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Freshwater neurotoxins and concerns for human, animal, and ecosystem health: A review of anatoxin-a and saxitoxin

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Neurotoxinas de água doce e preocupações com a saúde humana, animal e do ecossistema: uma revisão da anatoxina-a e da saxitoxina

ABSTRACT

Toxic cyanobacteria are a concern worldwide because they can adversely affect humans, animals, and ecosystems. However, neurotoxins produced by freshwater cyanobacteria are understudied relative to microcystin. Thus, the objective of this critical review was to provide a comprehensive examination of the modes of action, production, fate, and occurrence of the freshwater neurotoxins anatoxin-a and saxitoxin as they relate to human, animal, and ecosystem health. Literature on freshwater anatoxin-a and saxitoxin was obtained and reviewed for both laboratory and field studies. Current (2020) research identifies as many as 41 anatoxin-a producing species and 15 saxitoxin-producing species of freshwater cyanobacteria. Field studies indicate that anatoxin-a and saxitoxin have widespread distribution, and examples are given from every continent except Antarctica. Human and animal health concerns can range fromacute to chronic. However, few researchers studied chronic or sublethal effects of freshwater exposures to anatoxin-a or saxitoxin. Ecosystemhealth also is a concern, as the effects of toxicity may be far reaching and include consequences throughout the food web. Several gaps in knowledgewere identified for anatoxin-a and saxitoxin, including triggers of production and release, environmental fate and degradation, primary and secondary exposure routes, diel variation, food web effects, effects of cyanotoxin mixtures, and sublethal health effects on individual organisms and populations. Despite the gaps, this critical review facilitates our current understanding of freshwater neurotoxins and thus can serve to guide future research on anatoxin-a, saxitoxin, and other cyanotoxins.

Keywords: Harmful algal blooms, HABs, Cyanobacteria, Toxin production, Cyanotoxins, Ecosystem effects

RESUMO

Cianobactérias tóxicas são uma preocupação mundial porque podem afetar adversamente humanos, animais e ecossistemas. No entanto, neurotoxinas produzidas por de água doce as cianobactérias são pouco estudadas em relação a são pouco estudadas em relação à microcistina saxitoxina , uma vez que se relacionam com a saúde humana, animal e do ecossistema. A literatura sobre anatoxina-a e saxitoxina misturas de cianotoxinas e efeitos subletais à saúde em organismos e populações individuais. Apesar das lacunas, esta revisão crítica facilita nossa compreensão atual das neurotoxinas de água doce e, portanto, pode servir para “ orientar pesquisas futuras sobre anatoxina-a, saxitoxina e outras cianotoxinas.

Assim, o objetivo desta revisão crítica foi fornecer um exame abrangente dos modos de ação, produção, destino e ocorrência das neurotoxinas de água doce anatoxina-a efoi obtido e revisado para estudos de laboratório e de campo. A pesquisa atual (2020) identifica até 41 espécies produtoras de anatoxina-a e 15 espécies produtoras de saxitoxina de cianobactérias de água doce. Estudos de campo indicam que a anatoxina-a e a saxitoxina têm ampla distribuição, e exemplos são dados de todos os continentes, exceto a Antártida. As preocupações com a saúde humana e animal podem variar de agudas a crônicas. No entanto, poucos pesquisadores estudaram os efeitos crônicos ou subletais de exposições de água doce à anatoxina-a ou saxitoxina.

Palavras-chaves: Floração de algas nocivas, HABs, cianobactérias, produção de toxinas, cianotoxinas, efeitos no ecossistema

Introduction

Fossils of cyanobacteria date back 3.5 billion years and are the Earth’s oldest oxygen-producing organisms (Schopf, 2002). These microscopic, prokaryotic organisms have had a major effect on the Earth and are responsible for our modern-day oxygen-enriched atmosphere (Schopf, 2002; Paerl and Paul, 2012). Cyanobacteria, therefore, are essential to humans and other organisms that respire aerobically, as well as an important part of the food web, providing food for planktivores and affecting multiple trophic levels.

