and inhibits protein synthesis [3]. It targets kidneys, lungs, heart, spleen, eyes, ovaries, T-cells, neutrophils, and vascular endothelium [50]. CYN may induce oxidative stress, decrease cell viability, and damage mitochondria (discussed by Chichova et al. [35]).

2.5. Cytotoxicity of Depsipeptides (Table 5)

Depsipeptides are palmyramide A (Pal A), apratoxin D (AT D), coibamide A (CoA), ichthyopeptins A (Ich A) and B (Ich B), kahalalide F (KF), 4-Fluoro-3-methyl-benzylamino-KF (KF2), morpholin-4-yl-benzylamino-KF (KF4), homodolastatin 16 (HD16), lagunamide C–Lag C, pitipeptolides–Pit A-F, aurilides and wewakpeptins A-D. Depsipeptides show cytotoxic activity and are protease inhibitors selective for chymotrypsin, leukocyte, and pancreatic elastases. They negatively influence the metabolism of human astrocytes [63].

2.6. Cytotoxicity of Lipopolysaccharides (LPS, Table 6)

LPS consist of lipid A, the core polysaccharides (mainly glucosamine) and an outer polysaccharide chain, and are common compounds of the cell walls of cyanoprokaryotes and Gram-negative bacteria [49]. They have an inflammatory effect and promote cytokine secretion [3].

2.7. Cytotoxicity of Lyngbyatoxins (Table 7)

Lyngbyatoxins were first identified from Moorea producens (formerly Lyngbya majuscula). They are tumor-promoting agents which bound eucaryotic protein kinase C (PKC) isozymes [3].

2.8. Cytotoxicity of MCs (Table 8)

MC are cyclic nonribosomal heptapeptides with low molecular weight (800–1100 Da), which contain several uncommon nonproteinogenic amino acids such as N-methyldehydroalanin (MDHA) derivatives and the uncommon β-amino acid 3-amino-9-methoxy-2,6,8-trimethyldeca-4,6-dienoic acid (ADDA). MC are lipophilic toxins very resistant to hydrolysis, oxidation, and high temperatures. The main route of human exposure is the ingestion of contaminated drinking water, consumption of contaminated food or algal dietary supplements, and body contact, while more occasional routes are hemodialysis and inhalation. MC are classified mainly as hepatotoxins because they block eucaryotic PP (PP1, 2A and phosphoprotein phosphatases PPP4, PPP5) [2] through irreversible covalent binding [97]. Chronic and subchronic exposure to MC seems to be tumor promoting because they can increase the incidence of hepatic tumors in humans. MC could also enhance the oxidative stress. Additional target of MC in high concentrations is the ß-subunit of ATP synthase, causing mitochondrial apoptotic signaling. MC have hepatotoxic and tumor promoting action [3].

2.9. Cytotoxicity of Nodularins (Table 9)

Nodularins (NODs) are cyclic nonribosomal pentapeptides and contain several unusual nonproteinogenic amino acids such as N-methyl-didehydroaminobutyric acid and the ßβ-amino acid (all-S, all-E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid (ADDA). Ten variants have been discovered with nodularin-R being the predominant toxin variant. NODs are relatively stable compounds, with low sensitivity to light or temperature. NOD affects hepatocytes binding their PPs by noncovalent bonds, which increases the rate of phosphorylation. They are often attributed to gastroenteritis, allergic irritation reactions, and liver diseases. Nodularin-R is the most notorious as a potent hepatotoxin that may cause serious damage to the liver of humans and other animals. NODs have similar effects as microcystins and weak carcinogenicity [3].

2.10. Cytotoxicity of Retinoids from Cyanobacteria (Table 10)

Retinol, a novel retinoic acid (RA) analogue 7-hydroxy RA, 4-oxo-RA, and several analogues were identified in cyanobacterial blooms [110]. They act as RA receptors that may cause different malformations, as well as to have a teratogenic effect on aqueous animals.

2.11. Cytotoxicity of saxitoxins (Table 11)

Saxitoxin (SXT) is a collective name for a group of more than 20 cyclic nonribosomal peptide molecules, formed by sulphation at different sites of two basic molecules: SXT and neo-SXT. Based on their toxicology, SXT are grouped in three classes—carbamate derivatives, gonyautoxins, N-sulfocarbomoyl derivatives, and decarbomoyl derivatives—decarbamoylsaxitoxin. They have a neurotoxic effect by blocking voltage-gated sodium channels [3].

3. Limitations

Studies on cell cultures cannot reveal all possible effects of toxins on the human body. This is due to the following reasons: (1) no matter how many cultures are tested, they will not cover the whole variety of cells in the body; (2) there are often significant differences between the cells in culture, the primary cell lines and the cells in the body tissues in the quantity and quality of expressed proteins (genes expression), metabolic pathways and cell function [113–115]. Therefore, results from cells in culture cannot be directly transferred to the tissue of origin or of which they will form. (3) Numerous regulations are active continuously and simultaneously in the organism, and their cross-influence cannot be simulated in experiments with cell cultures. (4) Parameters like LC₅₀ or ID₅₀ are different for cells in culture and human body.

4. Perspectives

The use of cell cultures in toxicological studies will remain the main approach due to its speed, relatively low cost, reproducibility, precision with respect to the studied intracellular components, and ethical acceptability. The use of cell cocultures [116–118] and in vitro formed organ-like structures such as artificial neuronal network [119], cardiomyocyte spheroids with contractile activity [120], and organ-on-a-chip systems [121], which are functionally closer to the human body [11], will increase in the future.

5. Conclusion

The presence of all these data on the cytotoxicity of aeruginosins, anatoxins, cylindrospermopsin, depsipeptides, lipopolysaccharides, lyngbyatoxins, microcystins, nodularins, cyanobacterial retinoids, and saxitoxins in a review is a great advantage. It allows the advancement of research on CT using cell cultures by facilitating the selection of the most appropriate methods, conditions, and cell lines for toxicological and pharmacological studies. In addition, it could increase the use of CT in functional studies of their intracellular targets. Therefore, this review allows in one look to advance the toxicological, physiological, and pharmacological studies of CT by the knowledge of their harmful effects with a focus on human and animal health as well as on environmental protection.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

Iliyana Sazdova and Milena Keremidarska-Markova are Joint lead authors. This paper was funded by the Scientific Research Fund of the Ministry of Education and Science of Bulgaria (project KP-06-OPR 03/18 from 19.12.2018) and by the Ministry of Education and Science of Bulgaria (DO1-275/16.12.2019 “INFRAACT” of Bulgarian NRRI).

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