Emanuela Testai

Anatoxin-a(S) (ATX(S)) is, despite the similarity of the names, not structurally related to anatoxin-a: while the latter is an alkaloid, ATX(S) is an organophosphate (see below). It received its name during initial studies which isolated multiple toxic fractions from a strain of Anabaena sp. to which letters or suffixes were assigned. The “S” in the name denotes a characteristic symptom of exposure in mammals: “salivation”. Because of its totally different chemical structure and mechanism of action, Fiore et al. (2020) proposed renaming it to guanitoxin, advocating that the new name should reflect its chemical composition.

Chemical Structure

Anatoxin-a(S) is an N-hydroxyguanidine methyl phosphate ester with a molecular weight of 252 Da. It is the only known natural organophosphonate besides biomolecules such as DNA, RNA and ATP (Figure 2.5; Mahmood &C Carmichael, 1987). No structural variants of ATX(S) have been detected so far.

Anatoxin-a(S) decomposes rapidly in basic solutions but is relatively stable in neutral and acidic conditions (Matsunaga et al., 1989). It is inactivated at temperatures higher than 40 °C (Carmichael, 2001).

Toxicity: Mode of Action

Anatoxin-a(S) irreversibly inhibits acetylcholinesterase (AChE) in the neuromuscular junctions (but not in the central nervous system) blocking hydrolysis of the neurotransmitter. This results in acetylcholine accumulation, leading to nerve hyperexcitability. The acute neurological effects in mammals are muscle weakness, respiratory distress (dyspnoea) and convulsions preceding death, which occurs due to respiratory arrest (i.p. LDS0 in mice = 40-228 pg/kg bw,

Chemical structure of anatoxins-a(S). Molecular mass (monoisotopic)

Figure 2.5 Chemical structure of anatoxins-a(S). Molecular mass (monoisotopic): 252.099 Da; molecular weight (average): 252.212 g/mol.

lower in rats i.p. LDS0 = 5.3 mg/kg bw). Viscous mucoid hypersalivation is a typical symptom induced by ATX(S).

Data on oral administration as well as on subchronic and/or chronic toxicity are not available.

Derivation of Guideline Values For Anatoxin-A(S) in Water

No toxicological data are available for deriving an acute dose NOAEL or LOAEL as point of departure, and data on subchronic and chronic exposure are also lacking. Therefore, no TDI or guideline value can yet be derived for ATX(S).

New Zealand has established a limit as provisional maximum acceptable value of 1 pg/L for total ATX(S) content in drinking-water (Chorus, 2012).

Production, Occurrence and Environmental Fate

Anatoxin-a(S) has been reported from strains of Dolichospermum (Anabaena) flosaquae from Canada (Carmichael & Gorham, 1978), in both field samples and strains of D. lemmermannii from Denmark (Henriksen et al., 1997) and from Portugal (Fristachi & Sinclair, 2008), in D. flosaquae from the USA and Scotland (Matsunaga et ah, 1989; Codd, 1995), in D. spiroides from Brazil (Monserrat et ah, 2001), and in D. crassa from southern Brazil (Becker et ah, 2010).

The available literature on ATX(S) biosynthesis is scant, and the gene cluster responsible for the biosynthesis of ATX(S) has not yet been identified (Pearson et ah, 2016). Only the synthesis of the cyclic moiety of ATX(S) has been reported (Matsunaga et ah, 1989; Moura & Pinto, 2010).

The precursor for the guanidine group has been proposed to be L-arginine, which is hydroxylated at C4, as demonstrated by feeding studies (Moore et ah, 1992) with radiolabelled arginine and (4S)-4-hydroxy-arginine, but none of the further steps have been described to date.

The presence of ATX(S) in waterbodies is sparsely documented (Table 2.7); one of the reasons could be related to analytical difficulties such as the absence of analytical standards, and the possible co-occurrence of organo- phosphate pesticides in the environment, limiting the use of biological tests, including biosensors, based on AChE inhibition (Devic et ah, 2002). Indeed, mouse bioassays and acetylcholine esterase inhibition assays may be used to infer ATX(S) levels in environmental samples; however, these tests are not specific (Patocka et ah, 2011). This sometimes leads only to a qualitative description of detection, without quantification (Molica et ah, 2005). The only chance to use analytical methodologies, overcoming the lack of standards to identify the presence of the toxin, is the LC-MS/MS fragmentation pattern for ATX(S) in cyanobacterial cultures.

Highly variable ATX(S) contents were detected in three Danish lakes dominated by D. lemmermannii, reaching maximum contents of 3300 pg/g dw (Henriksen et ah, 1997).

The presence of ATX(S) was also suggested by results from acetylcholine esterase inhibition assay in cyanobacterial crusts in Qatar (Metcalf et ah, 2012).

Data on chemical breakdown in the natural water environment and biodegradation of this cyanotoxin are not available.

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