However, in aquatic environments, excessive reproduction and accumulation of cyanobacteria can lead to the formation of cyanobacterial blooms (Orihel et al., 2015; Zhao et al., 2019). These blooms can cause water supply and treatment issues, restrict recreation (Calado et al., 2019), deplete dissolved oxygen (Paerl, 1988; Janssen, 2019), and result in fish mortality (Sabart et al., 2015). More importantly, cyanobacteria that produce toxic metabolites, called cyanotoxins, are a global concern (Chorus and Bartram, 1999) because they may adversely affect humans, animals, and ecosystems.

Cyanotoxins are classified into three main groups based on their target tissue: dermatoxins, hepatotoxins, and neurotoxins (Chorus and Bartram, 1999). The most frequently studied freshwater toxin is the hepatotoxin microcystin (Merel et al., 2013). However, neurotoxins have different modalities and modes of action than microcystin and, therefore, likely behave differently on organisms and in the environment.

Neurotoxin groups include anatoxins, saxitoxins, ciguatoxins, and beta-N-methylamino-L-alanine (BMAA; Rutkowska et al., 2019). Three of these groups are known to be produced in freshwater environments: anatoxins, saxitoxins, and BMAA. Anatoxin-a and saxitoxin are two freshwater neurotoxins that have been linked to acute animal poisonings and, therefore, may have unknown ecological effects in wildlife and in ecosystems. Anatoxin-a has been implicated in animal mortality and can cause death in minutes (Edwards et al., 1992; Wood et al., 2007; Heiskary et al., 2014; Sabart et al., 2015; Carmichael and Boyer, 2016). Saxitoxin, which is well-studied in marine environments, is one of the most potent naturally occurring neurotoxins known (Wiese et al., 2010; Cusick and Sayler, 2013; Loftin et al., 2016). Despite the potency of these neurotoxins, anatoxin-a and saxitoxin are understudied in freshwater environments. Therefore, the focus of this critical review is on the neurotoxins anatoxin-a and saxitoxin and their effects on humans, animals, and freshwater ecosystems. This review provides background information on anatoxin-a and saxitoxin, in addition to (1) tables of research identifying cyanobacterial species with confirmed production of anatoxin-a and saxitoxin in isolated organisms, (2) tables of research identifying locations and concentrations of anatoxin-a and saxitoxin occurrence in the environment, and (3) a list of gaps in the current research for other researchers to utilize in their work on cyanotoxins in freshwater systems.

Some cyanobacteria have ecological niches that help them dominate over other cyanobacteria. Water clarity, total phosphorus, nitrogen, macrophyte cover, dissolved oxygen levels, water depth, and chemical oxygen demand can all play a role in cyanobacterial community composition (Beaver et al., 2018; Dalu and Wasserman, 2018), and the response to these environmental conditions are likely taxon specific. For example, Aphanizomenon can outcompete Anabaena in light-limited conditions (De Nobel et al., 1998). Furthermore, Anabaena (Wood et al., 2010) and Aphanizomenon (Moustaka-Gouni et al., 2017) can fix nitrogen from the atmosphere, which may play a role in their dominance in nitrogen-poor lakes. Nitrogen fixation is made possible by the formation of heterocytes, whereas other specialized cells, called akinetes, allow the cyanobacteria to remain dormant in sediments and survive harsh or even extreme conditions, reviving when conditions for growth are right (Moustaka-Gouni et al., 2017). The formation of heterocytes and akinetes may be why certain cyanobacteria and their toxins are so successful at surviving and persisting in the environment (Kaplan-Levy et al., 2010).

Salinity treatments were shown to reduce cyanobacterial cell membrane integrity (Rosen et al., 2018), and Li et al. (2015) determined that cyanobacterial blooms occurred more frequently at salinities below 5 practical salinity units. Conversely, some cyanobacteria, such as Aphanizomenon favaroloi, can withstand salt stress, giving them an advantage in brackish waters (Moustaka-Gouni et al., 2017). Whereas optimal conditions for some taxa have been characterized, the conditions that lead to dominance of one organism over another are complex. Moreover, the conditions that lead to the presence of toxin-producing strains within each species of cyanobacteria are not well understood.

