An Overview on Some Algal Toxins Developing Diseases and Cancer in Human

Salim M, Masroor MS and Parween S

Published on: 2021-01-24

Abstract

As the environment is full of microorganisms, the human life appeared in devoid of them have never been possible to us. While most of these microorganisms are beneficial to us, unfortunately, some of them have always been as toxic as poison. Though the toxic substances released by several microorganisms have already been documented in the literature but the studies on their effects on human and animals are not as adequate to derive any conclusion due to the delayed toxic effects developing ailments, diseases and even cancer in future courses of time. Therefore, more researches are still required to fill the gap. The present review is an attempt to discuss the various algae producing toxins causing diseases and cancer in human.

Keywords

Algae; Toxins; Diseases; Cancer

Introduction

Algae are the grasses of many waters. They have produced toxins causing various ailments, diseases and cancer in human and animals. Unfortunately, we are still not realizing the lethality of several algal forms causing harms to us. Harmful algal blooms are one of them. Algae have produced a diverse group of molecules ranging from simple ammonia to complicated polypeptides and polysaccharides. Similarly, their physiological effects are also varied ranging from the acute toxicity of paralytic shellfish poisoning of Gonyaulax, leading to death in a short period to the chronic toxicity of carrageenans of red algae, which induce carcinogenic and ulcerative tissue changes over long periods [1-4].

An algal bloom is a dense aquatic population of certain algae developed on the surface of water produced by adequate nutrients and salts coupled with sunlight for photosynthesis. The phytoplanktonic algae mostly containing dinoflagellates, diatoms and cyanobacteria flourishing on the surface of the water are comprehensively removing and releasing oxygen and toxins respectively. These toxins may contaminate the water causing illnesses in human and animals. They cause nausea, vomiting, headache, fever, mucosal irritations, gastroenteritis, neural problems, seizures, multiple organs failure and cancer especially hepatocarcinoma and even death ­[4-15]. Some other forms of toxic algae found in other natural places may also cause a dangerous threat to us [16-18]. The present review is an attempt to discussing different algae producing a variety of toxins with their effects on humans and animals.

Discussion

The algae producing many toxins with their effects on humans and animals are tabulated in Table 1 and briefly discussed as under:

Pyrrhophycophyta

The members of pyrrhophycophyta are generally known as dinoflagellates exhibiting the quality of bioluminescence, calling it as the “fire algae”. Most of these toxic dinoflagellates are found in oceans. They are all ichthyotoxic and non-carcinogenic. The paralytic shellfish poisoning is caused by the Gonyaulax and Pyrodinium phoneus. Saxitoxin and gonyautoxins are produced [5,19]. The icthyotoxicity is believed to be caused by the release of ammonia [20]. The symptoms of shellfish poisoning appear with numbness in lips, tongue and fingertips within a few minutes after ingestion of poisonous shellfish. The numbness is extended in legs, arms and neck causing muscular incoordination. The person feels like floating in the air. The mental symptoms vary. The death results due to respiratory distress and paralysis within 2 to 12 hours. And, those who survived for 24 hours are out of danger with no lasting effects [5] (Table 1).

Further, dinoflagellates also contribute to cause red tide. It plays an important role in causing natural water toxic. This is a rapid accumulation of dinoflagellates resulting in the discolouration and poisoning of water. The most important red tide alga to cause shellfish poisoning in human is Karenia brevis [3,21,22].

Karenia brevis is a marine photosynthetic dinoflagellate alga usually found in the waters of the Gulf of Mexico. This is a red tide alga producing a neurotoxin named as brevetoxin that is detrimental to marine life affecting the human populations where it occurs. The brevetoxin released by the K. brevis is found in the flesh of shellfish developing neurotoxic shellfish poisoning in humans giving rise to the symptoms of nausea, vomiting, respiratory and eye irritations developing asthma, emphysema or COPD. Brevetoxin is a neurotoxic, cyclic, polyether compound that binds to the voltage-gated sodium channels in human nerve cells leading to the disruption of common neurological functioning as neurological shellfish poisoning (NSP) [3,9,21] (Table 1, Figure 1).

