Melatonin administration alleviates 2,2,4,4-tetra-brominated diphenyl ether (PBDE-47)-induced necroptosis and secretion of inflammatory factors via miR-140-5p/TLR4/NF-κB axis in fish kidney cells

Abstract

2,2,4,4-tetra-brominated diphenyl ether (PBDE-47)—the dominant homologue of polybrominated diphenyl ethers—is a toxic environmental pollutant in the aquatic environment that continuously exists and bioaccumulates in the aquatic food chain. In experimental disease models, melatonin (MEL) has been reported to attenuate necroptosis and inflammatory responses. To further explore the mechanism underlying PBDE-47 toxicity and the mitigative impact of MEL detoxification, in this study, fish kidney cell models of PBDE-47 poisoning and/or MEL treatment were developed. The Ctenopharyngodon idellus kidney (CIK) cell line was treated with PBDE-47 (100 μM) and/or MEL (60 μM) for 24 h. Experimental data suggest that PBDE-47 exposure resulted in the enhancement of cytoplasmic Ca2+ concentration, induction of calcium dysmetabolism, decrease in the miR-140-5p miRNA level, upregulation of Toll-like Receptor 4 (TLR4) and nuclear factor-kappaB (NF-κB), triggering of receptor interacting serine/threonine kinase-induced necroptosis, and NF-κB pathway mediated secretion of inflammatory factors in CIK cells. PBDE-47-induced CIK cell damage could be mitigated by MEL through the regulation of calcium channels and the restoration of disorders of the miR-140-5p/TLR4/NF-κB axis. Overall, MEL relieved PBDE-47-induced necroptosis and the secretion of inflammatory factors through the miR-140-5p/TLR4/NF-κB axis. These findings enrich the current understanding of the toxicological molecular mechanisms of the PBDE-47 as well as the detoxification mechanisms of the MEL.