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Cyanotoxin

Although anecdotal reports of poisoning by date back over a thousand years, the modern scientific understanding of cyanotoxins began in the mid-20th century, with the first isolation of following livestock deaths in and microcystins identified in the . Cyanotoxins are toxic secondary metabolites produced by certain species of , also known as blue-green , that can cause adverse health effects in humans, animals, and aquatic life through , dermal contact, or . These toxins are primarily released during harmful algal blooms (HABs) in freshwater, brackish, and sometimes environments, often triggered by such as excess and from agricultural runoff or . capable of producing cyanotoxins include genera like , Dolichospermum (formerly ), and Cylindrospermopsis, which thrive in warm, eutrophic conditions worldwide. Cyanotoxins are classified into several chemical groups based on their toxicological targets, with hepatotoxins being the most prevalent and studied. Hepatotoxins, such as microcystins (over 200 variants identified, including microcystin-LR) and nodularins, primarily target the liver by inhibiting protein phosphatases, leading to cell damage and potential tumor promotion. Neurotoxins like , which acts as a mimicking the , and saxitoxins, which block voltage-gated sodium channels, disrupt nerve function, causing rapid paralysis and respiratory failure in exposed organisms. Other categories include cytotoxins such as cylindrospermopsin, which inhibits protein synthesis and damages kidneys and the , and dermatoxins like aplysiatoxin, responsible for skin irritations. These toxins vary in stability; for instance, microcystins can persist for weeks to months in water, while anatoxins degrade more quickly under sunlight. Human exposure to cyanotoxins occurs mainly through recreational water contact, drinking contaminated water, or consuming affected fish and shellfish, with documented cases leading to symptoms like nausea, vomiting, lethargy, and dermatitis. Between 2016 and 2018, the U.S. reported 389 human illnesses and 413 animal cases, including 369 deaths primarily among dogs and livestock, highlighting the acute risks to pets and wildlife. Regulatory guidelines, such as the World Health Organization's lifetime drinking water limit of 1 µg/L for microcystin-LR, and recreational thresholds (e.g., 8 µg/L in the U.S. EPA's advisory), aim to mitigate these risks, though monitoring challenges persist due to bloom variability. Environmentally, cyanotoxins contribute to ecosystem disruption by bioaccumulating in the food web, affecting zooplankton, fish, and birds through sublethal effects like reduced reproduction and oxidative stress. Concentrations in blooms can reach thousands of micrograms per liter, exacerbating water quality issues and leading to fish kills or biodiversity loss in affected water bodies. Ongoing research emphasizes the need for advanced detection methods and bloom prediction to address the growing incidence of HABs driven by climate change and pollution.

Introduction

Definition and Sources

Cyanotoxins are toxic secondary metabolites produced by , also known as blue-green , which are prokaryotic photosynthetic microorganisms capable of causing harm to humans, animals, and aquatic ecosystems. The physiological roles of these compounds in producing organisms are not fully understood but may include and . They can accumulate in water bodies, leading to environmental and health concerns. Over 300 different cyanotoxins have been identified to date, encompassing a diverse array of chemical structures that vary in potency and specificity. Cyanotoxins are synthesized intracellularly within cells and are primarily released into the surrounding environment upon and , often during the phase of harmful algal blooms. The main producer genera include , (now classified as Dolichospermum in some cases), Nodularia, Cylindrospermopsis, and Aphanizomenon, among others, which are commonly found in freshwater, brackish, and occasionally systems. These genera thrive under eutrophic conditions, where enrichment promotes their growth and subsequent toxin release. In terms of general properties, cyanotoxins exhibit a range of solubilities, with many being water-soluble (hydrophilic) and others lipophilic, allowing them to partition between aqueous phases and biological tissues. They demonstrate notable environmental stability, persisting in natural waters for weeks to months under typical conditions, though degradation can occur through photolysis, microbial activity, or chemical processes. Unlike toxins from eukaryotic , such as those produced by dinoflagellates, cyanotoxins are exclusively associated with prokaryotic , reflecting their distinct evolutionary and biosynthetic origins.

