Mechanistic insight into the neurodevelopmental toxicity of the novel pesticide pyrifluquinazon (PFQ) and its major metabolite in early-life stage zebrafish

Pyrifluquinazon (PFQ), a novel insecticide containing a heptafluoroisopropyl moiety, has seen increasing use. However, limited research has been conducted on the toxicological effects and mechanisms of PFQ in aquatic organisms. To investigate the toxicity and underlying mechanisms of PFQ and its primary metabolite dPFQ in aquatic organisms, morphological, behavioral, hormonal, multi-omics analyses, and molecular docking studies were conducted on zebrafish larvae after exposure. The results showed that both PFQ and dPFQ induced developmental abnormalities, behavioral impairment, hormonal disruptions, and alterations in neurologically related metabolites and gene expression in early-stage zebrafish. Notably, delayed retinal vascular development was observed, which is also likely linked to the neurodevelopmental toxicity. Subsequently, identification and relative quantification of PFQ metabolites suggested that its toxicity might be primarily attributed to dPFQ. Finally, an Adverse Outcome Pathway (AOP) was proposed, initiating with the binding of dPFQ to the TRPV4 protein and ultimately leading to neurodevelopmental toxicity. This study delineated the neurodevelopmental toxicity of PFQ and its toxicological mechanisms in zebrafish, emphasizing the hazards posed by pesticide metabolites to non-target organisms and highlighting inherent limitations of extrapolating in vitro toxicity experiments.