氯化镍暴露神经毒性与线粒体功能障碍的关系研究
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摘要
研究背景
重金属元素镍（Nickel），由于其在工业中的广泛应用，在生产与使用过程中常造成职业暴露，引起职业人群的健康危害。镍被机体摄入后，可分布于多个脏器，引起多器官毒性，神经毒性是其危害效应的重要表现之一。但镍的神经毒性效应的机制目前尚不明确。线粒体功能障碍是许多神经系统疾病的重要病因，也是多种环境刺激因素引起神经毒性的主要途径。近年研究发现，受缺氧诱导因子-1α (hypoxia-induciblefactor-1alpha, HIF-1α)调控的microRNA分子miRNA210能抑制硫铁簇组装支架蛋白（iron-sulfur cluster assemble scaffold，ISCU）的表达，引起的含硫铁簇（iron-sulfurcluster, FeS）能量代谢酶失活，由HIF-1α，miRNA210，ISCU构成的“调控轴”激活是多种细胞在缺氧条件下线粒体功能抑制的分子基础。而镍暴露也能够引起HIF-1α在细胞内聚积。基于上述分析，本课题以线粒体功能状态改变为切入点，通过动物和细胞两个水平，明确镍引起的神经毒性效应，揭示线粒体功能障碍在镍神经毒性效应中的作用；通过研究miRNA210介导的线粒体呼吸抑制，探讨线粒体在镍暴露条件下出现功能障碍的分子机制。
研究内容
①以昆明小鼠经口暴露可溶性镍化合物氯化镍(NiCl_2)为实验模型，利用Morris水迷宫和旷场实验评价镍对动物神经行为学的影响，明确镍对小鼠神经毒性效应的规律；在小鼠出现神经行为学改变的镍暴露条件下，检测动物大脑皮层组织的氧耗率、ATP含量、乳酸含量、NADH/NAD比值、氧化应激状态等反应线粒体功能状态的指标，探讨线粒体功能障碍在镍神经毒性效应中的作用；
②以小鼠原代培养神经元以及小鼠神经母瘤Neuro2a细胞为模型，以细胞活力、乳酸脱氢酶释放等方法评价NiCl_2对神经细胞的毒性效应；同时，检测NiCl_2对氧自由基水平、ATP含量、线粒体膜电位以及线粒体DNA的拷贝数等线粒体功能状态的影响；利用褪黑素和左旋肉碱这两种对线粒体功能有确切保护效应的化合物进行预处理，评价其通过维持线粒体功能拮抗镍神经细胞毒性；
③在镍暴露条件下，检测Neuro2a细胞中HIF-1α、miRNA210、ISCU等分子的表达变化，评价该调控轴的活化水平；并对miRNA210的表达进行正负调控，检测相应的ISCU的表达，FeS能量代谢酶活性以及线粒体功能状态的变化，验证miRNA210在镍引起的线粒体功能障碍中的作用。
研究结果
①50mg Ni/kg WT的NiCl_2经口暴露引起昆明小鼠在暴露3小时后出现空间记忆障碍及探索活性下降，这些神经行为学的于暴露24小时后逐渐恢复至对照组水平；NiCl_2暴露3小时，小鼠大脑皮层组织中检测到明显的镍元素蓄积，且线粒体功能出现障碍，包括有氧代谢抑制、自由基水平升高以及含FeS能量代谢酶失活；暴露24小时，随着镍元素的排泄，小鼠皮层组织中的线粒体功能基本恢复。
②NiCl_2对原代培养神经元及Neuro2a细胞造成显著的细胞毒性效应，并呈现剂量和时间依赖关系；MT和LC的预处理，通过清除线粒体氧自由基，维持ATP含量、线粒体膜电位及mtDNA的拷贝数等方面的保护作用，有效减轻镍引起的神经细胞毒性效应。
③NiCl_2暴露引起Neuro2a细胞HIF-1α蓄积、miRNA210高表达以及ISCU表达下调；在未暴露镍的细胞中，上调miRNA210的表达，出现FeS能量代谢酶活性下降及线粒体功能障碍；在暴露镍的细胞中，抑制miRNA210的表达，一定程度上缓解镍引起的FeS能量代谢酶活性下降及线粒体功能障碍；在引起小鼠神经行为学异常的镍暴露条件下，检测到小鼠皮层组织中的HIF-1α蓄积、miRNA210高表达以及ISCU表达下调。
研究结论
根据本课题的研究结果，获得以下结论：镍引起的线粒体功能障碍可能是其造成小鼠神经行为学改变和神经细胞毒性的重要原因，镍通过干扰线粒体的功能，影响神经细胞的生物学状态，从而表现出神经毒性效应；镍暴露引起HIF-1α—miRNA210—ISCU“调控轴”激活，由此造成的FeS合成抑制，FeS能量代谢酶失活可能是镍引起线粒体功能障碍的分子基础。本课题的研究进一步证实了可溶性镍化合物暴露的神经毒性效应，并为阐明镍的毒性机制提供了新的实验依据。
Background
Nickel (Ni) is widely used heavy metal in model industry. Industrial processing-relatedanthropogenic activities provide a considerable amount of Ni in the environment as a resultof mining, smelting, cement-production, combustion of fossil fuels, incineration of sewagesludge, electroplating. As a result, human exposure to Ni, both occupational and dietary, issuffered by its health hazard. Ni ingested by human distributes into multiple organs, andmanifests multiple