Comparative Effects of the Marine Algal Toxins Azaspiracid-1, -2, and -3 on Jurkat T Lymphocyte Cells

Twiner, Michael J.; El-Ladki, Racha; Kilcoyne, Jane; Doucette, Gregory J.

doi:10.1021/tx200553p

Cited by 23 publications

(49 citation statements)

References 48 publications

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“…Asterisks denote data with a significant difference (p < 0.05) between caspase activities in the presence and absence of the inhibitor. 16,36 Gross differences were observed between the cells lines upon comparison of maximal cytotoxicity. Protracted exposures of T lymphocytes to high AZA1 concentrations (≥50 nM) resulted in 90% cytotoxicity, whereas the intestinal and neuroblastoma cells experienced 53 and 46% cytotoxicity, respectively.…”

Section: ■ Discussionmentioning

confidence: 99%

Induction of Apoptosis Pathways in Several Cell Lines following Exposure to the Marine Algal Toxin Azaspiracid

Twiner

Hanagriff

Butler

et al. 2012

Chem. Res. Toxicol.

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Azaspiracids (AZAs) are polyether marine dinoflagellate toxins that accumulate in shellfish and represent an emerging human health risk. Although there have been no deaths associated with the AZA toxins, humans exposed to AZAs experience severe gastrointestinal symptoms. This toxin class has been shown to be highly cytotoxic, a teratogen to developing fish, and a possible carcinogen in mice. Just recently, the AZAs have been shown to be potassium channel inhibitors. This report employed multiple human cell lines [Jurkat T lymphocytes, Caco-2 intestinal cells, and BE(2)-M17 neuroblastoma cells] in characterizing cytotoxicity and pathways of apoptosis. Cytotoxicity experiments were consistent with published literature that has shown that AZA1 is cytotoxic in both a concentration- and time-dependent manner to each cell type tested, with mean EC(50) values ranging between 1.1 and 7.4 nM. Despite the absence of morphological indices indicating apoptosis, caspase-3/7 activity was higher in all cell types treated with AZA1. Furthermore, in T lymphocytes, the most sensitive cell type, the activities of initiator caspase-2 and caspase-10 and concentrations of intracellular cytochrome c were elevated. DNA fragmentation was also observed for T lymphocytes exposed to AZA1-AZA3. Collectively, our data confirm that AZA1 was highly cytotoxic to multiple cell types and that cells exposed to AZA1 underwent atypical apoptosis, possibly in conjunction with necrotic cytotoxicity.

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Section: ■ Discussionmentioning

confidence: 99%

Induction of Apoptosis Pathways in Several Cell Lines following Exposure to the Marine Algal Toxin Azaspiracid

Twiner

Hanagriff

Butler

et al. 2012

Chem. Res. Toxicol.

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“…The 37-epi-AZA1 was shown to be 5.1-fold more potent than the parent AZA1 (Table 5), making it comparable in potency (in vitro) to AZA2 and AZA3 (8.3-and 4.5-fold more potent than AZA1, respectively). 26 However, this work has shown the epimer to be highly unstable, rapidly converting back to its parent analogue at temperatures >20°C, and since all of the cytotoxicity experiments were run for a protracted period of time (up to 72 h) at 37°C, it was anticipated that there could be significant conversion of the epimer back to AZA1. As such, samples were taken frequently throughout the course of the study and subsequently analyzed by LC-MS to assess for these (or other) structural changes.…”

Section: Chemical Research In Toxicologymentioning

confidence: 98%

“…AZA2 is the most potent, followed by AZA3, AZA1, and then the hydroxylated AZA4 and AZA5. 9,16,26 The only target conclusively demonstrated for the AZAs has been the hERG potassium channel. 27 Liquid chromatography−mass spectrometry (LC-MS) is the reference method for the analysis of lipophilic marine biotoxins in shellfish.…”

Section: ■ Introductionmentioning

confidence: 99%

Epimers of Azaspiracids: Isolation, Structural Elucidation, Relative LC-MS Response, and in Vitro Toxicity of 37-epi-Azaspiracid-1

Kilcoyne

McCarron

Twiner

et al. 2014

Chem. Res. Toxicol.