Historical Discovery

The first documented instance of cyanotoxin poisoning dates to 1878 in Australia, when chemist George Francis reported the sudden deaths of approximately 40 sheep that had consumed water from Lake Alexandrina containing a dense bloom of blue-green algae, now recognized as cyanobacteria such as Nodularia spumigena. This observation, published in Nature, marked the initial scientific recognition of cyanobacterial toxicity in livestock, attributing the fatalities to the ingestion of algal scums that caused rapid onset of weakness, convulsions, and death. Similar anecdotal reports of livestock poisonings linked to cyanobacterial proliferations emerged in Europe during the late 19th century, though systematic investigations were limited at the time. During the 1930s, experimental and observational studies began to elucidate the toxic potential of specific , particularly neurotoxins produced by Anabaena flos-aquae. A notable incident occurred in 1931 along the in West Virginia, United States, where blooms of this species were associated with widespread fish kills and acute gastrointestinal illnesses affecting thousands of people, prompting early toxicological assessments that highlighted neuromuscular and paralytic effects. These events spurred the first targeted research into cyanobacterial extracts, confirming their role in vertebrate poisonings through bioassays on animals. The 1980s represented a breakthrough in cyanotoxin characterization, with the isolation of microcystin-LR, the predominant hepatotoxin, from strains. Researchers employed and to determine its cyclic heptapeptide structure, enabling precise identification and toxicity studies that revealed its potent liver-damaging effects via inhibition. This advancement facilitated broader screening of environmental samples and underscored microcystins as major contributors to cyanobacterial hazards. In the 1990s, the responded to growing evidence of human exposure risks by setting a provisional guideline value of 1 μg/L for total microcystins (equitoxic to microcystin-LR) in , based on toxicological data from establishing a for liver toxicity, with application of uncertainty and allocation factors. A pivotal event elevating public and scientific awareness was the 1996 Caruaru incident in , where microcystins from a Microcystis bloom contaminated the water supply used for at a clinic, resulting in visual disturbances, vomiting, and among 116 patients, with 52 fatalities by year's end. Post-mortem analyses confirmed microcystin concentrations up to 20 μg/L in the dialysis fluid, marking the first documented human deaths directly attributable to cyanotoxins and prompting international regulatory reforms. played a crucial role in these investigations, allowing rapid detection and quantification of toxins in complex matrices like water and tissues. Up to 2025, research has intensified on climate-driven expansions of cyanobacterial blooms, with warming temperatures and altered expected to increase bloom frequency and duration in temperate lakes, as evidenced by monitoring of global bodies. Concurrently, investigations from 2023 to 2024 have spotlighted emerging toxins like aetokthonotoxin, a biindole from the epiphytic cyanobacterium Aetokthonos hydrillicola associated with avian vacuolar myelinopathy, with PCR-based surveys detecting its producers in U.S. reservoirs and advancing LC-MS/MS detection methods for .

Occurrence and Environmental Context

Harmful Cyanobacterial Blooms

Harmful cyanobacterial blooms, also known as CyanoHABs, are dense proliferations of that form visible surface scums or mats in freshwater, brackish, and marine environments. These blooms typically arise in nutrient-enriched waters, where from agricultural runoff and discharge provides excess and , promoting rapid cyanobacterial growth under favorable conditions like stagnant water and high light availability. Globally, CyanoHABs are prevalent in large lakes and reservoirs, with notable examples including recurring blooms in , USA, where nutrient inputs from the surrounding watershed exacerbate the issue, and , Africa, where similar drives extensive surface coverage. The frequency and intensity of these blooms have increased worldwide due to climate warming, which elevates water temperatures and extends growing seasons for . In 2025, significant CyanoHABs occurred in including , , and , as well as the and lakes in , linked to prolonged summer heatwaves that promoted cyanobacterial growth. Cyanotoxins produced by blooming are initially stored intracellularly but are released extracellularly during bloom —when cells age and lyse—or through by and other organisms, leading to widespread dissemination in the . Not all CyanoHABs produce toxins, as variability depends on species composition, environmental stressors, and genetic factors within the bloom-forming populations, such as genera including and . Early detection of CyanoHABs relies on monitoring visual and ecological indicators, such as water discoloration ranging from to hues due to high concentrations, oxygen depletion from microbial decomposition of , and subsequent fish kills as hypoxic conditions intensify. These signs signal the need for immediate assessments to mitigate ecological disruptions.

