Chronic Kidney Disease Risk Posed by 1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) Benzene (EDPrB): An AOP of mTOR-Mediated Autophagy Dysregulation.
1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) benzene (EDPrB), a highly polluting fluorinated liquid-crystal monomers (FLCMs), accumulates in the kidneys over the long term. First, our study demonstrates that exposure to EDPrB can induce inflammatory responses and fibrosis in human renal cortical proximal tubule epithelial cells (HK-2), posing a risk of nephrotoxicity. Next, our study investigates the renal injury induced by EDPrB in male Kunming mice after 70-day exposure at 13, 130, and 1300 μg/kg bw/day, using an adverse outcome pathway (AOP) framework. Histopathological observations demonstrate that EDPrB corresponds to an elevated probability of developing chronic kidney disease (CKD). Proteomics and Western blot analysis revealed that mTOR signaling may be the mechanism by which EDPrB induces CKD in mice and causes damage to HK-2 cells. Finally, by treating EDPrB-exposed mice with RAPA, we demonstrated that activation of the mTOR signaling is the molecular initiating event driving EDPrB-induced CKD in mice. This study proposes an AOP framework focused on EDPrB-induced CKD. The molecular initiating event is identified as mTOR activation, followed by autophagy inhibition leading to inflammation and fibrosis as key events, ultimately resulting in CKD as an adverse outcome. This highlights the renal risks of FLCMs and supports stricter environmental release regulations.