Carbaryl-induced ototoxicity in rat postnatal cochlear organotypic cultures
Carbaryl-induced ototoxicity in rat postnatal cochlear organotypic cultures
复制标题
DOI：
10.1002/tox.22296
复制
发表时间：
2017-03-01
影响因子：
4.5
通讯作者：
Roth, Jerome A.
中科院分区：
文献类型：
--
作者：
Muthaiah, Vijaya Prakash Krishnan;Ding, Dalian;Roth, Jerome A.
西维因是一种广泛使用的氨基甲酸酯类杀虫剂，是一种强效抗胆碱酯酶剂，已知在长期接触后会诱发迟发性神经毒性。然而，其对耳蜗的潜在毒性作用，听觉的感觉器官，含有胆碱能传出神经元和乙酰胆碱受体的毛细胞（HC）和螺旋神经节神经元迄今尚未进行评估。为了评估西维因的耳毒性潜力，出生后第3天大鼠的耳蜗器官型培养物用剂量范围为50至500 M的西维因处理48 h至96 h。西维因以剂量和持续时间依赖性方式损害感觉HC和螺旋神经节神经元。HC和神经元损伤观察到西维因浓度低至50 M后96小时的治疗和100 M后48小时的治疗。毛细胞在耳蜗的高频基底区最大，并向顶端逐渐减少，与大多数耳毒性药物一致。与此相反，螺旋神经节神经元的损害是相似的幅度在基底和顶端区域的耳蜗。西维因损伤的特征是索马收缩，核浓缩和碎裂，和起泡，程序性细胞死亡的形态学特征。西维因可上调HC和螺旋神经节神经元中执行者caspase-3的表达，表明细胞损伤主要通过caspase介导的凋亡发生。这些结果表明，长期暴露于西维因和其他氨基甲酸酯抗胆碱酯酶可能是耳毒性。(C)2016 Wiley Periodicals，Inc.
Carbaryl, a widely used carbamate-based insecticide, is a potent anticholinesterase known to induce delayed neurotoxicity following chronic exposure. However, its potential toxic effects on the cochlea, the sensory organ for hearing that contains cholinergic efferent neurons and acetylcholine receptors on the hair cells (HC) and spiral ganglion neurons has heretofore not been evaluated. To assess ototoxic potential of carbaryl, cochlear organotypic cultures from postnatal day 3 rats were treated with doses of carbaryl ranging from 50 to 500 M for 48 h up to 96 h. Carbaryl damaged both the sensory HC and spiral ganglion neurons in a dose- and duration-dependent manner. HC and neuronal damage was observed at carbaryl concentrations as low as 50 M after 96-h treatment and 100 M after 48-h treatment. Hair cell was greatest in the high frequency basal region of the cochlea and progressively decreased towards the apex consistent with the majority of ototoxic drugs. In contrast, damage to the spiral ganglion neurons was of similar magnitude in the basal and apical regions of the cochlea. Carbaryl damage was characterized by soma shrinkage, nuclear condensation and fragmentation, and blebbing, morphological features of programmed cell death. Carbaryl upregulated the expression of executioner caspase-3 in HC and spiral ganglion neurons indicating that cellular damage occurred primarily by caspase-mediated apoptosis. These results suggest that chronic exposure to carbaryl and other carbamate anticholinesterases may be ototoxic. (C) 2016 Wiley Periodicals, Inc.