Abstract
Recently, Tetrodotoxin (TTX), a well-known pufferfish poison, and several analogues were detected in gastropods and bivalves from European waters. For this reason, the European Food Safety Authority (EFSA) has conducted a risk assessment of TTX in marine bivalves. Based on the results of the acute oral study in mice, “apathy” was selected as the most sensitive endpoint, and 0.25 μg/kg bw as the group Acute Reference Dose (ARfD) of TTX and its analogs was derived. Thus, in mice, oral administration of TTX is most sensitive to inducing “apathy”, a little-known toxic symptom in humans, suggesting an effect on the central nervous system.
For seeking the molecular mechanisms of acute poisoning due to TTX, we applied our Percellome Toxicogenomics that had been developed for the mechanism-based predictive toxicology using time- and dose-dependent transcriptomic responses induced by a chemical. The 24-hour Non-Observed Effect Level was selected as the high dose. Murine liver and hippocampal mRNA were collected after a single oral administration of TTX at each concentration of 0, 30, 100 and 300 μg/kg bw (4 doses x 4 time points, triplicate), and absolute gene expression levels of approximately 45,000 probe sets were obtained by the Percellome method using GeneChip MOE430v2 (Affymetrix) for comprehensive analysis. Signal networks related to stress responses and cytokines were extracted from both liver and hippocampus. Neuronal signatures in hippocampus were less pronounced than expected. The inter-organ relationship of acute TTX toxicity will be discussed based on comprehensive analysis on its molecular mechanism.
