Induction of Netosis by 2,2,4,4-Tetrabromodiphenyl Ether (BDE-47) in Cyprinus Carpio

Polybrominated diphenyl ethers (PBDEs), extensively utilized as brominated flame retardants, have attained pervasive application in diverse products, thereby manifesting as omnipresent contaminants in the global environmental landscape. Among the PBDEs, 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) exhibits the broadest distribution and is recognized for its adverse impact on fish. The formation of neutrophil extracellular traps (NETs) known as "NETosis" is a neutrophil antimicrobial mechanism that plays an important role in the immune system. However, the impact of BDE-47 on the aquatic animal immune system remains unknown. Therefore, our research investigated the toxic mechanism of BDE-47 to fish neutrophils. Firstly, the quantitative analysis of NETs showed that BDE-47 induced the synthesis of NETs. Furthermore, our findings demonstrated that BDE-47 could enhance reactive oxygen species (ROS) levels. The results also suggested that BDE-47 may play a role in promoting neutrophil autophagy and apoptosis. In addition, BDE-47 exposure inhibited the activities of oxidative stress-related antioxidant enzymes and increased malondialdehyde levels, thus causing oxidative stress. Finally, BDE-47 phosphorylated P38 and extracellular signal-regulated Kinase (ERK) pathway proteins. Collectively, BDE-47 promotes NETs formation by facilitating the ROS/P38/ERK axis and oxidative stress in carp neutrophils, promoting cellular autophagy, in addition to activating the mitochondrial apoptotic pathway, and this toxicity exists in a dose-dependent manner. The study investigated the fundamental mechanisms of BDE-47 on carp neutrophils. This investigation offered fresh perspectives on the immunotoxicological mechanisms of BDE-47 and provided a new basis for mitigating the adverse effects of BDE-47 on aquatic animals.