Factors Influencing Production

The production of cyanotoxins in is regulated by a complex interplay of abiotic and factors that influence both the growth of toxin-producing strains and the expression of biosynthetic pathways. Key environmental triggers include availability, where elevated levels, often in combination with , promote cyanobacterial dominance and subsequent toxin synthesis, as is frequently the limiting in freshwater systems. High nitrogen-to- (N:P) ratios can further favor non-nitrogen-fixing toxin producers like species by reducing competition from diazotrophs. is a critical driver, with optimal ranges of 20–30°C enhancing microcystin production in strains such as , as warmer conditions accelerate metabolic rates and bloom formation. Light intensity positively correlates with toxin biosynthesis, with moderate to high (typically 50–200 µmol photons m⁻² s⁻¹) upregulating for hepatotoxins like s, while extreme levels may inhibit it. Additionally, pH values between 7 and 9 support alkaline-tolerant , indirectly boosting toxin output by favoring their proliferation in stratified waters. Genetic mechanisms underpin the variability in cyanotoxin production, primarily through dedicated biosynthetic s that encode non-ribosomal synthetases and synthases. For instance, the mcy in directs the synthesis of microcystins, with its transcription modulated by environmental cues such as nutrient stress. , mediated by autoinducers like acyl-homoserine lactones, induces toxin pathways at high cell densities, coordinating population-level responses that enhance bloom toxicity and competitive advantages. Stress responses, including oxidative damage from light or metal exposure, further activate regulatory elements like the NtcA , which links status to mcy upregulation, thereby fine-tuning production under adverse conditions. Cyanotoxin output exhibits significant strain-specific variability, as not all cyanobacteria possess functional biosynthetic genes; for example, only about 50–80% of isolates produce microcystins, depending on genetic polymorphisms and prior evolutionary pressures. interactions, such as with non-toxic or by , can suppress toxin production in subordinate strains, though toxin release often deters herbivores and promotes dominance during blooms. amplifies these dynamics, with projections indicating a 20–50% increase in harmful cyanobacterial bloom frequency by 2050 due to rising temperatures, prolonged , and intensified nutrient runoff from events. These shifts are expected to elevate overall cyanotoxin concentrations in affected ecosystems. Recent research highlights emerging anthropogenic influences, such as , which can adsorb cyanotoxins and alter microbial communities to favor toxin-producing . Studies from 2024 demonstrate that and microplastics enhance the expression of biosynthesis genes (e.g., mcyD) in by providing attachment surfaces and leaching additives that stimulate growth, potentially increasing toxin yields by up to 30% under co-exposure scenarios. This interaction underscores the compounding risks of on cyanotoxin regulation in polluted waters.

Chemical Classification

Cyclic Peptides

Cyclic peptide cyanotoxins constitute a prominent class of hepatotoxins produced by various cyanobacteria, such as species of Microcystis, Nodularia, and Planktothrix. These compounds are distinguished by their rigid cyclic structures, which enhance their stability and bioavailability in aquatic environments. Unlike alkaloid cyanotoxins that primarily target neurological functions, cyclic peptides exert their toxicity through interference with cellular signaling pathways in the liver. The core structure of these toxins typically involves cyclic heptapeptides, as seen in microcystins, or pentapeptides, as in nodularins, both incorporating unusual that contribute to their potency. Microcystins feature a cyclo(-D-Ala-L-X-D-MeAsp-L-Z-Adda-D-Glu-N-Mdhb-) backbone, where Adda (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic ) is a β-amino essential for toxicity, and X and Z represent variable such as or . Nodularins share a similar but with a more compact cyclo(-D-MeAsp-L-Arg-Adda-D-Glu-Mdhb-) ring, where Mdhb is N-methyldehydroalanine. These structures yield molecular weights of approximately 900–1100 Da for microcystins and around 825 Da for nodularin-R. The cyclic nature and hydrophobic Adda residue enable strong to target enzymes while resisting enzymatic . Biosynthesis of cyclic peptide cyanotoxins proceeds via multimodular non-ribosomal peptide synthetases (NRPS), frequently hybrid with polyketide synthases (PKS), which assemble the peptide chain through adenylation, condensation, and tailoring steps without ribosomal involvement. In Microcystis aeruginosa, this process is governed by the mcy gene cluster spanning about 55 kb, encompassing bidirectional operons with genes mcyA–mcyE (NRPS/PKS hybrids for chain elongation and Adda incorporation) and accessory genes mcyF–mcyT (for modifications like racemization and methylation). Similar nda clusters direct nodularin production in Nodularia spumigena. This modular architecture allows for structural diversity through domain shuffling and substrate specificity variations. As hepatotoxins, cyclic peptides primarily inhibit protein phosphatases 1 (PP1) and (PP2A) with high affinity (IC<sub>50</sub> values in the nanomolar range), causing hyperphosphorylation of keratins and other proteins, which disrupts microfilaments and leads to intrahepatic hemorrhage and tumor promotion. Microcystins and nodularins demonstrate exceptional persistence in natural waters due to resistance to and oxidation, with half-lives typically ranging from 1–2 weeks under ambient conditions, though microbial can shorten this to days in biologically active systems. More than 300 congeners have been characterized, arising from substitutions and demethylations, while nodularins exhibit fewer variants (around 10). In harmful cyanobacterial blooms, concentrations can accumulate to 1000 μg/L or exceed 2000 μg/L in surface scums, posing significant risks to .

