纳米锰暴露对大鼠神经毒性及脉络丛相关基因转录水平的影响
Neurotoxicity of Nano Manganese and Its Effects on Choroid Plexus-related Gene Transcription in Rats
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摘要: 研究纳米二氧化锰（nano-MnO2）暴露后SD大鼠的神经毒性，以及对脉络丛相关基因转录水平的影响。将18只SD大鼠随机分为3组，分别为对照组、低剂量组和高剂量组。采用气管内注入法对大鼠进行染毒。低、高剂量组染毒剂量为200 mg·kg-1和400 mg·kg-1（以体质量计）的nano-MnO2悬浊液，对照组灌注等量生理盐水。每周染毒一次，连续染毒12周。染毒结束后，对各组大鼠进行神经行为测试；取大鼠脉络丛组织进行转录组学测序；固定脉络丛组织并进行组织病理学观察；取脑组织进行电镜观察。热板仪实验结果显示，高剂量组热痛反应时间较对照组显著增加（P<0.05）；旷场实验显示染毒后大鼠空间识别能力降低，兴奋性相对减弱；组织病理学结果显示，经nano-MnO2染毒后大鼠脉络丛上皮细胞轮廓模糊，胞内空泡明显增多且变形加重，细胞连接疏松；脑皮质髓鞘受损；高通量测序结果中，KEGG代谢通路分析显示，在上调基因中，编码代谢型谷氨酸受体的Grm系列基因显著表达，提示nano-MnO2干扰脑内的谷氨酸代谢；GO功能富集分析显示在分子功能类别中有关金属离子跨膜转运的钙、钾电压门控通道等相关基因表达差异较明显。nano-MnO2染毒对SD大鼠脉络丛上皮细胞造成一定程度的损伤，影响脉络丛转运活性。Abstract: To study the neurotoxicity of nano manganese dioxide (nano-MnO2) and the changes of transcription level of choroid plexus-related genes in SD rats exposed to nano-MnO2. 18 SD rats were randomly divided into three groups, namely control group, low dose group and high dose group. The rats in the low and high dose groups were treated with suspension of nano-MnO2 by intratracheal injection, at 200 mg·kg-1 and 400 mg·kg-1 body weight respectively. The rats in the control group were perfused with the same amount of normal saline. Each rat was perfused once a week for 12 weeks. After exposure, the neurobehavioral test was carried out with open field test and hot plate test. Rats' choroid plexus tissues were harvested for conducting transcriptome sequencing analysis, and fixed for observing histopathologic changes by HE stain. The ultrastructure of rats' brain tissue was observed through electron microscope. Compared with the control group, the reaction time of rats in the high-dose group significantly increased (P<0.05). The results of open field experiment indicated that the rats exposed to nano-MnO2 had a decreased ability of spatial recognition and excitability. The results of histopathology showed that after the rats were exposed to nano-MnO2, the outline of their choroid plexus epithelial cells turned blurred, the number of intracellular vacuoles increased obviously and the deformation was aggravated, and the cell junctions became loose. The ultrastructure of myelin sheath of cerebral cortex was damaged as observed through electron microscope. Nano-MnO2 notably up-regulated the Grm series genes, which encoded the metabotropic glutamate receptor, thus interfering with the metabolism of glutamate by KEGG pathway analysis. Nano-MnO2 significantly interfered with the expression of genes related to transmembrane transport of metal ions, such as calcium and potassium voltage-gated channels. Subsequently, the choroid plexus transport activity was damaged by nano-MnO2 as shown in the GO functional enrichment analysis. Nano-MnO2 can influence the neurobehavior, damage the structure of cortex and choroid plexus epithelial cells, and affect the transport activity of choroid plexus.