Table 1: A list of some carcinogenic and lethal toxins with their toxins producing algae and targeted organs.


S.N.

Groups of Algae

Names of Algae

Toxins Released

Targeted Organs

References

1.

Pyrrhophycophyta (Dinoflagellates)

Karenia brevis

Neurotoxin, Brevetoxin

Neurological shellfish poisoning causing disruption of sodium channel in human

[2,9,21]

 

Gambier discus toxicus

Neurotoxin,

Ciguatoxin

Neurological Ciguatera fish poisoning causing disruption of sodium and potassium channels in human

[10,25,26]

 

Alexandrim

Neurotoxin, Saxitoxin

Paralytic shellfish poisoning in human

[15]

2.

Chrysophycophyta (Diatoms)

Pseudo

nitzschia

Neurotoxin Domoic acid

Amnesic shellfish poisoning in human causing short term memory loss

[22,27,28]

3.

Chlorophycophyta (Green Algae)

Caulerpa

Caulerpin, Caulerpicin

Toxicity in humans include numbness, peripheral cold sensations, rapid and difficult breathing, depression and loss of balance

[18,29,33]

4.

Rhodophycophyta (Red Algae)

Gracillaria, Fucellaria, Eucheuma, Gigartina, Hypnea, Rhodomenia, Chondrus

Carrageenans

Ulcerative and carcinogenic tissue changes; colorectal breast and liver cancer

[2,35,39]

Figure 1: Skeletal formula of Brevetoxin.

Gambierdiscus toxicus is also a dinoflagellate that produces several polyether marine toxins like ciguatoxin, maitotoxin, gambierol and gambieric acid causing a disease in human and animals known as ciguatera. This is a unicellular microalga causing primarily ciguatera fish poisoning in Polynesia and was discovered by Yasumoto and Bagnis from the Gambiers Islands in the late 1970s [23,24]. Ciguatoxin is a potent neurotoxin that alerts the activity of voltage-gated sensitive sodium and potassium channels [25,26]. The seriousness of the symptoms depends upon the susceptibility and the amount of ciguatoxin ingested by an individual. Its effect appears within a few hours with a large array of symptoms such as gastrointestinal and neurological symptoms such as paresthesia in the extremities and perioral area and the inversion of the perception of hot and cold. Further, these symptoms are more magnified with hypersalivation, itching, asthma, ataxia, arthralgia, myalgia and vertigo [10,26] (Table 1, Figure 2).

Figure 2: Skeletal formula of ciguatoxin.

Third, in the series of toxic red tide dinoflagellates harmful to humans causing well known paralytic shellfish poisoning (PSP) is Alexandrium producing saxitoxins. It occurs in the waters of the Gulf of Maine (U.S.A.) every year. This particular toxin was discovered from Alexandrium in 1927 from central California and has been regarded as one of the most deadly algal toxins developing usually ataxia, numbness, incoherence and in extreme cases respiratory paralysis and death [15] (Table 1, Figure 3).

Figure 3: Skeletal formula of Saxitoxin.

Chrysophycophyta

The other important microorganism causing red tide is belonging to another group of algae named as diatoms like Nitschia, Amphora and Pseudonitzschia producing domoic acid as neurotoxin causing various harms to invertebrate and vertebrate animals [22]. It has got a high affinity with glutamate receptors causing amnesic shellfish poisoning developing short term memory loss in human. Exposure to this toxin may also affect the brain developing seizures and possibly death [28].

Some other algae belonging to this group such as Prymnesium parvum and Ochromonas have also shown to contain certain cytotoxic, ichthyotoxic and hemolytic toxins. They have caused granulomatous lesions similar to tuberculosis in fishes [27] (Table 1, Figure 4).

Figure 4: Skeletal formula of Domoic acid.