Alkaloids

Alkaloid cyanotoxins are small-molecule compounds characterized by nitrogen-containing heterocyclic rings and basic functional groups, distinguishing them from larger peptide-based toxins. These structures exhibit diversity, with featuring bicyclic scaffolds and cylindrospermopsins incorporating tricyclic moieties linked to a uracil derivative. The biosynthesis of these alkaloids relies on hybrid enzyme systems combining polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS), which facilitate the iterative assembly of carbon chains and incorporation of nitrogenous units. For , the process is governed by the ana gene cluster (comprising anaA through anaG and associated open reading frames), a 29 kb locus identified in producer strains like sp. strain 37, enabling the formation of the bicyclic core through polyketide extension and cyclization. Prominent examples include , a secondary that acts as a potent at nicotinic receptors, leading to overstimulation and rapid ; its intraperitoneal LD50 in mice is 0.25 mg/kg. Cylindrospermopsin, a hepatotoxin and cytotoxin, primarily inhibits eukaryotic protein synthesis by interfering with ribosomal function and depletion, with an oral LD50 of approximately 2–6 mg/kg in mice. Saxitoxins, tricyclic guanidinium produced by certain freshwater , block voltage-gated sodium channels to cause paralytic effects, with an intraperitoneal LD50 of 10 μg/kg in mice. Aetokthonotoxin, a pentabrominated biindole discovered in 2021 from the epiphytic cyanobacterium Aetokthonos hydrillicola, represents a more recent addition; it functions as a putative by acting as a protonophore that uncouples mitochondrial . In cyanobacterial blooms, anatoxin-a concentrations can reach up to 1 mg/L in surface scums, posing acute risks during environmental proliferations. Notable global incidents underscore these dangers, including multiple dog deaths in U.S. lakes in 2023, such as a confirmed case in Clear Lake, California, linked to anatoxin exposure from algal mats.

Other Toxins

Lipopolysaccharides (LPS), also known as endotoxins, are integral components of the outer cell wall in all Gram-negative cyanobacteria, distinguishing them as universal structural features across these organisms. These molecules consist of a lipid A core anchored in the outer membrane, linked to a core oligosaccharide and an O-antigen polysaccharide chain, though cyanobacterial LPS often lacks typical bacterial components like heptose and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO), featuring instead unique elements such as 4-linked glucose in the core and odd-chain hydroxylated fatty acids in lipid A. LPS are released into the environment primarily during cyanobacterial cell lysis, contributing to the toxicity of bloom decay products, and exhibit pyrogenic properties by inducing fever through inflammatory responses, as well as causing skin irritation and hypersensitivity upon direct contact. Compared to LPS from pathogenic Gram-negative bacteria like Escherichia coli, cyanobacterial variants are generally less potent, with lower lethality (LD<sub>50</sub> of 40–425 mg/kg in mice versus 5–24 mg/kg for bacterial LPS) and reduced pyrogenicity, potentially due to structural variations in the lipid A region. Another notable non-peptide, non-alkaloid cyanotoxin is β-N-methylamino-L-alanine (BMAA), a non-proteinogenic amino acid produced by diverse cyanobacterial taxa, including both free-living and symbiotic species such as those in the genera Nostoc, Anabaena, and Microcystis. BMAA acts as a neurotoxin by mimicking the excitatory neurotransmitter glutamate, leading to excitotoxicity through overactivation of glutamate receptors. Its biosynthesis occurs via non-ribosomal peptide synthetase (NRPS)-like pathways, involving enzymes that assemble the molecule from serine and methylamine precursors, as identified through genomic analyses of producing strains. BMAA has been linked to the high incidence of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) in Guam, where concentrations in cyanobacterial symbionts of cycads reached up to 37 μg/g dry weight, biomagnifying through the food web to levels of 3,556 μg/g in flying foxes and 6.6 μg/g in human brain tissues of affected individuals. Unlike many cyanotoxins, BMAA biomagnifies across trophic levels in aquatic and terrestrial food webs, with up to 44-fold increases from phytoplankton to zooplankton, facilitating indirect exposure via seafood consumption. Lesser-known cyanotoxins in this category include dermatoxins such as aplysiatoxins, polyketide-derived compounds produced by marine cyanobacteria like Moorea producens (formerly Lyngbya majuscula), which induce severe inflammation and blistering upon contact. Recent reviews highlight their role in during blooms, with structural analogs like debromoaplysiatoxin exhibiting similar C-activating mechanisms, though remains strain-specific and less widespread than major hepatotoxins. These toxins differ from cyclic peptides and alkaloids in their primarily inflammatory or glutamate-mimetic actions, with LPS providing a baseline endotoxin presence in all Gram-negative and BMAA uniquely capable of trophic transfer, underscoring their distinct ecological and exposure risks.

