Exploring potential targets and mechanisms of PCB52-induced cardiotoxicity: Integration of network toxicology and zebrafish experimental evidence

2,2′,5,5′-Tetrachlorobiphenyl (PCB52) exhibits high environmental mobility and bioaccumulation potential. Studies have associated elevated levels of serum PCB52 with an increased risk of cardiac diseases, yet the underlying mechanisms of its cardiotoxicity remain inadequately investigated. In this study, potential PCB52 targets and cardiotoxicity-related targets were retrieved from multiple online databases, and 150 potential targets of PCB52-induced cardiotoxicity were obtained. Protein-protein interaction (PPI) network was constructed for the potential targets. Twelve hub genes (STAT1, FN1, TP53, CCL2, ACE, PARP1, NFKB1, MTOR, HDAC2, RELA, ATM, and APP) were identified from the network using 7 algorithms from cytoHubba plugin in Cytoscape. Molecular docking was employed to validate the interactions between PCB52 and hub targets. Enrichment analysis focusing on the hub genes indicated oxidative stress, apoptosis, nuclear factor kappa-B (NF-κB) activation, and inflammatory pathways were primary processes involved. Following exposure to three concentrations of PCB52 (10, 200, and 1000 μg/L), zebrafish exhibited pericardial edema (PE), with the highest incidence of 16.4 % observed at the highest concentration. Additionally, zebrafish experiments revealed a dose-dependent increase in sinus venosus (SV)-bulbus arteriosus (BA) distance and superoxide dismutase (SOD) activity, along with a decrease in heart rate. Furthermore, dose-dependent transcriptomic analyses emphasized the significance of apoptosis and the mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, our study investigated the cardiotoxic effects of PCB52 and proposed a potential toxic mechanism cascade, which warrants further validation through subsequent experiments.