Cyanotoxin production by cyanobacteria is believed to be an ancient trait. Saxitoxin, for example, was present 2.1 billion years ago (Murray et al., 2011). As such, the cyanotoxins target fundamental cellular processes in a wide range of organisms. Cyanotoxins may have originated as a defense mechanism against grazing pressure or competition; some cyanotoxins are allelopathic, inhibiting the growth of other organisms such as algae that compete for resources (Christoffersen, 1996; Holland and Kinnear, 2013). Another plausible explanation is that cyanotoxins contribute to cellular physiology by improving homeostasis, photosynthesis, or growth rates (Holland and Kinnear, 2013). Alternatively, the production of toxins may be a mechanism that shapes the cyanobacterial community as a whole rather than individual organisms, the differing niches and traits among individuals contributing to the survival of cyanobacteria (Wang et al., 2020). Janssen (2019) raised the question of whether some cyanotoxins have no ecotoxicological significance or if they have received too little scientific attention to determine their ecological function.

Cellular cyanotoxin content is specific to the cyanobacterial strain (Chorus and Bartram, 1999) and may vary by up to four orders of magnitude (Christoffersen, 1996). Therefore, low abundances of some organisms may still result in high cyanotoxin concentrations, and understanding cyanobacterial accumulations are important. Under certain conditions, such as warmer temperatures, adequate light, low manganese, or high nutrient inputs (Feuchtmayr et al., 2010; Orihel et al., 2015), cyanobacterial abundance increases rapidly. Excess nutrient inputs, in the form of nitrogen and phosphorus from both natural and human sources, have received attention as a primary cause of cyanobacterial blooms (Wang et al., 2010; Agnihotri, 2014), although cyanotoxin presence in oligotrophic lakes is causing some to challenge the current paradigms (Reynolds, 1998; Carey et al., 2012; Glibert, 2017). The decoupling of cyanotoxins, either spatially or temporally, from cyanobacteria is a concern due to the lack of visual cues that cyanotoxins are present (Christensen et al., 2019).

Several researchers have reviewed the literature on cyanobacteria (e.g. Quiblier et al., 2013; Ger et al., 2014), but reviews on cyanotoxins other than microcystin, and to a lesser extent cylindrospermopsin, are sparse. Most cyanotoxin papers focus on certain aspects of cyanotoxins. For example, Preece et al. (2017) covered the occurrence of cyanotoxins in coastal environments, and Moy et al. (2016) reported on the biotransport of cyanotoxins to riparian food webs. Other aspects of cyanotoxins covered in the literature include the effects of sample preparation and storage on cyanotoxin analysis (Kamp et al., 2016), effects of exposure, including acute animal and human poisonings and fatalities (Carmichael et al., 2001; Wood, 2016), exposure routes (Codd et al., 1999; Facciponte et al., 2018), exposures to toxins in health supplements (Dietrich et al., 2008), bioaccumulation (Al-Sammak et al., 2014), or negative and positive aspects of cyanobacteria and cyanotoxins, ranging from cancer-causing to cancer-fighting properties (Zanchett and Oliveira-Filho, 2013). At least one researcher reviewed extreme environments (Cirés et al., 2017), concluding that cyanotoxins can thrive in hot springs, polar deserts, alkaline lakes, and hypersaline environments.

However, with the exception of a few papers (e.g. Osswald et al., 2007; Aráoz et al., 2010; D’Anglada et al., 2015; Rutkowska et al., 2019), most papers are not specific to neurotoxins and, none specifically focused on freshwater neurotoxins and their effects on animals and ecosystems. Janssen (2019) went beyond microcystin and other low molecular weight toxins (e.g. anatoxin-a and saxitoxin) and reviewed products of cyanobacteria called cyanobacterial peptides, reporting cyanobacterial peptides can occur just as frequently and at similar concentrations as microcystins. We built from Janssen’s (2019) question of whether some cyanobacterial metabolites have no ecotoxicological significance or whether they simply have received too little attention, and therefore, extend this idea to the understudied neurotoxins, anatoxin-a and saxitoxin.