Toxicity Mechanisms

Hepatotoxins

Hepatotoxins are a of cyanotoxins that primarily target the liver, inducing damage through disruption of key cellular processes in hepatocytes. Microcystins and nodularins, the most studied hepatotoxins, exert their by covalently binding to and inhibiting serine/ protein phosphatases 1 (PP1) and 2A (PP2A), which are essential for regulating states of cellular proteins. This inhibition leads to hyperphosphorylation of target proteins, including those involved in cytoskeletal integrity, resulting in structural collapse, blebbing, and loss of cell shape in liver cells. The binding affinity is exceptionally high, with microcystin-LR exhibiting inhibition constants () below 0.1 for both PP1 and PP2A. Uptake of these hepatotoxins into hepatocytes occurs via specific organic anion transporting polypeptides (OATPs), such as OATP1B1 and OATP1B3 in humans, which facilitate across the sinusoidal membrane, concentrating the toxins in the liver and enhancing their hepatoselectivity. Nodularins operate through a similar inhibition mechanism, with values of 0.026 nM for PP2A and 1.8 nM for PP1, leading to comparable cytoskeletal and morphological disruptions in hepatic cells. In contrast, cylindrospermopsin, another potent hepatotoxin, targets protein synthesis by inhibiting ribosomal biogenesis and function, a process mediated by hepatic (CYP450) activation, which generates reactive metabolites that further impair translation. Both microcystins and cylindrospermopsin induce in hepatocytes, characterized by elevated (ROS) production, which damages mitochondria and triggers through pathways involving activation and DNA fragmentation. This oxidative damage exacerbates phosphatase inhibition effects, promoting cell death and liver inflammation. In models, acute exposure to microcystins via intravenous or intraperitoneal routes yields LD50 values of 50-100 μg/kg body weight in mice, manifesting as rapid hepatocyte . low-dose exposure in rats promotes hepatic tumor formation, supporting the International Agency for Research on Cancer (IARC) classification of microcystin-LR as a possible (Group 2B), based on evidence of preneoplastic lesion promotion. Recent advances in synthetic chemistry have enabled the production of analogs, facilitating detailed mechanistic studies of inhibition and without relying on natural isolates, as highlighted in reviews of cyanotoxin pathways up to 2023. These analogs have been instrumental in elucidating structure-activity relationships, such as modifications to the Adda moiety that modulate binding potency and cellular uptake.