Chlorophycophyta

Caulerpa produces two main toxins named as caulerpin and caulerpicin [18,29]. Their toxicity has been studied in rats [30]. Since this is an edible alga their toxicity is important as it becomes toxic during the rainy season. The most affected country is the Philippines. Their toxicity includes numbness, peripheral cold sensations, rapid and difficult breathing, slight depression and the loss of balance [30]. Moreover, the hemolytic, ichthyotoxic and non-carcinogenic toxins are also produced by the Chetomorpha minima, Ulva pertusa and U. lactuca [17,31-33] (Table 1, Figure 5).

Rhodophycophyta

The toxin named carrageenan is produced by the Rhodophycophycean members like Gracilaria, Fucellaria, Eucheuma, Gigartina, Hypnea, Rhodomenia and Chondrus (Table 1, Figure 6) [34]. Carrageenans are widely used in the food industry for thickening and stabilizing properties as gelly, without considering their ill effects in humans for the last 500 years. This has been a good vegetarian alternative to gelatin in confectioneries. But, their main applications are in dairy and meat products, due to their firm binding to proteins.

Figure 6: Skeletal formulae of Carrageenans.

The carrageenans are composed of alternating derivatives of galactose, 3, 6 – anhydrogalactose and sulfated galactose [34]. These carrageenan molecules induce some serious physiological effects including the induction of carcinogenic and ulcerative tissue changes over long periods [2,35-38]. Carrageenans also produce edema, granuloma, chronic inflammatory responses and the activation of Hagemann factor. Carrageenans via the activation of Hagemann’s factor and kinins enhance thrombosis [40]. The oral administration of carrageenans produces hepatotoxicity in animals, colorectal tumors in rats and breast cancer in human [16,39,41].

Cyanophycophyta and Cyanotoxins

Cyanotoxins are secondary metabolites produced by cyanobacteria. They pose a threat to humans and the environment [7,8,42]. They are found almost everywhere in oceans, lakes and rivers as well as on land. Cyanotoxins form red tide or harmful algal blooms [43]. Approximately, over 100 cyanotoxins are known today but only a few of them have been studied well. Their chemical structures fall into three broad groups viz. cyclic peptides, alkaloids and lipopolysaccharides (Table 2). All these cyanotoxins have been studied in the light of future teratogenicity, reproductive toxicity and their carcinogenicity studies. Further, depending on the human organs affected these cyanotoxins are classified as either hepatotoxins, neurotoxins or skin and gastrointestinal irritants. Most hepatotoxins are cyclopeptides like microcystins and nodularin [44,45]. Though, they usually accumulate in the liver, their exposure even in low doses may cause liver tumours and cancer [46,47]. The researches on cyanobacterial carcinogenicity and tumor promotion have mainly focused on hepatotoxins like microcystins, nodularin and cylindrospermopsin. However, cyanobacteria could also produce other metabolites with potential tumour-promoting effects [48]. In brief, microcystins and nodularin inhibit protein phosphatases, cylindrospermopsin inhibits protein synthesis and anatoxin and saxitoxins block neuronal signal transmission. Some of these cyanotoxins discussed here are tabulated in table 2.

Table 2: A list of some carcinogenic and lethal cyanotoxins with their toxins producing cyanobacteria and targeted organs.


S.No.

Cyanotoxins

Cyanobacteria

Type of Toxins and Targeted Organs

References

 1. Cyclic Peptides

a.

Microcystins

Microcystis, Anabaena,

Anabenopsis,

Oscillatoria, Nostoc

Carcinogenic, Hepatotoxic,

Liver, colon and testicular cancer

[12,13,55,67]

b.

Nodularins

Nodularia

Carcinogenic, Hepatotoxic,

Liver cancer

[56,68,69]

c.

Anatoxins

Anabaena,

Oscillatoria

Non-carcinogenic,

Neurotoxic

[88]

 2. Alkaloids

a.

Saxitoxins

Anabaena,

Lyngbya,

Cylindrospermopsis

Non-carcinogenic,

Neurotoxic

[88]

b.