Section snippets

The neurotoxins—categories and mode of action

Neurotoxins are a group of compounds that have clear biological effects on the nervous system but differ in chemical structure and mode of action (Rutkowska et al., 2019). Anatoxins and saxitoxins are neurotoxin classes with numerous variants. The anatoxins consist of three categories: anatoxin-a, homoanatoxin-a, and anatoxin-a(s). However, anatoxin-a(s) is structurally unrelated to anatoxin-a and homoanatoxin-a (Miller et al., 2017; Rutkowska et al., 2019), and a recent suggestion to rename it 

Anatoxin-a and saxitoxin—production, isolation, and identification

The earliest cases of anatoxin-a and saxitoxin in freshwater environments were reported in the 1960s. Anatoxin-a, isolated from a cyanobacterial accumulation that killed cattle, was first called Very Fast Death Factor because it killed mice in 2–5 min (Gorham et al., 1964; Devlin et al., 1977). The earliest freshwater detection of another potent toxin was isolated from a strain of Aphanizomenon flos–aquae from Kezar Lake in New Hampshire, USA (Sawyer et al., 1968). This potent toxin was later

Environmental fate

Once anatoxin-a and saxitoxin are produced, their persistence in the aquatic environment will depend, to some extent, on persistence traits in the cyanobacteria species that produce them. For example, the ability of Aphanizomenon to fix nitrogen allows it to remain in low nitrogen environments (Wood et al., 2010; Moustaka-Gouni et al., 2017), the salt tolerance of Aphanizomenon favaroloi can help it thrive in brackish waters (Moustaka-Gouni et al., 2017), and the ability of some cyanobacteria

Freshwater neurotoxin occurrence

The laboratory studies identifying cyanobacterial species that produce neurotoxins (Table 1, Table 2) are important to understanding how those neurotoxins are produced and released in the natural environment. However, with all the complexities of a natural system, we wanted to look at anatoxin-a and saxitoxin occurrence in freshwater environments (Table 3, Table 4). Only studies that included field collections and toxin analysis are included in Table 3, Table 4. Studies were excluded if samples 

Health effects in humans and other animals

In humans, poisonings attributed to cyanotoxins have been recorded as far back as the Han dynasty (206 BCE–220 CE) in China (Chorus and Bartram, 1999). Acute and chronic health effects of cyanotoxins have included visual disturbances, vomiting, and acute liver failure (Carmichael et al., 2001), as well as dermatologic, gastrointestinal (Chorus and Bartram, 1999), respiratory (Falconer, 1996), and neurologic symptoms (Aráoz et al., 2010; Al-Sammak et al., 2014; Carmichael and Boyer, 2016).

Ecosystem effects of cyanobacteria and neurotoxins

Although sublethal effects due to neurotoxin exposure have received less attention than large mortality events, they may be important indicators of ecosystem health. Cyanobacteria are important components of freshwater ecosystems, not only in producing oxygen through photosynthesis (Hudnell, 2008), but also serving as food for planktivores (Paerl and Paul, 2012) and water birds, and forming symbiotic relationships with animals and plants (D’Anglada et al., 2015). Cyanotoxins can affect trophic

Research gaps and directions

The aim of this review was to synthesize the findings of individual studies that examined anatoxin-a and saxitoxin, in order to report on the effects of these neurotoxins to humans, animals, and freshwater ecosystems. Research on the occurrence of anatoxins and saxitoxins in freshwater systems is relatively scarce when compared to research on other cyanotoxins, especially microcystin. Cyanotoxin research is a growing field and the tables of literature summarized allow for an examination of

Conclusions and implications

The neurotoxins anatoxin-a and saxitoxin are produced globally by many freshwater cyanobacteria. Neurotoxins produced by cyanobacteria could be an important part of freshwater ecosystem function. However, the current research has not determined why these neurotoxins are produced, and our understanding is limited in terms of what triggers their production and release and what effects, particularly sublethal effects, they have on freshwater ecosystems. For resource managers, implications include

CRediT authorship contribution statement

Victoria G. Christensen: Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review & editing. Eakalak Khan: Methodology, Writing – review & editing, Visualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank Hayley Olds, U.S. Geological Survey (USGS), for assisting with our literature search. This work was funded in part by the USGS Toxic Substances Hydrology and Contaminant Biology Programs. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government.

References (212)

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