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Since azaspiracid-1 (AZA1) was identified in 1998, the number of AZA analogues has increased to over 30. The development of an LC-MS method using a neutral mobile phase led to the discovery of isomers of AZA1, AZA2, and AZA3, present at ~2-16% of the parent analogues in phytoplankton and shellfish samples. Under acidic mobile phase conditions, isomers and their parents are not separated. Stability studies showed that these isomers were spontaneous epimerization products whose formation is accelerated with the application of heat. The AZA1 isomer was isolated from contaminated shellfish and identified as 37-epi-AZA1 by nuclear magnetic resonance (NMR) spectroscopy and chemical analyses. Similar analysis indicated that the isomers of AZA2 and AZA3 corresponded to 37-epi-AZA2 and 37-epi-AZA3, respectively. The 37-epimers were found to exist in equilibrium with the parent compounds in solution. 37-epi-AZA1 was quantitated by NMR, and relative molar response studies were performed to determine the potential differences in LC-MS response of AZA1 and 37-epi-AZA1. Toxicological effects were determined using Jurkat T lymphocyte cells as an in vitro cell model. Cytotoxicity experiments employing a metabolically based dye (i.e., MTS) indicated that 37-epi-AZA1 elicited a lethal response that was both concentration- and time-dependent, with EC50 values in the subnanomolar range. On the basis of EC50 comparisons, 37-epi-AZA1 was 5.1-fold more potent than AZA1. This data suggests that the presence of these epimers in seafood products should be considered in the analysis of AZAs for regulatory purposes.

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“…This provides additional evidence for the close relationship between Azadinium and Amphidoma not only from a phylogenetic perspective, but also on a metabolic basis. Moreover, AZA-2 is reported to be 8.3 fold more cytotoxic compared to AZA-1 (Twiner et al, 2012), although recent research indicate that AZA-2 is less toxic compared to AZA-1 both by oral and intraperitoneal application in the mouse assay . Finally, AZA-2 is determined as the predominant AZA in shellfish of the southern Atlantic coast before (Taleb et al, 2006;Vale et al, 2008).…”

Section: Toxinsmentioning

confidence: 99%

Amphidoma languida (Amphidomatacea, Dinophyceae) with a novel azaspiracid toxin profile identified as the cause of molluscan contamination at the Atlantic coast of southern Spain

Tillmann

Jaén²,

Fernandez³

et al. 2017

Harmful Algae

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A B S T R A C TAzaspiracids (AZA) are a group of food poisoning phycotoxins that are known to accumulate in shellfish. They are produced by some species of the planktonic dinophycean taxon Amphidomataceae. Azaspiracids have been first discovered in Ireland but are now reported in shellfish from numerous global sites thus showing a wide distribution. In shellfish samples collected in 2009 near Huelva (Spain), AZA was also found along the Andalusian Atlantic coast for the first time. Analysis using LC-MS/MS revealed the presence of two different AZA analogues in different bivalve shellfish species (Chamelea gallina, Cerastoderma edule, Donax trunculus, and Solen vagina). In a number of samples, AZA levels exceeded the EU regulatory level of 160 mg AZA-1 eq. kg À1 (reaching maximum levels of >500 mg AZA-1 eq. kg À1 in Chamelea gallina and >250 mg AZA-1 eq. kg À1 in Donax trunculus) causing closures of some local shellfish production areas. One dinophyte strain established from the local plankton during the AZA contamination period and determined as Amphidoma languida was in fact toxigenic, and its AZA profile disclosed it as the causative species: it contained AZA-2 as the main compound and the new compound AZA-43 initially detected in the shellfish. AZA-43 had the same mass as AZA-3, but produced different collision induced dissociation (CID) spectra. High resolution mass spectrometric measurements indicated that there is an unsaturation in the H, I ring system of AZA-43 distinguishing it from the classical AZA such as AZA-1, -2, and -3. Furthermore, the Spanish strain was different from the previously reported AZA profile of the species that consist of AZA-38 and AZ-39. In molecular phylogenetics, the Andalusian strain formed a monophyletic group together with other strains of Am. languida, but ITS sequences data revealed surprisingly high intragenomic variability. The first Andalusian case of AZA contamination of shellfish above the EU regulatory limit reported here clearly revealed the risk of azaspiracid poisoning (AZP) for this area and also for the Atlantic coast of Iberia and North Africa. The present study underlines the need for continuous monitoring of AZA and the organisms producing such toxins.

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Comparative Effects of the Marine Algal Toxins Azaspiracid-1, -2, and -3 on Jurkat T Lymphocyte Cells

Cited by 23 publications

References 48 publications

Induction of Apoptosis Pathways in Several Cell Lines following Exposure to the Marine Algal Toxin Azaspiracid

Induction of Apoptosis Pathways in Several Cell Lines following Exposure to the Marine Algal Toxin Azaspiracid

Epimers of Azaspiracids: Isolation, Structural Elucidation, Relative LC-MS Response, and in Vitro Toxicity of 37-epi-Azaspiracid-1

Amphidoma languida (Amphidomatacea, Dinophyceae) with a novel azaspiracid toxin profile identified as the cause of molluscan contamination at the Atlantic coast of southern Spain

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