toxicities, including neurotoxicity. However, the exact mechanism ofnickel’s neurotoxicity is not well understood. Mitochondrial dysfunction is the primarypathogenesis of various neurologic syndrome, and route by which the environment stimulusexert their neurotoxicity. In recently reports, the activation of regulation-axis which isconsisted by hypoxia-inducible factor-1alpha (HIF-1α), miRNA210, and iron-sulfur clusterassemble scaffold (ISCU) participates in the mitochondrial function inhibition duringhypoxia condition. As well as, nickel induces the accumulation of HIF-1α in normoxia.Therefore, the purpose of this study is to investigate the role of mitochondrial dysfunctionin Ni-induced neurotoxicity, and to explore whether the activation of regulation-axisunderlies the Ni caused mitochondrial dysfunction.
Methods
①Kunming mice were orally administered nickel chloride (NiCl_2), andneurobehavioral performance was evaluated using the Morris water maze and open fieldtests at different time points. Ni amounts in neurologic tissues and mitochondrial functionalstates, including O2consumption, ATP concentrations, lactate concentrations, ratios ofNADH/NAD, oxidative stress and iron-sulfur cluster (FeS) containing metabolism enzymesin the cerebral cortex were analyzed at the same time points at which neurobehavioralchanges were evident.
②The cell viability and LDH release were applied to evaluate the cytotoxicity ofNiCl_2on primary cultured neurons and Neuro2a cell line. Parallel, the effects of Ni on cellular ROS levels, ATP concentrations, mitochondrial membrane potential and mtDNAcopy number and mtRNA transcript level were assayed for identification the Ni-inducedmitochondrial dysfunction. In addition, the pretreatments of mitochondrial protective agents,melatonin and L-carnitine, before Ni exposures were used to elucidate whether they couldprotest against the Ni-induced cytotoxicity through maintaining the mitochondria function.
③The expression levels of HIF-1α, miRNA210, ISCU were measured after NiCl_2exposure. Then, the microRNA slices which mimic or inhibit the expression of miRNA210were transfected into cells. The expression of ISCU, mitochondrial function and activity ofFeS enzymes were assayed in transfected cells. Finally, the expression of HIF-1α,miRNA210and ISCU were investigated in the cerebral cortex of Ni-treated mice.
