Sung Min Lee (Korea Research Institute of Chemical Technology)

Myung Ae Bae (Korea Research Institute of Chemical Technology)

Sung Min Lee (Korea Research Institute of Chemical Technology)

Kyu-Seok Hwang (Korea Research Institute of Chemical Technology)

Seong Soon Kim (Korea Research Institute of Chemical Technology)

Kyeoung A Lee (Korea Research Institute of Chemical Technology)

Woojin Jung (Korea Research Institute of Chemical Technology)

Jung Yoon Yang (Korea Research Institute of Chemical Technology)

Byunghoi Lee (Korea Research Institute of Chemical Technology)

Dae-Seop Shin (Korea Research Institute of Chemical Technology)

Kahyeon Kim (Korea Research Institute of Chemical Technology)

Myung Ae Bae (Korea Research Institute of Chemical Technology)

Embryonic exposure to serotonergic agents is known to disrupt normal neurodevelopment and neurotransmitter balance. To assess neurotoxic potential of tegaserod (brand name Zelnorm; a 5-HT4 receptor agonist), zebrafish embryos were exposed to its EC20 concentration, determined from a survival-based dose–response assay. Then, behavioral responses were investigated using the light/dark transition test, followed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) to quantify 31 endogenous neurochemicals.

In this study, tegaserod exposure induced anxiety-like behavior, characterized by reduced locomotor activity during dark phases and elevated locomotor activity during light phases in zebrafish larvae. To understand the underlying mechanisms, we quantitatively analyzed a broad range of neurochemical systems, including histaminergic, cholinergic, dopaminergic, serotonergic/kynurenergic, and GABAergic metabolites in zebrafish larvae. Our data indicated that tegaserod exposure increased endogenous levels of acetylcholine, dopamine, norepinephrine, serotonin, and γ-aminobutyric acid, while decreasing glutamate levels compared to the control group. Furthermore, dysregulation of both the serotonergic and GABAergic systems, including impaired serotonin synthesis and imbalanced excitatory/inhibitory ratio, was associated with the observed anxiety-like behavior. These findings demonstrate that embryonic exposure to tegaserod induces behavioral impairment and disrupts neurotransmitter metabolism in zebrafish larvae. This study highlights the potential developmental neurotoxicity of tegaserod and its application in neurochemical profiling for neurotoxicity assessment.