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Marine Drugs
Special Issues
Tetrodotoxins: Detection, Biosynthesis and Biological Effects
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Tetrodotoxins: Detection, Biosynthesis and Biological Effects

A special issue of Marine Drugs (ISSN 1660-3397). This special issue belongs to the section "Marine Toxins".

Deadline for manuscript submissions: closed (21 December 2023) | Viewed by 15375

Special Issue Editor

Dr. Manolis Mandalakis

E-Mail Website
Guest Editor
Institute of Marine Biology, Biotechnology and Aquaculture, Hellenic Centre for Marine Research (HCMR), 71500 Heraklion, Greece
Interests: bioanalysis; biomolecules; biotoxins; metabolites; bioactive compounds; analytical chemistry; mass spectrometry; chromatography; biotechnology; marine biological resources; bacteria; sponges; fish; marine products

Special Issue Information

Dear Colleagues,

Tetrodotoxin (TTX) is a heat-stable, highly hydrophilic and potent neurotoxin mainly found in marine organisms, such as pufferfish, toadfish, gastropods and crabs. About 1–4 mg of this toxin can be lethal to humans, and several cases of TTX intoxication are reported every year, especially in East Asia, where consumption of certain pufferfish species is relatively high. Endosymbiotic bacteria are generally considered to be the primary source of TTX, but the exact processes/factors shaping the biosynthesis, regulation and accumulation of TTX remain unclear. Given the risk to public health, there is increasing interest in measuring TTX levels in pufferfish and other edible marine organisms (e.g., oysters, scallops). Since this toxin has been found to coexist with almost 30 structural analogues of varying toxicity, there is also interest in assessing the profile of individual analogues rather than TTX alone. Over the last decade, comprehensive analysis of TTXs has become less challenging due to the advent of robust columns for hydrophilic interaction liquid chromatography (HILIC) and the development of mass-spectrometry-based detection methods. However, alternative techniques enabling rapid, sensitive, inexpensive or on-the-spot screening are also needed.

The aim of this Special Issue is to gather the most recent research on the detection, biosynthesis and biological effects of tetrodotoxin. All papers dealing with novel detection tools, toxic effects, additional unexplored bioactivities, biological synthesis, regulation, accumulation, occurrence of TTX in aquatic organisms and relevant microbiological studies are welcome.

Dr. Manolis Mandalakis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • occurrence and levels of tetrodotoxin
  • detection and quantification
  • analytical methods
  • toxicology
  • bioactivity
  • biosynthetic processes
  • bioaccumulation

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Published Papers (5 papers)