Results
①50mg Ni/kg WT NiCl_2administration caused deficits in both spatial memory andexploring activity in mice and that nickel was deposited in their cerebral cortex.Mitochondrial dysfunction manifested as decreased O2consumption and ATPconcentrations, lactate and NADH accumulation, and oxidative stress. Meanwhile, theactivity of prototypical iron-sulfur clusters (ISCs) containing enzymes that are known tocontrol aerobic metabolism, including complex I and aconitase, were inhibited followingnickel deposition.
②NiCl_2treatment significantly increased the cell viability loss and lactatedehydrogenase (LDH) release in primary cultured neurons and Neuro2a cells. In addition,nickel exposure significantly elevated reactive oxygen species (ROS) and malondialdehyde(MDA) levels disrupted the mitochondrial membrane potential, ATP concentrations anddecreased mtDNA copy numbers and mtRNA transcript levels in both kind of cells.However, all of the cytotoxicity and mitochondrial dysfunctions that were triggered bynickel were efficiently attenuated by pretreatment with melatonin and L-carnitine.
③NiCl_2exposure lead to significant HIF-1α, rather than HIF-1β, accumulation inNeuro2a cells. MiRNA210was overexpressed by nickel treatment following a dose andtime-dependent manner, which accompanied with ISCU down-regulation. The gain-andloss-of-function assays revealed that miRNA210controlled the ISCU suppression, energymetabolism alternation and ISCs contained metabolic enzymes inactivation under nickelexposure. Dual luciferase reporter assay revealed that ISCU was the direct target ofmiRNA210. In the cerebral cortex of Ni-treated mice, it was found that high levels of HIF-1α and miRNA210, low levels of ISCU.
Conclusion
Overall, our data suggest that Ni-induced mitochondrial dysfunction may result in theneurotoxicity of nickel which manifested as neurobehavioral changes in mice andcytotoxicity in nerve cells. In nickel exposure conditions, the activation ofHIF-1α-miRNA210-ISCU regulation-axis, which contributed to inhibition of FeS assembleand inactivation of FeS containing metabolism enzymes, may be the mechanism thatunderlies the Ni-induced mitochondrial dysfunction. A better understanding of how nickelimpacts mitochondrial function may provide insight into the prevention of nickelneurotoxicity.
重金属元素镍（Nickel），由于其在工业中的广泛应用，在生产与使用过程中常造成职业暴露，引起职业人群的健康危害。镍被机体摄入后，可分布于多个脏器，引起多器官毒性，神经毒性是其危害效应的重要表现之一。但镍的神经毒性效应的机制目前尚不明确。线粒体功能障碍是许多神经系统疾病的重要病因，也是多种环境刺激因素引起神经毒性的主要途径。近年研究发现，受缺氧诱导因子-1α (hypoxia-induciblefactor-1alpha, HIF-1α)调控的microRNA分子miRNA210能抑制硫铁簇组装支架蛋白（iron-sulfur cluster assemble scaffold，ISCU）的表达，引起的含硫铁簇（iron-sulfurcluster, FeS）能量代谢酶失活，由HIF-1α，miRNA210，ISCU构成的“调控轴”激活是多种细胞在缺氧条件下线粒体功能抑制的分子基础。而镍暴露也能够引起HIF-1α在细胞内聚积。基于上述分析，本课题以线粒体功能状态改变为切入点，通过动物和细胞两个水平，明确镍引起的神经毒性效应，揭示线粒体功能障碍在镍神经毒性效应中的作用；通过研究miRNA210介导的线粒体呼吸抑制，探讨线粒体在镍暴露条件下出现功能障碍的分子机制。
