Molecular insights into developmental toxicity induced by PCB77 exposure on zebrafish via integrating transcriptomics with adverse outcome pathway.

Abstract

Polychlorinated biphenyls (PCBs), a typical type of persistent organic pollutants (POPs), were previously widely employed as insulating and heat exchange fluids in transformers and capacitors. Despite knowledge of its adverse effects, the precise mechanism underlying PCB77 toxicity remains enigmatic. In this study, we utilized zebrafish as a model organism to explore the toxic effects of various concentrations of PCB77 (10, 200, and 1000 μg/L) and its molecular toxicity mechanisms. Upon exposure to dosages of PCB77 throughout embryonic and larval stages, the zebrafish exhibited adverse phenotypic manifestations, including deformities, decreased heart rates, increased distances between the bulbus arteriosus (BA) and sinus venosus (SV) and reduced locomotor ability. Transcriptome analysis revealed the common enriched pathways across all PCB77 concentration groups, such as retinol metabolism, steroid hormone biosynthesis, and metabolism of xenobiotics by cytochrome P450, which are closely related to the activity of cytochrome P450 (cyp1a) enzymes. Furthermore, Adverse Outcome Pathway (AOP) framework which integrates AOPs and dose-dependent transcriptomics to predict PCB77-induced adverse outcomes (AOs) revealed that aryl hydrocarbon receptor (AhR) associated AOPs triggered by PCB77 exposure may increase early-life stage mortality and decrease cardiac development, indicating that the primary toxic pathways of PCB77 in zebrafish may involve AhR-mediated signaling. Besides, molecular docking modeling demonstrated that PCB77 could bind to the groove within the AhR domain, suggesting that PCB77 induces embryotoxicity in zebrafish through its interaction with AhR. Collectively, these findings not only deliver a thorough examination of PCB77-induced developmental toxicity as well as the underlying mechanisms, but also validate the efficacy of the analytical approach leveraging AOP framework in unraveling toxicity mechanisms of environmental contaminants, which holds promise for risk assessment associated with novel environmental pollutants.