Neurotoxins

Cyanobacterial neurotoxins primarily target the , disrupting and leading to rapid onset of symptoms such as muscle , , and seizures. These toxins include , saxitoxins, and β-N-methylamino-L-alanine (BMAA), each with distinct molecular mechanisms that interfere with neural signaling. Unlike hepatotoxins that cause slower metabolic damage in the liver, neurotoxins induce acute neural disruption, often resulting in death within minutes to hours if exposure levels are high. Anatoxin-a, a bicyclic produced by genera such as and Aphanizomenon, acts as a potent at nicotinic acetylcholine receptors in the , mimicking and causing persistent muscle . This leads to overstimulation followed by blockade of , resulting in tremors, convulsions, loss of coordination, and ultimately respiratory due to diaphragmatic failure. The intraperitoneal LD50 for in mice is approximately 250 μg/kg, highlighting its high . Binding occurs rapidly and competitively at sites with high affinity, exacerbating the excitatory effects on the central and peripheral nervous systems. Saxitoxins, a group of alkaloids synthesized by freshwater like and Aphanizomenon, bind to and block voltage-gated sodium channels in nerve and muscle cells, preventing sodium influx necessary for generation. This inhibition halts nerve impulse propagation, causing progressive starting from peripheral muscles and leading to and potential seizures in severe cases. Saxitoxins can transfer through aquatic food webs, accumulating in that filter-feed on toxin-producing , posing risks via human consumption. The toxin exhibits high-affinity binding to sodium channels, with a (Kd) of approximately 10 nM, ensuring potent and reversible blockade at low concentrations. BMAA, a non-proteinogenic generated by symbiotic in plants like cycads and free-living species such as , induces by acting as a , particularly at NMDA receptors, leading to excessive calcium influx and neuronal damage. Additionally, BMAA is misincorporated into proteins in place of serine, causing misfolding, aggregation, and impaired cellular function, which contributes to chronic neurodegeneration. Acute exposure can trigger seizures and behavioral alterations, while long-term low-level exposure is associated with progressive neurological decline. Recent 2024 studies have strengthened links between BMAA exposure and sporadic (ALS), demonstrating its role in TDP-43 and α-synuclein aggregation in neuronal models, as well as gene-environment interactions increasing ALS incidence risk.

Dermatotoxins and Endotoxins

Dermatotoxins and endotoxins represent a class of cyanotoxins primarily responsible for inflammatory and irritant effects upon direct contact or during cyanobacterial blooms. Endotoxins, particularly lipopolysaccharides (LPS) embedded in the outer membranes of Gram-negative , trigger immune responses by binding to (TLR4) on immune cells, initiating signaling cascades that lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). This activation can escalate to a in severe cases, contributing to . High-exposure scenarios, such as ingestion or from bloom-contaminated water, may result in endotoxemia, characterized by elevated circulating LPS levels and fever-like symptoms. Cyanobacterial LPS exhibits lower potency compared to neurotoxins and hepatotoxins, with median lethal doses (LD50) exceeding 100 mg/kg in animal models, reflecting its role more as an irritant than a direct cytotoxic agent. Concentrations of LPS in bloom-affected waters vary with bloom density and environmental factors, particularly in dense accumulations of species like . Dermatotoxins, such as aplysiatoxins produced by marine cyanobacteria including Lyngbya majuscula, exert their effects through activation of (PKC), a enzyme in pathways that promotes and epithelial disruption. This PKC activation underlies tumor promotion in chronic exposures and acute skin blistering upon contact, as the toxins disrupt keratinocyte integrity and induce histamine release. Structurally, aplysiatoxins are polyether lactones featuring a macrocyclic core with brominated aromatic rings, enabling their lipophilic interaction with cellular membranes. Exposure to these dermatotoxins and endotoxins during blooms commonly manifests as , with symptoms including redness, itching, and vesicular rashes on exposed skin; ocular and nasal irritation may also occur from aerosolized particles. Chronic low-level exposures have been associated with heightened allergic responses, such as respiratory sensitization, in recent epidemiological studies monitoring bloom-prone areas.

