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 μM) for 24 h revealed that auditory nerve fibers (ANFs) and vestibular nerve endings were destroyed even at low doses (10 and 50 μM). 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 μM), 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.

中文翻译：

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胆红素在大鼠耳蜗和前庭器官型培养物中诱导的神经毒性和耳毒性作用。

高胆红素血症患者和动物模型暴露于高水平的胆红素会导致感音神经性耳聋。然而，胆红素引起的内耳（包括耳蜗和前庭器官）损伤的机制尚不清楚。本研究从出生后第3天暴露于不同浓度（0、10、50、100或250μM胆红素的大鼠）的第3天大鼠获得的耳蜗和前庭器官型培养物的分析显示，听觉神经纤维（ANFs）和前庭神经末梢是即使在低剂量（10和50μM）下也可被破坏。此外，随着胆红素剂量的增加，螺旋神经节神经元（SGNs）和前庭神经节神经元（VGNs）会逐渐收缩，并伴随着核浓缩或碎裂，呈剂量依赖性。耳蜗和前庭毛细胞（HCs）的丧失仅在用最高浓度的胆红素（250μM）处理的外植体中才明显，胆红素诱导的主要凋亡最可能是通过外在的凋亡途径发生的。因此，目前的结果表明，与感觉性HC相比，内耳神经元和纤维对胆红素诱发的神经毒性更敏感，并且表现出更严重的损伤，这说明了高胆红素血症患者的听觉神经病和前庭病变的根本原因。