Unveiling the Underexplored Neurotoxicity of 2,6-Dichloro-1,4-benzoquinone: Insights from Network Toxicology and In Vivo Models

Abstract

Halobenzoquinone disinfection byproducts (DBPs) are emerging drinking water contaminants with high toxic potency, among which 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ) is the most frequently detected. Despite the advances achieved in the toxicity of 2,6-DCBQ, its toxicological profile remains incompletely characterized. Herein, we integrated network toxicology with mouse and zebrafish models to explore the toxicity of 2,6-DCBQ. Network toxicology analysis highlighted neurotoxicity as a high-priority predicted end point and identified neuroinflammation and monoaminergic disruption as candidate molecular events. After 28 days of oral exposure, 2,6-DCBQ accumulated in a dose-dependent manner in the mouse brain and induced reactive gliosis and inflammatory responses, particularly in the prefrontal cortex and the hypothalamus. Most dopamine and serotonin receptors exhibited varying degrees of suppression, whereas HTR3A was consistently upregulated across all examined brain regions. Molecular docking and molecular dynamics simulation provided preliminary evidence for the potential interaction between 2,6-DCBQ and HTR3A. In zebrafish larvae, environmentally relevant 2,6-DCBQ exposure also reduced dopaminergic neuron fluorescence and brain 5-HT levels and led to affective disorder-like behavior characterized by increased dark preference. These findings identify neuroinflammation and disrupted monoaminergic signaling as prominent features of 2,6-DCBQ-induced neurotoxicity and highlight the potential mental health risks of halobenzoquinone DBPs.