研究内容
①以昆明小鼠经口暴露可溶性镍化合物氯化镍(NiCl_2)为实验模型，利用Morris水迷宫和旷场实验评价镍对动物神经行为学的影响，明确镍对小鼠神经毒性效应的规律；在小鼠出现神经行为学改变的镍暴露条件下，检测动物大脑皮层组织的氧耗率、ATP含量、乳酸含量、NADH/NAD比值、氧化应激状态等反应线粒体功能状态的指标，探讨线粒体功能障碍在镍神经毒性效应中的作用；
②以小鼠原代培养神经元以及小鼠神经母瘤Neuro2a细胞为模型，以细胞活力、乳酸脱氢酶释放等方法评价NiCl_2对神经细胞的毒性效应；同时，检测NiCl_2对氧自由基水平、ATP含量、线粒体膜电位以及线粒体DNA的拷贝数等线粒体功能状态的影响；利用褪黑素和左旋肉碱这两种对线粒体功能有确切保护效应的化合物进行预处理，评价其通过维持线粒体功能拮抗镍神经细胞毒性；
③在镍暴露条件下，检测Neuro2a细胞中HIF-1α、miRNA210、ISCU等分子的表达变化，评价该调控轴的活化水平；并对miRNA210的表达进行正负调控，检测相应的ISCU的表达，FeS能量代谢酶活性以及线粒体功能状态的变化，验证miRNA210在镍引起的线粒体功能障碍中的作用。
研究结果
①50mg Ni/kg WT的NiCl_2经口暴露引起昆明小鼠在暴露3小时后出现空间记忆障碍及探索活性下降，这些神经行为学的于暴露24小时后逐渐恢复至对照组水平；NiCl_2暴露3小时，小鼠大脑皮层组织中检测到明显的镍元素蓄积，且线粒体功能出现障碍，包括有氧代谢抑制、自由基水平升高以及含FeS能量代谢酶失活；暴露24小时，随着镍元素的排泄，小鼠皮层组织中的线粒体功能基本恢复。
②NiCl_2对原代培养神经元及Neuro2a细胞造成显著的细胞毒性效应，并呈现剂量和时间依赖关系；MT和LC的预处理，通过清除线粒体氧自由基，维持ATP含量、线粒体膜电位及mtDNA的拷贝数等方面的保护作用，有效减轻镍引起的神经细胞毒性效应。
③NiCl_2暴露引起Neuro2a细胞HIF-1α蓄积、miRNA210高表达以及ISCU表达下调；在未暴露镍的细胞中，上调miRNA210的表达，出现FeS能量代谢酶活性下降及线粒体功能障碍；在暴露镍的细胞中，抑制miRNA210的表达，一定程度上缓解镍引起的FeS能量代谢酶活性下降及线粒体功能障碍；在引起小鼠神经行为学异常的镍暴露条件下，检测到小鼠皮层组织中的HIF-1α蓄积、miRNA210高表达以及ISCU表达下调。
研究结论
根据本课题的研究结果，获得以下结论：镍引起的线粒体功能障碍可能是其造成小鼠神经行为学改变和神经细胞毒性的重要原因，镍通过干扰线粒体的功能，影响神经细胞的生物学状态，从而表现出神经毒性效应；镍暴露引起HIF-1α—miRNA210—ISCU“调控轴”激活，由此造成的FeS合成抑制，FeS能量代谢酶失活可能是镍引起线粒体功能障碍的分子基础。本课题的研究进一步证实了可溶性镍化合物暴露的神经毒性效应，并为阐明镍的毒性机制提供了新的实验依据。
Background
Nickel (Ni) is widely used heavy metal in model industry. Industrial processing-relatedanthropogenic activities provide a considerable amount of Ni in the environment as a resultof mining, smelting, cement-production, combustion of fossil fuels, incineration of sewagesludge, electroplating. As a result, human exposure to Ni, both occupational and dietary, issuffered by its health hazard. Ni ingested by human distributes into multiple organs, andmanifests multiple toxicities, including neurotoxicity. However, the exact mechanism ofnickel’s neurotoxicity is not well understood. Mitochondrial dysfunction is the primarypathogenesis of various neurologic syndrome, and route by which the environment stimulusexert their neurotoxicity. In recently reports, the activation of regulation-axis which isconsisted by hypoxia-inducible factor-1alpha (HIF-1α), miRNA210, and iron-sulfur clusterassemble scaffold (ISCU) participates in the mitochondrial function inhibition duringhypoxia condition. As well as, nickel induces the accumulation of HIF-1α in normoxia.Therefore, the purpose of this study is to investigate the role of mitochondrial dysfunctionin Ni-induced neurotoxicity, and to explore whether the activation of regulation-axisunderlies the Ni caused mitochondrial dysfunction.