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18 pages, 13595 KiB  
Article
Transcriptomic Profiling of Tetrodotoxin-Induced Neurotoxicity in Human Cerebral Organoids
by Zhanbiao Liu, Zhe Wang, Yue Wei, Jingjing Shi, Tong Shi, Xuejun Chen and Liqin Li
Mar. Drugs 2023, 21(11), 588; https://doi.org/10.3390/md21110588 - 10 Nov 2023
Cited by 2 | Viewed by 2299
Abstract
Tetrodotoxin (TTX) is an exceedingly toxic non-protein biotoxin that demonstrates remarkable selectivity and affinity for sodium channels on the excitation membrane of nerves. This property allows TTX to effectively obstruct nerve conduction, resulting in nerve paralysis and fatality. Although the mechanistic aspects of [...] Read more.
Tetrodotoxin (TTX) is an exceedingly toxic non-protein biotoxin that demonstrates remarkable selectivity and affinity for sodium channels on the excitation membrane of nerves. This property allows TTX to effectively obstruct nerve conduction, resulting in nerve paralysis and fatality. Although the mechanistic aspects of its toxicity are well understood, there is a dearth of literature addressing alterations in the neural microenvironment subsequent to TTX poisoning. In this research endeavor, we harnessed human pluripotent induced stem cells to generate cerebral organoids—an innovative model closely mirroring the structural and functional intricacies of the human brain. This model was employed to scrutinize the comprehensive transcriptomic shifts induced by TTX exposure, thereby delving into the neurotoxic properties of TTX and its potential underlying mechanisms. Our findings revealed 455 differentially expressed mRNAs (DEmRNAs), 212 differentially expressed lncRNAs (DElncRNAs), and 18 differentially expressed miRNAs (DEmiRNAs) in the TTX-exposed group when juxtaposed with the control cohort. Through meticulous Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein–protein interaction (PPI) analysis, we ascertained that these differential genes predominantly participate in the regulation of voltage-gated channels and synaptic homeostasis. A comprehensive ceRNA network analysis unveiled that DEmRNAs exert control over the expression of ion channels and neurocytokines, suggesting their potential role in mediating apoptosis. Full article
(This article belongs to the Special Issue Tetrodotoxins: Detection, Biosynthesis and Biological Effects)
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16 pages, 1150 KiB  
Article
Assessing the Toxicity of Lagocephalus sceleratus Pufferfish from the Southeastern Aegean Sea and the Relationship of Tetrodotoxin with Gonadal Hormones
by Thekla I. Anastasiou, Eirini Kagiampaki, Gerasimos Kondylatos, Anastasios Tselepides, Panagiota Peristeraki and Manolis Mandalakis
Mar. Drugs 2023, 21(10), 520; https://doi.org/10.3390/md21100520 - 29 Sep 2023
Cited by 5 | Viewed by 2998
Abstract
Given the dramatic increase in the L. sceleratus population in the southeastern Aegean Sea, there is growing interest in assessing the toxicity of this pufferfish and the factors controlling its tetrodotoxin (TTX) content. In the present study, liver, gonads, muscle and skin of [...] Read more.
Given the dramatic increase in the L. sceleratus population in the southeastern Aegean Sea, there is growing interest in assessing the toxicity of this pufferfish and the factors controlling its tetrodotoxin (TTX) content. In the present study, liver, gonads, muscle and skin of 37 L. sceleratus specimens collected during May and June 2021 from the island of Rhodes, Greece, were subjected to multi-analyte profiling using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in order to quantitate TTX and evaluate whether this biotoxin interrelates with hormones. TTX and its analogues 4-epiTTX, 11-deoxyTTX, 11-norTTX-6-ol, 4,9-anhydroTTX and 5,11/6,11-dideoxyTTX were detected in all tissue types. Liver and gonads were the most toxic tissues, with the highest TTX concentrations being observed in the ovaries of female specimens. Only 22% of the analyzed muscle samples were non-toxic according to the Japanese toxicity threshold (2.2 μg TTX eq g−1), confirming the high poisoning risk from the inadvertent consumption of this species. Four steroid hormones (i.e., cortisol, testosterone, androstenedione and β-estradiol) and the gonadotropin-releasing hormone (GnRH) were detected in the gonads. Androstenedione dominated in female specimens, while GnRH was more abundant in males. A positive correlation of TTX and its analogues with β-estradiol was observed. However, a model incorporating sex rather than β-estradiol as the independent variable proven to be more efficient in predicting TTX concentration, implying that other sex-related characteristics are more important than specific hormone-regulated processes. Full article
(This article belongs to the Special Issue Tetrodotoxins: Detection, Biosynthesis and Biological Effects)
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12 pages, 1968 KiB  
Article
Levels of Tetrodotoxins in Spawning Pufferfish, Takifugu alboplumbeus
by Masaki Asano, Chihiro Ishizaki, Taiga Tomonou, Masato Kihara, Masaaki Ito, Shino Yasukawa, Kyoko Shirai, Hikaru Oyama, Shin Izawa, Reona Kawamura, Kanae Saito, Rei Suo, Ryota Nakahigashi, Masaatsu Adachi, Toshio Nishikawa, Haruo Sugita and Shiro Itoi
Mar. Drugs 2023, 21(4), 207; https://doi.org/10.3390/md21040207 - 25 Mar 2023
Cited by 3 | Viewed by 2281
Abstract
