2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces early hearing loss in guinea pigs via activating AhR to trigger mitochondrial and endoplasmic reticulum stress-regulated autophagy.

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.