Cylindro

spermopsins

Cylindrospermopsis

Carcinogenic,

Neurotoxic

[78-82]

c.

Lyngbyatoxins

Lyngbya

Carcinogenic,

Skin and G. I. Tract

[83-85]

 3. Polyketides

a.

Aplysiatoxins

Lyngbya,

Oscillatoria

Carcinogenic,

Skin and G. I. Tract

[84]

 4. Amino acids

a.

BMAA

Nostoc

Genotoxic, Neurotoxic,

Brain and Nervous System

[85,87]

Cyclic Peptide, Microcystins

Microcystins (MCs) are released by the cyanobacteria Microcystis aeruginosa. These are produced as secondary metabolites. Nearly, 50 different microcystins have so far been isolated. They are released into the water after the death of algae. These are cyclic peptides containing only 7 amino acids and can even persist after boiling (Table 2, Figure 7). Data on exposure to microcystins are mainly originated from some epidemiological studies. In China, surface water contaminated with microcystins used for drinking purposes has developed a high incidence of primary liver cancer [49]. Similarly, several cases of primary liver cancers were also reported from certain regions of Serbia as the citizens made use of blooming water reservoirs for drinking purposes [11]. In 1996, a biological accident was reported from Caruaru, Brazil. Here, microcystins contaminated water was used for hemodialysis patients causing several deaths mainly due to liver failure [50]. Exposure to microcystins resulted in morphological and functional changes in hepatocytes leading to the swollen and hemorrhagic liver with dissociation and disruption of epithelial tissues [51,52]. It can also lead to either necrosis, apoptosis or cell proliferation [12] assuming that microcystin could be an initiator [53-56] and promoter [57,58] of carcinogenesis [13]. In 2006 in Lyon, France, the International Agency for Research on Cancer (IARC), assessed the cancerogenesis of MC-LR and concluded that MC-LR is a possible carcinogen for humans, classifying it as a group 2B carcinogen [59].

Further, researches are required to determine the exact effect on gene regulation developing cancer [13]. Microcystins inhibit a class of enzyme known as protein phosphatases [60]. The phosphorylated proteins thus produced destroys the liver. It initiates abnormal apoptosis and cancer cell proliferation. It has been reported that MC-LR covalently binds the cystine residues of PP1 and PP2A [61]. As a result, inhibition of PP1 and PP2A leads to hyperphosphorylation of functional and cytoskeletal proteins and finally to cell apoptosis [6,62-65]. Microcystins are capable of causing cellular damage following uptake via anion transporting polypeptides (OATP). Several OATPs have been prominently found to express in cancers. Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, glutathione depletion and generation of reactive oxygen species (ROS). ROS are known to damage DNA. In this context, the cyanobacterial cyclopeptides have been reported to produce free radicals and alter intracellular reduced glutathione [54-56]. These genotoxic effects include DNA fragmentation, chromosomal aberrations, DNA- protein cross-links, micronuclei formation, loss of heterozygosity and even base substitution mutations [47,55]. Lastly, the tumour-promoting activity of microcystins is well documented and was reported as the strongest tumor promoters to date especially in liver [11,53,58,66]. Further, it has also been reported that microcystin crosses the blood-testis barrier and destroys the DNA repair mechanism. It increases the expression of protooncogenes involved in response to cell cycle arrest and abnormal apoptosis in testis [67].

Figure 7: Skeletal formula of Microcystin.

Cyclic Peptide, Nodularins

The cyanotoxin nodularin is secreted by the cyanobacteria Nodularia spumigena. This is a solid non-ribosomal pentapeptide substance. The N. spumigena are among the largest cyanobacterial mass occurring throughout the world. Nodularins are very much similar to microcystins in their structure and function. Sometimes, microcystins are often extended to nodularin. This is also hepatotoxic cyanotoxin causing liver cancer similar to microcystins. It affects cytoskeleton and cytoskeletal proteins. Nodularin also promoted tumor formation [56]. It inhibits the functions of protein phosphatase 1 (PP-1), protein phosphatase 2A (PP-2A) and protein phosphatase 3 (PP-3). These enzymes act by removing the phosphate from protein causing liver cancer [65,68]. It produces reactive oxidative species (ROS) especially superoxide and hydroxyl radicals which causes DNA damage [69]. Symptoms of nodularin exposure include blistering around the mouth, sore throat, headache, abdominal pain, nausea, vomiting, diarrhoea, cough and pneumonia. Chronic symptoms are jaundice, bleeding, swollen abdomen, a liver filled with blood, mental disorientation, confusion, non-sleepiness and finally coma [69] (Table 2, Figure 8).

