Comparison of the acute inhibitory effects of Tetrodotoxin (TTX) in rat and human neuronal networks for risk assessment purposes

Emma E.J Kasteel,Remco H.S Westerink

doi:10.1016/j.toxlet.2017.02.014

Emma E.J Kasteel, Remco H.S Westerink

Open Access

https://doi.org/10.1016/j.toxlet.2017.02.014

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Journal: Toxicology Letters	Publication Date: Feb 10, 2017
Citations: 53	License type: cc-by

Affiliation: Utrecht University

Abstract

Tetrodotoxin (TTX) is an extremely toxic marine neurotoxin. TTX inhibits voltage-gated sodium channels, resulting in a potentially lethal inhibition of neurotransmission. Despite numerous intoxications in Asia and Europe, limited (human) toxicological data are available for TTX. Additionally, the degree of interspecies differences for TTX is not well established, hampering the use of available (animal) data for human risk assessment and establishing regulatory limits for TTX concentrations in (shell)fish.We therefore used micro-electrode array (MEA) recordings as an integrated measure of neurotransmission to demonstrate that TTX inhibits neuronal electrical activity in both primary rat cortical cultures and human-induced pluripotent stem cell (hIPSC)-derived iCell® neurons in co-culture with hIPSC-derived iCell® astrocytes, with IC50 values of 7 and 10nM, respectively.From these data combined with LD50 values and IC50 concentrations of voltage-gated sodium channels derived from literature it can be concluded that interspecies differences are limited for TTX. Consequently, we used experimental animal data to derive a human acute reference dose of 1.33μg/kg body weight, which corresponds to maximum concentration of TTX in shellfish of 200μg/kg.

Highlights

Tetrodotoxin (TTX) is a potent neurotoxin that is naturally present in certain marine and terrestrial species
We earlier demonstrated the suitability of rat cortical cultures grown on Multi-well microelectrode array (mwMEA) to investigate the effects of various marine neurotoxins, including TTX, on neuronal activity (Nicolas et al, 2014)
Our results demonstrate that TTX potently and concentrationdependently inhibits neuronal electrical activity in both models

Summary

Introduction

Tetrodotoxin (TTX) is a potent neurotoxin that is naturally present in certain marine and terrestrial species. While the presence of TTX used to be confined to Asia and especially Japan, TTX has been found in the last decade in marine organisms, including shellfish, in Europe (Turner et al, 2015; Rodriguez et al, 2008; Vlamis et al, 2015). The appearance of TTX in European shellfish is an emerging problem and uniform regulatory limits for TTX have not yet been set as TTX is currently under review by the European Food Safety Authority (EFSA)

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