Methods
①Kunming mice were orally administered nickel chloride (NiCl_2), andneurobehavioral performance was evaluated using the Morris water maze and open fieldtests at different time points. Ni amounts in neurologic tissues and mitochondrial functionalstates, including O2consumption, ATP concentrations, lactate concentrations, ratios ofNADH/NAD, oxidative stress and iron-sulfur cluster (FeS) containing metabolism enzymesin the cerebral cortex were analyzed at the same time points at which neurobehavioralchanges were evident.
②The cell viability and LDH release were applied to evaluate the cytotoxicity ofNiCl_2on primary cultured neurons and Neuro2a cell line. Parallel, the effects of Ni on cellular ROS levels, ATP concentrations, mitochondrial membrane potential and mtDNAcopy number and mtRNA transcript level were assayed for identification the Ni-inducedmitochondrial dysfunction. In addition, the pretreatments of mitochondrial protective agents,melatonin and L-carnitine, before Ni exposures were used to elucidate whether they couldprotest against the Ni-induced cytotoxicity through maintaining the mitochondria function.
③The expression levels of HIF-1α, miRNA210, ISCU were measured after NiCl_2exposure. Then, the microRNA slices which mimic or inhibit the expression of miRNA210were transfected into cells. The expression of ISCU, mitochondrial function and activity ofFeS enzymes were assayed in transfected cells. Finally, the expression of HIF-1α,miRNA210and ISCU were investigated in the cerebral cortex of Ni-treated mice.
Results
①50mg Ni/kg WT NiCl_2administration caused deficits in both spatial memory andexploring activity in mice and that nickel was deposited in their cerebral cortex.Mitochondrial dysfunction manifested as decreased O2consumption and ATPconcentrations, lactate and NADH accumulation, and oxidative stress. Meanwhile, theactivity of prototypical iron-sulfur clusters (ISCs) containing enzymes that are known tocontrol aerobic metabolism, including complex I and aconitase, were inhibited followingnickel deposition.
②NiCl_2treatment significantly increased the cell viability loss and lactatedehydrogenase (LDH) release in primary cultured neurons and Neuro2a cells. In addition,nickel exposure significantly elevated reactive oxygen species (ROS) and malondialdehyde(MDA) levels disrupted the mitochondrial membrane potential, ATP concentrations anddecreased mtDNA copy numbers and mtRNA transcript levels in both kind of cells.However, all of the cytotoxicity and mitochondrial dysfunctions that were triggered bynickel were efficiently attenuated by pretreatment with melatonin and L-carnitine.
③NiCl_2exposure lead to significant HIF-1α, rather than HIF-1β, accumulation inNeuro2a cells. MiRNA210was overexpressed by nickel treatment following a dose andtime-dependent manner, which accompanied with ISCU down-regulation. The gain-andloss-of-function assays revealed that miRNA210controlled the ISCU suppression, energymetabolism alternation and ISCs contained metabolic enzymes inactivation under nickelexposure. Dual luciferase reporter assay revealed that ISCU was the direct target ofmiRNA210. In the cerebral cortex of Ni-treated mice, it was found that high levels of HIF-1α and miRNA210, low levels of ISCU.
Conclusion
Overall, our data suggest that Ni-induced mitochondrial dysfunction may result in theneurotoxicity of nickel which manifested as neurobehavioral changes in mice andcytotoxicity in nerve cells. In nickel exposure conditions, the activation ofHIF-1α-miRNA210-ISCU regulation-axis, which contributed to inhibition of FeS assembleand inactivation of FeS containing metabolism enzymes, may be the mechanism thatunderlies the Ni-induced mitochondrial dysfunction. A better understanding of how nickelimpacts mitochondrial function may provide insight into the prevention of nickelneurotoxicity.
引文
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