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杨强强, 张广智, 吴芳芳, 等. 基于二氧化锰纳米片实现let-7a向癌细胞的可视化递送及其体外抗癌研究[J]. 聊城大学学报:自然科学版, 2021, 34(2):42-48 Yang Q Q, Zhang G Z, Wu F F, et al. Delivery of let-7a to cancer cells visually based on MnO2 nanosheets and the anti-cancer research in vitro[J]. Journal of Liaocheng University:Natural Science Edition, 2021, 34(2):42-48(in Chinese)
Nosrati N, Hassanpour-Ezzati M, Mousavi S Z, et al. Comparison of MnO2 nanoparticles and microparticles distribution in CNS and muscle and effect on acute pain threshold in rats[J]. Nanomedicine Journal, 2014, 1(3):180-190 Li T, Shi T T, Li X B, et al. Effects of nano-MnO2 on dopaminergic neurons and the spatial learning capability of rats[J]. International Journal of Environmental Research and Public Health, 2014, 11(8):7918-7930 潘洋, 张鑫源. 纳米硅以及纳米三氧化二铁对大鼠中枢神经行为的影响[J]. 中国医学创新, 2018, 15(25):14-17 Pan Y, Zhang X Y. The effects of nano-Si and nano-Fe2O3 on central nervous behavior in rats[J]. Medical Innovation of China, 2018, 15(25):14-17(in Chinese)
赵世君, 孙保亮, 李月春, 等. 脉络丛上皮细胞及其神经保护作用[J]. 中华细胞与干细胞杂志(电子版), 2016, 6(5):321-326 Zhao S J, Sun B L, Li Y C, et al. Choroid plexus epithelial cells and its neuroprotective effects[J]. Chinese Journal of Cell and Stem Cell (Electronic Edition), 2016, 6(5):321-326(in Chinese) 敬海明, 刘建中, 高文晖, 等. 氯化锰对大鼠血-脑脊液屏障的损伤作用[J]. 中国药理学与毒理学杂志, 2011, 25(4):364-368 Jing H M, Liu J Z, Gao W H, et al. Injury of chloride manganese to blood cerebrospinal fluid barrier in rats[J]. Chinese Journal of Pharmacology and Toxicology, 2011, 25(4):364-368(in Chinese)
马海阳. C. jejuni对周围神经的损伤及其流行病学调查[D]. 石家庄:河北医科大学, 2012:15 Ma H Y. Investigations of peripheral nerve lesions caused by C. jejuni and its epidemiology[D]. Shijiazhuang:Hebei Medical University, 2012:15(in Chinese) 王月, 徐冰红, 刘虎, 等. 溶质转运蛋白超家族的功能及结构研究进展[J]. 现代生物医学进展, 2017, 17(24):4775-4783 , 4793 Wang Y, Xu B H, Liu H, et al. Research progress on the function and structure of solute carrier superfamily transporters[J]. Progress in Modern Biomedicine, 2017, 17(24):4775-4783, 4793(in Chinese)
Chen X, Wu G Z, Zhang Z, et al. Neurotoxicity of Mn3O4 nanoparticles:Apoptosis and dopaminergic neurons damage pathway[J]. Ecotoxicology and Environmental Safety, 2020, 188:109909 Zhang X, Yue Z K, Zhang H J, et al. Repeated administrations of Mn3O4 nanoparticles cause testis damage and fertility decrease through PPAR-signaling pathway[J]. Nanotoxicology, 2020, 14(3):326-340 Tootoonchi M H, Hashempour M, Blackwelder P L, et al. Manganese oxide particles as cytoprotective, oxygen generating agents[J]. Acta Biomaterialia, 2017, 59:327-337 Oszlánczi G, Vezér T, Sárközi L, et al. Functional neurotoxicity of Mn-containing nanoparticles in rats[J]. Ecotoxicology and Environmental Safety, 2010, 73(8):2004-2009 Singh S P, Kumari M, Kumari S I, et al. Toxicity assessment of manganese oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral exposure[J]. Journal of Applied Toxicology, 2013, 33(10):1165-1179 Zheng Y Y, Zhang H, Hu Y P, et