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Bilirubin‐induced Neurotoxic And Ototoxic Effects In Rat Cochlear And Vestibular Organotypic Cultures

Haibo Ye, Y. Xing, L. Zhang, J. Zhang, H. Jiang, D. Ding, H. Shi, Shankai Yin
Published 2019 · Medicine

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Highlightsbilirubin‐induced ototoxicity.bilirubin‐induced neuronal apoptosis.Possible mechanisms underlying ANSD and vestibulopathy. Abstract Exposure to high levels of bilirubin in hyperbilirubinemia patients and animal models can result in sensorineural deafness. However, the mechanisms underlying bilirubin‐induced damage to the inner ear, including the cochlear and vestibular organs, remain unknown. The present analyses of cochlear and vestibular organotypic cultures obtained from postnatal day 3 rats exposed to bilirubin at varying concentrations (0, 10, 50, 100, or 250 &mgr;M) for 24 h revealed that auditory nerve fibers (ANFs) and vestibular nerve endings were destroyed even at low doses (10 and 50 &mgr;M). Additionally, as the bilirubin dose increased, spiral ganglion neurons (SGNs) and vestibular ganglion neurons (VGNs) exhibited gradual shrinkage in conjunction with nuclei condensation or fragmentation in a dose‐dependent manner. The loss of cochlear and vestibular hair cells (HCs) was only evident in explants treated with the highest concentration of bilirubin (250 &mgr;M), and bilirubin‐induced major apoptosis most likely occurred via the extrinsic apoptotic pathway. Thus, the present results indicate that inner ear neurons and fibers were more sensitive to, and exhibited more severe damage following, bilirubin‐induced neurotoxicity than sensory HCs, which illustrates the underlying causes of auditory neuropathy and vestibulopathy in hyperbilirubinemia patients.
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