CH-223191

2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is a ubiquitous environmental pollutant linked to early neurotoxicity, but its effects on hearing loss during early development remain unclear. We exposed weanling guinea pigs to BDE-47 (1, 10, 50 mg/kg/day) via gavage for 28 days, finding increased hearing thresholds at 0.5 and 4 kHz, hair cell damage, and elevated AhR, LC3B, and P-SQSTM1 levels. In vitro, BDE-47 reduced HEI-OC1 cell viability dose dependently, increasing AhR, oxidative stress (MitoTracker, MitoSOX, ROS), and activating the Keap1-Nrf2 antioxidant pathway. Elevated autophagosomes, P-SQSTM1 and LC3B-II, were observed, indicating autophagic flux inhibition. The AhR inhibitor CH223191 mitigated these effects, while Mdivi-1 (mitochondrial division inhibitor) reduced ROS and autophagy, suggesting AhR promotes mitochondrial oxidative stress, impairing autophagy. BDE-47 also increased ER-Tracker fluorescence, reduced lysosomes, and altered UPR markers (Calnexin, PDI, IRE1-α, Bip, Erol-α, PERK, and Chop), most of which were attenuated by CH223191. The ER stress inhibitor TUDCA further alleviated ROS, Keap1-Nrf2 dysregulation, and autophagy disruption. Our findings demonstrate that early BDE-47 exposure induces hearing impairment via AhR-mediated mitochondrial oxidative stress and ER stress, suppressing autophagy. These findings enhance our understanding of environmental chemical-induced ototoxicity and provide valuable insights for both auditory disorder risk assessment and therapeutic strategies for hearing preservation.

Chronic kidney disease (CKD) is a common disorder with increasing prevalence and morbidity worldwide. However, the present agents do not effectively inhibit pathological processes. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediated various diseases. Acteoside (ATS) is a commercial ATP-competitive inhibitor of protein kinase C. Clinical study showed ATS mitigated Th22 cell disorder and proteinuria in patients with immunoglobulin A nephropathy. This study analyzed AHR and nuclear factor kappa B (NF-κB) p65 expression in CKD patients. We compared the effects of ATS and its isomer isoacteoside (IAT) on renal function to identify their active functional group of antifibrosis in adenine-induced CKD rats. We further determined the effects of their active functional group on AHR signalling and inflammation pathway. The results showed increasing intrarenal AHR and NF-κB p65 expression in CKD patients. ATS improved renal function and fibrosis while IAT did not significantly improve fibrosis in CKD rats. Both ATS and IAT inhibited intrarenal mRNA expression of AHR and its downstream genes while ATS not IAT significantly inhibited nuclear AHR protein expression. Structure-activity analysis indicated that ATS-containing caffeic acid group by ester bond binding is transformed from C-11 to C-15 becoming IAT leads to a weakened inhibition of fibrosis and AHR nuclear translocation, indicating that caffeic acid group is bioactive functional group of ATS. Furthermore, ATS not IAT significantly regulated protein expression of NF-κB p65 and nuclear factor erythroid 2-related factor 2 (Nrf2) as well as their downstream gene products. Similar results were observed in indole-3-acetic acid (IAA)-induced NRK-52E cells. However, IAT did not show a significant effect. The inhibitory effects of ATS on NF-κB and Nrf2 pathways were partially abolished in IAA-stimulated NRK-52E cells treated with CH223191. However, ATS did not affect AHR expression in IAA-induced NRK-52E cells treated with BAY 11-7082. Therefore, ATS was identified as an AHR antagonist that ameliorated CKD by improving NF-κB/Nrf2 signalling axis. Conclusively, ATS holds promise as a chemical scaffold for the development of new antifibrotic agents.