TBBPS caused necroptosis and inflammation in hepatocytes by blocking PINK1-PARKIN-mediated mitochondrial autophagy.

The widespread use of Tetrabromobisphenol S (TBBPS), as an alternative to tetrabromobisphenol A (TBBPA), has been detected at high frequency in environmental media in recent years, TBBPS can enter the body via the digestive tract and other routes, thus long-term TBBPS exposure may cause adverse health effects. Therefore, it is necessary to evaluate the toxicological effects of TBBPS. In the current work, two cell models of the liver were used (a human-derived cell line THLE-2 and a murine-derived AML12). The liver cells were then exposed to different concentrations of TBBPS. The results of cell proliferation assays showed that TBBPS resulted in a significant attenuation of the proliferative capacity of liver cells. Further results from ELISA and Western-blot assays showed that TBBPS induced an inflammatory response in liver cells by detecting the levels of inflammatory factors, such as TNFα, IL-1β and IL-6. We also found that TBBPS promoted the necroptosis in liver cells by evaluating the levels of RIP3 and pMLKL, and the use of inhibitors of necroptosis confirmed that the type of cell death induced by TBBPS belongs to necroptosis. Molecular mechanistic studies showed that TBBPS suppressed mitochondrial autophagy mediated by the PINK1-PARKIN signaling pathway, which led to accumulation of damaged mitochondria in THLE-2 and AML12 cells. Subsequently, accumulated ROS activated necroptosis of liver cells. Current toxicological studies suggest that we need to better control and regulate the production and use of TBBPS, the current work provide a reference for studying the toxicology of TBBPS.