BDNF-TrkB信号通路在生命早期镉暴露致小鼠认知功能障碍中的作用  

Role of BDNF-TrkB signaling pathway in early-life cadmium exposure induced cognitive dysfunction in mice

作　　者：史岩 杨斯琪 王友刚 伍秋梅 李金泉 SHI Yan;YANG Siqi;WANG Yougang;WU Qiumei;LI Jinquan(Brain Science and Advanced Technology Institute,School of Medicine,Wuhan University of Science and Technology,Wuhan,Hubei 430065,China;College of Medicine,Wuhan University of Bioengineering,Wuhan,hubei 430415,China)

机构地区：[1]武汉科技大学医学部脑科学先进技术研究院,湖北武汉430065 [2]武汉生物工程学院医药学院,湖北武汉430415

出　　处：《环境与职业医学》2024年第11期1283-1289,共7页Journal of Environmental and Occupational Medicine

基　　金：湖北省高校优秀中青年科技创新团队项目(T2022004);武汉科技大学“十四五”湖北省优势特色学科(群)项目(2023C0106)。

摘　　要：[背景]随着工业化高速发展,镉已经成为我国耕地土壤中的主要重金属污染物,严重影响人类健康。已有研究发现镉暴露可以导致个体认知功能障碍,但对于更易受到各种毒素侵害且对神经发育至关重要的生命早期的镉暴露诱发子代认知功能损伤的机制研究十分匮乏。[目的]探讨脑源性神经营养因子/酪氨酸激酶受体B(BDNF-TrkB)信号通路在生命早期镉暴露致小鼠认知功能障碍中的作用机制。[方法]将12只8周龄C57BL/6妊娠小鼠随机分为2组,分别是对照组和镉暴露组,每组6只。暴露时间从妊娠期第4.5天开始到哺乳期第21天结束(E4.5~P21),暴露期间给予饮用蒸馏水或氯化镉溶液(2.5 mg·kg^(–1)·d^(–1))。哺乳期结束后,对照组和镉暴露组子代小鼠均给予饮用蒸馏水直到8周龄,称取小鼠体重并检测生化指标判断镉暴露对小鼠毒性作用;检测脑镉含量判断可能造成的神经毒性及进行行为学(Y迷宫、Morris水迷宫)测试检测子代小鼠认知功能情况;子代小鼠脑组织进行尼式染色和高尔基染色,观察小鼠脑海马区的病理变化;使用实时定量PCR(qPCR)和蛋白质免疫印迹法(WB)检测小鼠脑组织BDNF-TrkB通路及突触相关蛋白的mRNA和蛋白表达水平。[结果]与对照组相比,镉暴露组小鼠体重及肝肾功能未见明显改变(P>0.05)。与对照组相比,镉暴露组小鼠脑镉含量增加,差异具有统计学意义(P<0.001);出现了认知功能障碍相关行为学变化,差异具有统计学意义(P均<0.05);海马区尼式染色组织结构异常,神经元数量减少,核固缩增加,差异具有统计学意义(P<0.01);海马区高尔基染色可见树突棘密度减少,差异具有统计学意义(P<0.001);海马区BDNF-TrkB通路相关mRNA及突触相关mRNA含量下降,差异具有统计学意义(P均<0.05);海马区BDNF-TrkB通路相关蛋白及突触相关蛋白表达降低,差异具有统计学意义(P均<0.05)。[结论]生命早期镉暴露�[Background]With the rapid industrialization,cadmium has become a primary heavy metal pollutant in cultivated land soil in China,which seriously affects human health.Previous studies have found that cadmium exposure associates with cognitive dysfunction in individuals,but there is a lack of research on the mechanism of cadmium exposure associated cognitive impairment in offspring in early life which is more vulnerable to various toxins and crucial for development of the neuro.[Objective]To explore the potential mechanism of brain-derived neurotrophic factor/tyrosine kinase receptor B(BDNF-TrkB)signaling pathway in cognitive dysfunction in mice after cadmium exposure in early-life.[Methods]Twelve 8-week-old C57BL/6 pregnant mice were randomly divided into 2 groups,namely control group and cadmium exposure group,with 6 mice in each group.The exposure period was from pregnancy day 4.5 to lactation day 21(E4.5-P21),during which distilled water or cadmium chloride solution(2.5 mg·kg^(–1)·d^(–1))was given.After lactation,the offspring of the control group and the cadmium exposure group were given distilled water until 8 weeks ofage.Then the toxicity effects of cadmium exposure on mice were evaluated by body weight and selected biochemical indicators.Thecadmium content in brain was detected and the learning and memory ability was tested by Y maze and Morris water maze to evaluatecognitive function of offspring mice.Histopathological changes of the hippocampus were observed after Nissl staining and Golgi staining.The mRNA and protein expression levels of the BDNF-TrkB pathway and synapse were detected by real-time quantitative PCR(qPCR)andWestern blot.[Results]Compared with the control group,no significant change was found in body weight,liver or kidney function in the cadmium exposuregroup(P>0.05).However,compared with the control group,the cadmium content in brain was increased in the cadmium exposuregroup(P<0.001).The behavioral changes associated with cognitive dysfunction were positive in the cadmium exposure

关 键 词：生命早期 镉 脑源性神经营养因子/酪氨酸激酶受体B 突触 认知功能障碍 

分 类 号：R12[医药卫生—环境卫生学]