Health and Ecological Impacts

Effects on Humans

Humans can be exposed to cyanotoxins through multiple routes, including ingestion of contaminated , consumption of such as and that bioaccumulate toxins, and recreational activities like where dermal contact or of aerosolized occurs. Acute primarily manifests as gastrointestinal symptoms such as , , , and , often linked to hepatotoxins like microcystins; neurotoxins such as anatoxins and saxitoxins can cause , tingling, numbness, and in severe cases, respiratory . Dermal may lead to skin rashes, itching, blisters, or , while of cyanotoxin-laden aerosols can provoke respiratory irritation or hay fever-like symptoms. These effects typically resolve with supportive care, but high-dose exposures have resulted in hospitalization, particularly from liver enzyme elevation due to hepatotoxins. Chronic exposure to cyanotoxins poses risks of long-term organ damage and disease. Microcystins, potent hepatotoxins, have been associated with liver cell damage and increased risk of hepatocarcinogenesis in epidemiological studies from regions with endemic exposure, such as parts of China where contaminated drinking water correlates with higher hepatocellular carcinoma rates. Similarly, the neurotoxin β-N-methylamino-L-alanine (BMAA), produced by certain cyanobacteria, has been linked to neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) through environmental correlations and detection in brain tissues of affected individuals. These chronic effects stem from repeated low-level ingestion via water or food chains, potentially exacerbating oxidative stress and protein misfolding in vulnerable neural tissues. Certain populations face heightened risks from cyanotoxin exposure due to physiological vulnerabilities. Children under six years old, pregnant and nursing women, the elderly, individuals with pre-existing liver conditions, and those undergoing treatment are particularly susceptible, as their higher water intake relative to body weight or impaired pathways amplify impacts. The recommends a provisional guideline value of 1 μg/L for microcystin-LR in to protect against both acute and chronic effects, a threshold adopted by many national standards. Epidemiological data indicate a rising trend in cyanotoxin-related illnesses, with U.S. poison center reports showing a ten-fold increase in acute poisonings since 1920, though underreporting likely underestimates the global burden. Recent outbreaks, such as those in U.S. lakes from 2010 to 2022, have affected hundreds through recreational and exposure, leading to symptoms like gastrointestinal distress in exposed communities. Economically, cyanotoxin events contribute to significant costs, including over $1 billion in the U.S. from 2010 to 2020 for prevention, treatment, and beach closures that disrupt and . These impacts underscore the need for vigilant monitoring to mitigate risks.

Effects on Animals and Ecosystems

Cyanotoxins exert significant toxic effects on various animal species, leading to acute mortality and chronic health impairments. In , exposure to cylindrospermopsin has caused fatal poisonings, as evidenced by an incident in northwest , , where three cows and ten calves died after consuming water from a farm dam contaminated with the toxin-producing cyanobacterium Cylindrospermopsis raciborskii. populations suffer from damage due to cyanotoxins, which disrupt and cause tissue necrosis, resulting in , respiratory distress, and mass die-offs during blooms. Birds are particularly vulnerable to neurotoxins like , which induces rapid paralysis and death; historical outbreaks in linked Anabaena blooms to multiple bird kills, with symptoms including staggering and respiratory failure. Beyond direct toxicity, cyanotoxins disrupt ecosystems through and trophic cascades. The β-N-methylamino-L-alanine (BMAA) biomagnifies in food webs, accumulating at high concentrations in flying foxes (Pteropus mariannus) that feed on seeds contaminated by , reaching levels up to 3,556 μg/g in their tissues and posing risks to predators. Eutrophication-driven blooms favor toxigenic cyanobacterial strains over non-toxic , shifting community structures in hypereutrophic lakes where low-to-moderate doses promote the dominance of toxin-producers like . These proliferations exacerbate oxygen depletion, creating hypoxic dead zones as decomposing bloom biomass consumes dissolved oxygen, suffocating aquatic life and altering habitat suitability. Recent studies highlight emerging impacts on amphibians from chronic cyanotoxin exposure. In 2024 research, low concentrations of microcystin-LR (as little as 0.5 μg/L) induced oxidative damage, inflammation, and histological changes in larval amphibians, potentially leading to developmental abnormalities and reduced survival rates, underscoring under-reported risks to amphibian populations. Indirect ecological consequences include diminished fisheries productivity and heightened vulnerability of endangered species. Cyanotoxin blooms reduce fish yields by causing direct mortality and habitat degradation, leading to economic losses in recreational and commercial inland fisheries through decreased catch efficacy and population declines. Endangered manatees (Trichechus manatus) in Florida face compounded threats from cyanobacterial proliferations in coastal lagoons, where toxins degrade seagrass beds essential for foraging and contribute to emaciation and mortality events linked to poor water quality.