Figure 8: Skeletal formula of Nodularin.

Cyclic Peptide, Anatoxin

Saxitoxins and anatoxin-a(s) are among the non-carcinogenic, most neurotoxic substances known to us. Anatoxin-a(s) is the only known naturally occurring organophosphate cholinesterase inhibitor causing strong salivation (the ‘s’ in its name stands for salivation), cramps, tremor, diarrhoea, nausea and vomiting committing extremely rapid death within minutes [66,70]. There are multiple variants including anatoxin-a, homoanatoxin-a and anatoxin-a(s). These toxins are mainly associated with Anabaena, Oscillatoria, Microcystis, and Cylindrospermum (Table 2). Anatoxin bound to neuronal nicotinic acetylcholine receptors affecting the central nervous system neurotoxins [71,72]. There is no information available on the carcinogenicity of anatoxin-a in human and animals or their potential carcinogenic precursor effects. Similarly, there is limited information available regarding the mutagenicity or genotoxicity of anatoxin-a. No long term bioassay studies on the tumorigenicity of anatoxin-a have been identified so far. However, there are some controversial reports available regarding the genotoxicity, teratogenicity, developmental toxicity and induced apoptosis of anatoxin-a [73-77] (Table 2, Figure 9).

Figure 9: Skeletal formula of Anatoxin.

Alkaloid, Saxitoxin

Saxitoxin is a neurotoxin released by certain blue-green algae like Anabaena, Lyngbya and Cylindrospermopsis. It belongs to the family of paralytic shellfish poisoning (PSP) toxins. When toxic marine dinoflagellates are consumed by the shellfish, the toxins are stored and transferred to the consumers of shellfish. Saxitoxin is a non-carcinogenic neurotoxin acting as a selective sodium channel blocker preventing normal cellular function and leading to nervous shutdown causing paralysis [66] (Table 2, Figure 10).

Figure 10: Skeletal formula of Saxitoxin.

Alkaloid, Cylindrospermopsin

Cylindrospermopsin is an alkaloid isolated from Cylindrospermopsis raciborskii [78,79]. It has been reported to be as genotoxic, probable mutagenic and is potentially carcinogenic. Further, it is a general cytotoxin that not only modifies the DNA and RNA covalently but blocks the protein biosynthesis very efficiently. This can interact with DNA and RNA and produces DNA adducts and there is evidence for clastogenicity and micronucleus formation in a cultured human white cell line incubated with cylindrospermopsin [80,81]. A preliminary trial of carcinogenicity in mice indicated the presence of excess tumors providing support for a more definitive carcinogenicity trial [82]. It would be a premature attempt to establish cylindrospermopsin as a possible human carcinogen because of their very limited current data available [79] (Table 2, Figure 11).

Figure 11: Skeletal formula of Cylindrospermosin.

Alkaloid, Lyngbyatoxin

Lyngbyatoxin is derived from a cyanobacteria Moorea producens, formerly known as Lyngbya majuscula [83]. This is a potent tumor producing cyanotoxin in animals. Lyngbyatoxin A is a known potent tumor promoter by its ability to strongly induce Protein Kinase C (PKC) causing cancer [84]. Lyngbya majuscula, sometimes, grows epiphytically on edible algae such as Acanthophora spicifera, which is eaten in Indonesia and the Philippines [85] (Table 2, Figure 12).

Figure 12: Skeletal formula of Lyngbyatoxin.