al. MnO nanoparticles with potential application in magnetic resonance imaging and drug delivery for myocardial infarction[J]. International Journal of Nanomedicine, 2018, 13:6177-6188 Crossgrove J S, Allen D D, Bukaveckas B L, et al. Manganese distribution across the blood-brain barrier. Ⅰ. Evidence for carrier-mediated influx of managanese citrate as well as manganese and manganese transferrin[J]. Neurotoxicology, 2003, 24(1):3-13 何雨欣, 冯颖, 刘晶晶, 等. 氯化锰亚急性染毒对大鼠血脑脊液屏障功能及神经行为的影响[J]. 毒理学杂志, 2020, 34(3):197-202 , 227 He Y X, Feng Y, Liu J J, et al. Effect of manganese chloride sub-acute exposure on the behavior and barrier function of blood cerebrospinal fluid barrier of rats[J]. Journal of Toxicology, 2020, 34(3):197-202, 227(in Chinese)
Meng C Y, Han Y F, Liu Y L, et al. Resveratrol alleviate the injury of mice liver induced by cadmium sulfide nanoparticles[J]. The Kaohsiung Journal of Medical Sciences, 2019, 35(5):297-302 Limbach L K, Wick P, Manser P, et al. Exposure of engineered nanoparticles to human lung epithelial cells:Influence of chemical composition and catalytic activity on oxidative stress[J]. Environmental Science & Technology, 2007, 41(11):4158-4163 Lundborg M, Eklund A, Lind B, et al. Dissolution of metals by human and rabbit alveolar macrophages[J]. British Journal of Industrial Medicine, 1985, 42(9):642-645 Nosrati N, Hassanpour-Ezzati M, Mousavi S Z, et al. Comparison of MnO2 nanoparticles and microparticles distribution in CNS and muscle and effect on acute pain threshold in rats[J]. Nanomedicine Journal, 2014, 1(3):180-190 Sun A, Wang J. Choroid plexus and drug removal mechanisms[J]. The AAPS Journal, 2021, 23(3):61 Dani N, Herbst R H, McCabe C, et al. A cellular and spatial map of the choroid plexus across brain ventricles and ages[J]. Cell, 2021, 184(11):3056-3074.e21 冯佩佩, 翟福骏, 蒋守芳, 等. 醋酸铅与纳米硫化铅染毒对大鼠血脑脊液屏障的影响[J]. 中华劳动卫生职业病杂志, 2016, 34(5):340-345 Feng P P, Zhai F J, Jiang S F, et al. Blood cerebrospinal fluid barrier damage of rats induced by lead acetate or nano-lead exposure[J]. Chinese Journal of Industrial Hygiene and Occupational Diseases, 2016, 34(5):340-345(in Chinese)
王璨. 锰干扰SNARE复合物介导的突触囊泡融合导致谷氨酸和γ-氨基丁酸释放障碍的实验研究[D]. 沈阳:中国医科大学, 2019:81-82 Wang C. Study on manganese induces Glu and GABA release disorder by disrupting SNARE complex-mediated synaptic vesicle fusion[D]. Shenyang:China Medical University, 2019:81 -82(in Chinese)
徐斌. 锰干扰谷氨酸代谢和NMDA受体表达及MK-801对其防护作用的研究[D]. 沈阳:中国医科大学, 2010:23 Xu B. Protective effect of MK-801 on manganese disturbing glutamate metabolism and NMDA receptor expression[D]. Shenyang:China Medical University, 2010:23 (in Chinese)
刘俊平, 张茂林, 周立社, 等. 谷氨酸及其受体在脑梗死中的作用[J]. 包头医学院学报, 2006, 22(1):115-118 刘杨, 宋晗, 官瑞丽, 等. 铅暴露对神经元和脉络丛上皮细胞的损伤机制研究[J]. 实用预防医学, 2017, 24(6):641-645 Liu Y, Song H, Guan R L, et al. Mechanisms of lead exposure-induced damages in neuron and choroidal epithelial cells[J]. Practical Preventive Medicine, 2017, 24(6):641-645(in Chinese)
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