Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors

Molgó, Jordi; Marchot, Pierre; Aráoz, Rómulo; Benoit, Évelyne; Iorga, Bogdan I.; Zakarian, Armen; Taylor, Palmer; Bourne, Yves; Servent, Denis

doi:10.1111/jnc.13995

Cited by 63 publications

(62 citation statements)

References 95 publications

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“…At the dose of 220 µg kg −1 and above, PnTx-G induced lethal effects within 30 minutes after its administration. Before death, mice showed piloerection, prostration, hypothermia, abdominal breathing, paralysis of the hind limbs, and cyanosis, consistent with nicotinic receptors blocking action by PnTx-G [23][24][25][26][27][28][29][30]. No signs of toxicity were recorded in survived mice.…”

Section: Discussionmentioning

confidence: 61%

“…No significant changes in serum markers of liver, kidney, and/or muscle damage (AST, ALT, GLDH, creatinine, CPK) or of selected ions (Na + , K + , Ca 2+ , Cl − , P i ) as indices of electrolytes homeostasis have been recorded. The absence of significant morphological tissues alterations in the main organs could be related to a fast functional damage induced by the toxin, such as neuromuscular block consequent to the antagonistic effect on nicotinic acetylcholine receptors [23][24][25][26][27][28][29][30], rather than a structural tissue damage. On the other hand, the nicotinic receptors antagonism might be at the basis of the main neuromuscular signs of mice before death (prostration, respiratory depression and hind limbs paralysis).…”

Section: Discussionmentioning

confidence: 99%

“…The toxicity is ascribed mainly to a specific interaction and blockage of muscle-and neuronal-type nicotinic acetylcholine receptors, known to be involved in synaptic transmissions at central and peripheral nervous system as well as at skeletal neuromuscular junction level. In particular, PnTXs bind muscle nicotinic acetylcholine receptors more potently than neuronal ones [23][24][25][26][27][28][29][30]. Intraperitoneal injection of these toxins in mice has been shown to induce skeletal muscle paralysis, respiratory depression, and lethal effects within less than one hour.…”

Section: Introductionmentioning

confidence: 99%

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Acute Oral Toxicity of Pinnatoxin G in Mice

Sosa

Pelin

Cavion

et al. 2020

Toxins

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Pinnatoxin G (PnTx-G) is a marine cyclic imine toxin produced by the dinoflagellate Vulcanodinium rugosum, frequently detected in edible shellfish from Ingril Lagoon (France). As other pinnatoxins, to date, no human poisonings ascribed to consumption of PnTx-G contaminated seafood have been reported, despite its potent antagonism at nicotinic acetylcholine receptors and its high and fast-acting toxicity after intraperitoneal or oral administration in mice. The hazard characterization of PnTx-G by oral exposure is limited to a single acute toxicity study recording lethality and clinical signs in non-fasted mice treated by gavage or through voluntary food ingestion, which showed differences in PnTx-G toxic potency. Thus, an acute toxicity study was carried out using 3 h-fasted CD-1 female mice, administered by gavage with PnTx-G (8–450 µg kg−1). At the dose of 220 µg kg−1 and above, the toxin induced a rapid onset of clinical signs (piloerection, prostration, hypothermia, abdominal breathing, paralysis of the hind limbs, and cyanosis), leading to the death of mice within 30 min. Except for moderate mucosal degeneration in the small intestine recorded at doses of 300 µg kg−1, the toxin did not induce significant morphological changes in the other main organs and tissues, or alterations in blood chemistry parameters. This acute oral toxicity study allowed to calculate an oral LD50 for PnTx-G equal to 208 μg kg−1 (95% confidence limits: 155–281 µg kg−1) and to estimate a provisional NOEL of 120 µg kg−1.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute Oral Toxicity of Pinnatoxin G in Mice

Sosa

Pelin

Cavion

et al. 2020

Toxins

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“…Gymnodimines (GYMs), spirolides (SPXs), pinnatoxins (PnTXs), pteriatoxins (PtTXs), prorocentrolides, spiro-prorocentrimine, portimines, and symbioimines belong to cyclic imines (CIs), a family of marine biotoxins produced by dinoflagellates and accumulated in shellfish [1][2][3]. These compounds share as a common structural motif an imine group in a cyclic moiety, which has been identified as a pharmacophore with biological activity [4,5].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Cyclic Imines in Mussels (Mytilus galloprovincialis) from Galicia (NW Spain) by LC-MS/MS

Moreiras

Leão

Gago-Martı́nez

2019

IJERPH

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Cyclic imines (CIs) are being considered as emerging toxins in the European Union, and a scientific opinion has been published by the European Food Safety Authority (EFSA) in which an assessment of the risks to human health related to their consumption has been carried out. Recommendations on the EFSA opinion include the search for data occurrence of CIs in shellfish and using confirmatory methods by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which need to be developed and optimized. The aim of this work is the application of LC-MS/MS to the analysis of gymnodimines (GYMs), spirolides (SPXs), pinnatoxins (PnTXs), and pteriatoxins (PtTXs) in mussels from Galician Rias, northwest Spain, the main production area in Europe, and therefore a representative emplacement for their evaluation. Conditions were adjusted using commercially available certified reference standards of GYM-A, SPX-1, and PnTX-G and evaluated through quality control studies. The EU-Harmonised Standard Operating Procedure for determination of lipophilic marine biotoxins in molluscs by LC-MS/MS was followed, and the results obtained from the analysis of eighteen samples from three different locations that showed the presence of PnTXs and SPXs are presented and discussed. Concentrations of PnTX-G and SPX-1 ranged from 1.8 to 3.1 µg/kg and 1.2 to 6.9 µg/kg, respectively, and PnTX-A was detected in the group of samples with higher levels of PnTX-G after a solid phase extraction (SPE) step used for the concentration of extracts.

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“…No food intoxication related to the group of cyclic imines has been reported so far. Still, cyclic imines have been shown to exert neurological effects in mice [31], and most spirolides including SPX-1 were shown to selectively inhibit nicotinic acetylcholine receptors [32]. …”

Section: Introductionmentioning

confidence: 99%

Mixtures of Lipophilic Phycotoxins: Exposure Data and Toxicological Assessment

et al. 2018

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Lipophilic phycotoxins are secondary metabolites produced by phytoplanktonic species. They accumulate in filter-feeding shellfish and can cause human intoxication. Regulatory limits have been set for individual toxins, and the toxicological features are well characterized for some of them. However, phycotoxin contamination is often a co-exposure phenomenon, and toxicological data regarding mixtures effects are very scarce. Moreover, the type and occurrence of phycotoxins can greatly vary from one region to another. This review aims at summarizing the knowledge on (i) multi-toxin occurrence by a comprehensive literature review and (ii) the toxicological assessment of mixture effects. A total of 79 publications was selected for co-exposure evaluation, and 44 of them were suitable for toxin ratio calculations. The main toxin mixtures featured okadaic acid in combination with pectenotoxin-2 or yessotoxin. Only a few toxicity studies dealing with co-exposure were published. In vivo studies did not report particular mixture effects, whereas in vitro studies showed synergistic or antagonistic effects. Based on the combinations that are the most reported, further investigations on mixture effects must be carried out.

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Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors

Cited by 63 publications

References 95 publications

Acute Oral Toxicity of Pinnatoxin G in Mice

Acute Oral Toxicity of Pinnatoxin G in Mice

Analysis of Cyclic Imines in Mussels (Mytilus galloprovincialis) from Galicia (NW Spain) by LC-MS/MS

Mixtures of Lipophilic Phycotoxins: Exposure Data and Toxicological Assessment

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