Detection and Management

Analytical Methods

Analytical methods for cyanotoxins encompass a range of and techniques designed to detect and quantify these compounds in , , and sediments, targeting major classes such as hepatotoxins (e.g., microcystins), neurotoxins (e.g., anatoxins), and others like cylindrospermopsins. serves as a primary screening tool, particularly for microcystins, offering rapid qualitative or semi-quantitative results with a sensitivity of approximately 0.1 μg/L due to its antibody-based detection of the ADDA moiety common to these toxins. This method is cost-effective and suitable for high-throughput monitoring but requires confirmation for specificity, as it may cross-react with structurally similar variants. For precise identification and quantification, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the gold standard confirmatory technique, enabling multi-toxin panels that simultaneously analyze diverse cyanotoxins with limits of detection (LOD) as low as 0.01 μg/L. This approach separates congeners based on mass-to-charge ratios and fragmentation patterns, providing structural confirmation essential for . Biosensors, including electrochemical and optical variants, facilitate rapid field testing by integrating biorecognition elements like antibodies or aptamers with transducers, yielding results in minutes without extensive sample preparation. Sampling protocols emphasize integrated collections to capture vertical gradients, often using depth-integrated samplers or multiple discrete depths during blooms to represent average concentrations. Distinguishing intracellular from extracellular forms involves or , while cell counts via complement direct measurements; quantitative (qPCR) detects -encoding genes (e.g., mcyE for microcystins) to assess potential production risks, though gene presence does not always correlate with actual levels. Standardized protocols include EPA Method 545, which employs LC-MS/MS for quantifying cylindrospermopsins and anatoxins in with method detection limits around 0.07 μg/L for cylindrospermopsin. For beta-N-methylamino-L-alanine (BMAA), a , advancements through 2024 incorporate automated analysis-high-performance liquid chromatography (AAA-HPLC) with detection for separation, as well as DNA aptamer-based biosensors for improved specificity in complex matrices like cyanobacterial extracts. Key challenges in cyanotoxin analysis arise from congener variability, with over 300 variants requiring broad-spectrum methods to avoid underestimation, and matrix effects in or sediments that suppress in LC-/MS, necessitating matrix-matched calibration or . These issues underscore the need for method validation across diverse environmental samples to ensure accuracy.

Mitigation and Regulation

Mitigation and regulation of cyanotoxins focus on preventing exposure through source water management, water treatment processes, and establishing enforceable or advisory limits to protect , particularly in supplies. The (WHO) provides guideline values for cyanotoxins in to minimize risks from chronic exposure, with a provisional guideline of 1 μg/L for microcystin-LR, based on its potential as a liver . In the United States, the Environmental Protection Agency (EPA) issues non-enforceable Advisories (HAs) under the for unregulated contaminants like cyanotoxins, recommending levels such as 0.3 μg/L for microcystins (10-day HA for bottle-fed infants), 1.6 μg/L for school-age children and adults, and 0.7 μg/L for cylindrospermopsin (10-day HA for children). EPA has not established a numerical HA for , though a Effects Support exists. Some U.S. states, such as , have adopted regulations requiring routine testing and treatment for microcystins and cylindrospermopsin in sources vulnerable to harmful algal blooms (HABs), with action levels aligned to EPA HAs. Regulatory approaches emphasize monitoring and public notification to manage risks during HAB events. The EPA recommends that public water systems develop Cyanotoxin Management Plans, including routine source water monitoring for cell counts and toxin levels, with immediate action if concentrations exceed levels, such as switching to alternative sources or enhanced . Internationally, the WHO advocates for a multi-barrier approach in plans, integrating cyanotoxin guidelines with broader microbial and chemical standards to address sporadic blooms driven by . While no federal Maximum Contaminant Levels (MCLs) exist for cyanotoxins in the U.S. as of 2025, the EPA's Contaminant Candidate List (CCL) prioritizes them; notably, in January 2025, EPA announced a preliminary regulatory determination not to regulate cylindrospermopsin from CCL 5, with ongoing research into long-term health effects. Mitigation strategies begin with source water protection to reduce cyanobacterial growth, including plans that limit and inputs from and , as these are primary bloom triggers. In water treatment, conventional processes like , , , and can remove up to 90% of extracellular cyanotoxins when optimized, but intracellular toxins require careful handling to avoid cell lysis during pre-oxidation. Advanced methods, such as granular (GAC) adsorption, achieve over 95% removal of microcystins, while or oxidation effectively degrades many cyanotoxins without forming harmful byproducts when dosed appropriately. Membrane , including , provides an additional barrier by rejecting toxin-laden cells, though it must be combined with disinfection to ensure microbial safety. During blooms, utilities are advised to lower treatment flow rates and use polymer aids to enhance particle removal, minimizing breakthrough risks.