Department of Occupational Health Comprehensive Management, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen 518020, China.
Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Ecotoxicol Environ Saf. 2023 Apr 1;254:114721. doi: 10.1016/j.ecoenv.2023.114721. Epub 2023 Mar 3.
Ethylbenzene (EB) is widely distributed at low levels in the environment from vehicle emissions, industrial discharge, cigarette smoke, and in some food and consumer products. Evidence shows that EB exposure is associated with hearing loss, yet the mechanisms are unclear. This study aimed to explore the role of the Wnt/β-catenin signaling pathway, which plays a key role during cochlear development, in EB-induced hearing loss. In vitro, we found that EB treatment decreased the viability of cochlear progenitor cells (CPCs), isolated from the cochleae of neonatal rats and crucial for cochlear hair cells generation and hearing construction, via inducing mitochondrial impairments and excessive apoptosis. These were accompanied by the inactivation of the Wnt/β-catenin signaling cascade, as manifested by the decreased levels of related molecules β-catenin, LEF-1 and Lgr5. These findings were further confirmed by knocking down β-catenin and immunofluorescence analysis. Interestingly, adenovirus-mediated β-catenin overexpression activated the Wnt/β-catenin signaling network, alleviated mitochondrial impairments, reduced cell apoptosis, therefore promoting CPCs survival under EB treatment conditions. Finally, using adult Sprague-Dawley rats as an in vivo model with EB inhalation for 13 weeks, we found that exposure to EB decreased body weight gain, increased the hearing thresholds at different exposure stages, along with Wnt/β-catenin signaling pathway suppression in cochlear tissue. More importantly, cochlear microinjection of recombinant lentivirus expressing β-catenin significantly reversed EB-elicited these deleterious effects. Collectively, our results indicate that EB induces hearing loss by triggering mitochondrial impairments and excess apoptosis in CPCs via suppressing the Wnt/β-catenin signaling, and provide clues for the possible therapy.
苯乙烯（EB）广泛存在于环境中，主要来自于机动车排放、工业排放、香烟烟雾以及一些食品和消费产品。有证据表明 EB 暴露与听力损失有关，但具体机制尚不清楚。本研究旨在探讨 Wnt/β-catenin 信号通路在 EB 诱导的听力损失中的作用。在体外，我们发现 EB 处理通过诱导线粒体损伤和过度凋亡，降低了从新生大鼠耳蜗分离的耳蜗祖细胞（CPCs）的活力，而 CPCs 对耳蜗毛细胞的生成和听力结构至关重要。这伴随着 Wnt/β-catenin 信号级联的失活，表现为相关分子β-catenin、LEF-1 和 Lgr5 的水平降低。这些发现通过敲低β-catenin 和免疫荧光分析得到了进一步证实。有趣的是，腺病毒介导的β-catenin 过表达激活了 Wnt/β-catenin 信号网络，减轻了线粒体损伤，减少了细胞凋亡，从而促进了 CPCs 在 EB 处理条件下的存活。最后，我们使用成年 Sprague-Dawley 大鼠作为 EB 吸入 13 周的体内模型，发现暴露于 EB 会降低体重增加，增加不同暴露阶段的听力阈值，同时抑制耳蜗组织中的 Wnt/β-catenin 信号通路。更重要的是，耳蜗内注射表达β-catenin 的重组慢病毒显著逆转了 EB 引起的这些有害影响。总之，我们的研究结果表明，EB 通过抑制 Wnt/β-catenin 信号通路，在 CPCs 中触发线粒体损伤和过度凋亡，导致听力损失，并为可能的治疗提供了线索。
