Bhatia Pankaj, Mehmood Shomaila, Doyon-Reale Nicole, Rosati Rita, Stemmer Paul M, Jamesdaniel Samson
Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, United States.
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI, United States.
Front Cell Neurosci. 2024 Jul 22;18:1408208. doi: 10.3389/fncel.2024.1408208. eCollection 2024.
Exposure to heavy metal lead can cause serious health effects such as developmental neurotoxicity in infants, cognitive impairment in children, and cardiovascular and nephrotoxic effects in adults. Hearing loss is one of the toxic effects induced by exposure to lead. Previous studies demonstrated that exposure to lead causes oxidative stress in the cochlea and disrupts ribbon synapses in the inner hair cells.
This study investigated the underlying mechanism by evaluating the changes in the abundance of cochlear synaptosomal proteins that accompany lead-induced cochlear synaptopathy and hearing loss in mice. Young-adult CBA/J mice were given lead acetate in drinking water for 28 days.
Lead exposure significantly increased the hearing thresholds, particularly at the higher frequencies in both male and female mice, but it did not affect the activity of outer hair cells or induce hair cell loss. However, lead exposure decreased wave-I amplitude, suggesting lead-induced cochlear synaptopathy. In agreement, colocalization of pre- and post-synaptic markers indicated that lead exposure decreased the number of paired synapses in the basal turn of the cochlea. Proteomics analysis indicated that lead exposure increased the abundance of 352 synaptic proteins and decreased the abundance of 394 synaptic proteins in the cochlea. Bioinformatics analysis indicated that proteins that change in abundance are highly enriched in the synaptic vesicle cycle pathway.
Together, these results suggest that outer hair cells are not the primary target in lead-induced ototoxicity, that lead-induced cochlear synaptopathy is more pronounced in the basal turn of the cochlea, and that synaptic vesicle cycle signaling potentially plays a critical role in lead-induced cochlear synaptopathy.
接触重金属铅会对健康造成严重影响，如婴儿发育性神经毒性、儿童认知障碍以及成人的心血管和肾毒性作用。听力损失是铅暴露引起的毒性作用之一。先前的研究表明，铅暴露会导致耳蜗氧化应激并破坏内毛细胞中的带状突触。
本研究通过评估铅诱导的小鼠耳蜗突触病变和听力损失过程中伴随的耳蜗突触体蛋白丰度变化，来探究其潜在机制。将年轻成年CBA/J小鼠的饮用水中加入醋酸铅，持续28天。
铅暴露显著提高了听力阈值，尤其是在雄性和雌性小鼠的较高频率下，但它不影响外毛细胞的活性或诱导毛细胞损失。然而，铅暴露降低了I波振幅，表明铅诱导了耳蜗突触病变。与此一致的是，突触前和突触后标记物的共定位表明，铅暴露减少了耳蜗基底转中配对突触的数量。蛋白质组学分析表明，铅暴露增加了耳蜗中352种突触蛋白的丰度，并降低了394种突触蛋白的丰度。生物信息学分析表明，丰度发生变化的蛋白质在突触小泡循环途径中高度富集。
总之，这些结果表明，外毛细胞不是铅诱导耳毒性的主要靶点，铅诱导的耳蜗突触病变在耳蜗基底转中更为明显，并且突触小泡循环信号可能在铅诱导的耳蜗突触病变中起关键作用。