Tetrodotoxin (TTX), also known as pufferfish toxin, is an extremely potent neurotoxin thought to be used as a biological defense compound in organisms bearing it. Although TTX was thought to function as a chemical agent for defense and anti-predation and an attractant for [...] Read more.
Tetrodotoxin (TTX), also known as pufferfish toxin, is an extremely potent neurotoxin thought to be used as a biological defense compound in organisms bearing it. Although TTX was thought to function as a chemical agent for defense and anti-predation and an attractant for TTX-bearing animals including pufferfish, it has recently been demonstrated that pufferfish were also attracted to 5,6,11-trideoxyTTX, a related compound, rather than TTX alone. In this study, we attempted to estimate the roles of TTXs (TTX and 5,6,11-trideoxyTTX) in the pufferfish, Takifugu alboplumbeus, through examining the location of TTXs in various tissues of spawning pufferfish from Enoshima and Kamogawa, Japan. TTXs levels in the Kamogawa population were higher than those in the Enoshima population, and there was no significant difference in the amount of TTXs between the sexes in either population. Individual differences were greater in females than in males. However, the location of both substances in tissues differed significantly between sexes: male pufferfish accumulated most of their TTX in the skin and liver and most of their 5,6,11-trideoxyTTX in the skin, whereas females accumulated most of their TTX and 5,6,11-trideoxyTTX in the ovaries and skin. Full article
(This article belongs to the Special Issue Tetrodotoxins: Detection, Biosynthesis and Biological Effects)
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16 pages, 1993 KiB  
Article
Tetrodotoxin Decreases the Contractility of Mesenteric Arteries, Revealing the Contribution of Voltage-Gated Na+ Channels in Vascular Tone Regulation
by Joohee Park, Coralyne Proux, William Ehanno, Léa Réthoré, Emilie Vessières, Jennifer Bourreau, Julie Favre, Gilles Kauffenstein, César Mattei, Hélène Tricoire-Leignel, Daniel Henrion, Claire Legendre and Christian Legros
Mar. Drugs 2023, 21(3), 196; https://doi.org/10.3390/md21030196 - 22 Mar 2023
Cited by 1 | Viewed by 2109
Abstract
Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of [...] Read more.
Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na+ (NaV) channels. In arteries, NaV channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of NaV channels in vascular tone using TTX. We first characterized the expression of NaV channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which scn2a and scn1b were the most abundant transcripts, suggesting that murine vascular NaV channels consist of NaV1.2 channel subtype with NaVβ1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmitter release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks NaV channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications. Full article
(This article belongs to the Special Issue Tetrodotoxins: Detection, Biosynthesis and Biological Effects)
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16 pages, 1600 KiB  
Systematic Review
Efficacy and Security of Tetrodotoxin in the Treatment of Cancer-Related Pain: Systematic Review and Meta-Analysis
by Miguel Á. Huerta, Javier de la Nava, Antonia Artacho-Cordón and Francisco R. Nieto
Mar. Drugs 2023, 21(5), 316; https://doi.org/10.3390/md21050316 - 21 May 2023
Cited by 4 | Viewed by 4782
Abstract
The pharmacological treatment of cancer-related pain is unsatisfactory. Tetrodotoxin (TTX) has shown analgesia in preclinical models and clinical trials, but its clinical efficacy and safety have not been quantified. For this reason, our aim was to perform a systematic review and meta-analysis of [...] Read more.
The pharmacological treatment of cancer-related pain is unsatisfactory. Tetrodotoxin (TTX) has shown analgesia in preclinical models and clinical trials, but its clinical efficacy and safety have not been quantified. For this reason, our aim was to perform a systematic review and meta-analysis of the clinical evidence that was available. A systematic literature search was conducted in four electronic databases (Medline, Web of Science, Scopus, and ClinicalTrials.gov) up to 1 March 2023 in order to identify published clinical studies evaluating the efficacy and security of TTX in patients with cancer-related pain, including chemotherapy-induced neuropathic pain. Five articles were selected, three of which were randomized controlled trials (RCTs). The number of responders to the primary outcome (≥30% improvement in the mean pain intensity) and those suffering adverse events in the intervention and placebo groups were used to calculate effect sizes using the log odds ratio. The meta-analysis showed that TTX significantly increased the number of responders (mean = 0.68; 95% CI: 0.19–1.16, p = 0.0065) and the number of patients suffering non-severe adverse events (mean = 1.13; 95% CI: 0.31–1.95, p = 0.0068). However, TTX did not increase the risk of suffering serious adverse events (mean = 0.75; 95% CI: −0.43–1.93, p = 0.2154). In conclusion, TTX showed robust analgesic efficacy but also increased the risk of suffering non-severe adverse events. These results should be confirmed in further clinical trials with higher numbers of patients. Full article
(This article belongs to the Special Issue Tetrodotoxins: Detection, Biosynthesis and Biological Effects)
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