Polyketides, Aplysiatoxin

Aplysiatoxin is also produced by Moorea producens having the same effects as reported by the lyngbyatoxin. This is secreted to protect themselves from predation by fishes. Aplysiatoxin is a potent carcinogen inducing tumor production in human. However, it acts as a powerful activator of protein kinase C which is linked with some anticancer effects [84].

Figure 13: Skeletal formula of Aplysiatoxin.

B-methylamino-L-alanine (BMAA)

The cyanobacteria Nostoc produces genotoxic cyanotoxin BMAA which grows in the roots of the Cycad plant and found in waterways and damp soil. BMAA is a non-protein amino acid which can cross the blood-brain barrier. It causes several neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). BMAA in the brain tissue is gets misincorporated into nerve cell proteins causing misfolding and ultimately cell death. Clumps of misfolded proteins may form the aggregates in the brains of those who die of neurodegenerative diseases. In fact, BMAA substituted itself with the amino acid L-serine creating a faulty protein within the cell. ALS paralyzes patients often from the periphery inward and most patients die within three years when they can no longer breathe or swallow. Only 10 % of cases are thought to be inherited, often termed as familial ALS with 15 to 20 % of these are linked to mutation in the SOD1 (superoxide dismutase) gene [86,87] (Table 2, Figure 14).

Figure 14: Skeletal formula of BMAA.

Conclusion

The algal toxins are important as their toxic effects are lethal to human and animals. They also cause diseases and cancer in human. These algae found in nature in various forms especially as algal blooms producing lethal toxins in nature are formed by the dinoflagellates, diatoms and the blue-green algae. Karenia brevis is one of the most important dinoflagellates producing a neurotoxic named as brevetoxin developing neurotoxic shellfish poisoning (NSP) in human [9]. Another important red tide marine microorganisms as diatoms, Pseudonitzschia produces domoic acid, a potent neurotoxin causing shellfish poisoning in human developing short term memory loss and seizures [22,28].

Blue-green algal blooms form thick mats causing ecological harm by making it difficult for aquatic life to thrive. They not only block sunlight for creatures living below the water surface but can also use up the oxygen required by other life forms creating the oxygen-depleted “dead zone”. Also, most of the blooms produce toxins causing a dangerous threat to human and animals. Cyanotoxins are produced by green algae. More than 100 cyanotoxins are known today but, unfortunately only a few of them are studied well. Some of them are microcystins, nodularins, anatoxins, saxitoxins, cylindrospermopsins, lyngbyatoxins, aplysiatoxins and BMAA. Most of these cyanotoxins are either hepatotoxic, neurotoxic or skin and gastrointestinal irritants. The researches on cyanobacterial carcinogenicity are mainly focused on microcystins and other hepatotoxins developing liver cancer in human. In a nutshell, microcystins and nodularins inhibit protein phosphatases, cyclindrospermopsin inhibits protein synthesis and anatoxin and saxitoxins block neuronal signal transmission [8,12,13,19,42,43,68,69,82,88].

Last but not the least the toxins produced by the Caulerpa, a chlorophycophyte is caulerpin and caulerpicin causing major threat in the Philippines during the rainy season. Similarly, the toxin produced by the Rhodophycophytes is carrageenans causing cancer in humans [16].

Abbreviations

MC – Microcystin

AD – Alzheimer's disease

PD – Parkinson’s disease

RNA – Ribonucleic acid

DNA – Deoxyribonucleic acid

PP1 – Protein Phosphatase 1

PP2 – Protein Phosphatase 2

PP3 – Protein Phosphatase 3

SOD – Superoxide dismutase

PKC – Protein Kinase C

ROS – Reactive oxygen species

PSP – Paralytic shellfish poisoning

NSP – Neurological shellfish poisoning

BMAA – B-methylamino-L-alanine

ALS – Amyotrophic lateral sclerosis

OATP – Organo anion- transporting polypeptides

COPD – Chronic obstructive pulmonary disease

IARC – International Agency for Research on Cancer

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