Tetrabromophthalate bis(2-ethylhexyl) ester (TBPH) exposure induces renal inflammation injury by activating MAVS-IRF3 signaling pathway in vitro and in vivo models.

Tetrabromophthalate bis(2-ethylhexyl) ester (TBPH) is a common brominated flame retardant, which exhibits environmental persistence, the potential for bioaccumulation, and concerning toxicological effects. But until now, there is limited data on TBPH-induced nephrotoxicity. Therefore, this study assessed the impact of TBPH exposure on renal cells and tissues through in vitro and in vivo models. A series of biochemical experiments, including Western-blot, indirect immunofluorescence, ELISA, SiRNA, H&E and immunohistochemistry were carried out. In in vitro models, TBPH exposure dose-dependently inhibited renal cell proliferation. In addition, TBPH exposure induces significant inflammation through the mitochondrial retinoic acid-inducible gene I-mitochondrial antiviral-signaling protein (RIG-I-MAVS) signaling pathway, and TBPH treatment also results in oxidative stress responses across two distinct renal cell models. In vivo, TBPH exposure induces renal tissue damage and abnormal renal function. Additionally, TBPH treatment induces renal inflammation and fibrosis, demonstrated by up-regulation of characteristic markers (such as TNF-α/IL-6 for inflammation; α-SMA/fibronectin for fibrosis). Mechanistic investigations revealed that TBPH exposure causes kidney damage through impaired mitochondrial autophagy and excessive mitochondrial fission. These findings underscore TBPH's nephrotoxic potential and the necessity for further investigation into the risks associated with prolonged, low-dose exposure. Additionally, appropriate regulatory measures should be developed to mitigate its environmental and health impacts.