Ferroptosis-driven neurobehavioral impairment in zebrafish embryos: Mechanistic links to developmental dibutyl phthalate exposure.

Abstract

Dibutyl phthalate (DBP), a ubiquitous chemical contaminant detected in various environmental matrices, poses growing concerns regarding its ecotoxicity and public health risks. In this study, zebrafish (Danio rerio) model was used to investigate the ferroptosis-mediated neurotoxicity elicited by iron dyshomeostasis and lipid peroxidation, upon developmental DBP exposure. DBP-induced ferroptosis compromised zebrafish embryogenesis, leading to reduced tail bent rate and heart rate, as well as elevated mortality and deformity. Larval neurobehavioral deficits, assessed through spontaneous locomotion, light/dark transition, and vibrational startle response assays, manifested as significant hypoactivity in total distance, velocity, maximum acceleration, and cumulative mobility. Importantly, these impairments were notably attenuated by the iron chelator of deferasirox. Metabolomic profiling revealed profound perturbations in the signaling pathway of Neuroactive ligand-receptor interaction, as indicated by KEGG enrichment analyses. Consistently, neurotransmitter levels (serotonin, dopamine, taurine, acetylcholine) and transcriptional markers related to neurodevelopment were suppressed by DBP, but differentially restored upon co-treatment with deferasirox. These mechanistic findings bridge environmental ecotoxicology with vertebrate developmental risk prediction, underscoring the urgency of developing potential management and intervention strategies to address phthalates exposure during critical developmental windows.