Neurotoxicity of nanomaterials: evaluation of subcellular redox state

纳米材料的神经毒性：亚细胞氧化还原状态的评估

• 批准号: 7341276
• 负责人: GARY W MILLER
• 金额: $ 40.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341276
• 关键词: Acetylcysteine; Address; Adverse effects; Animals; Antioxidants; Attenuated; Bioavailable; Biological; Biological Models; Brain region; Cell model; Chemicals; Cultured Cells; Disease; Dopamine; Dose; Equilibrium; Evaluation; Exposure to; Free Radicals; Glutathione; In Vitro; Injury; Iron; Magnetism; Measures; Mitochondria; Modeling; Neurodegenerative Disorders; Neurons; Neurotoxins; Nuclear; Oxidation-Reduction; Oxidative Stress; Oxidopamine; Parkinson Disease; Population; Process; Research Personnel; Resolution; Role; Series; Substantia nigra structure; System; Testing; Thioredoxin; Toxic effect; Transgenic Mice; alpha Tocopherol; brain tissue; chemical property; dopaminergic neuron; exposed human population; fullerene C60; in vivo; iron oxide; manganese oxide; nanomaterials; nanoparticle; nanoscale; neuron component; neurotoxicity; novel; oxidation; pars compacta; programs; research study; response; titanium dioxide

DESCRIPTION (provided by applicant) The ability to several manufactured nanomaterials to induce oxidative stress has been suggested to be the most appropriate means of assessing the potential toxicity of manufactured nanomaterials. Since oxidative stress is a common pathogenic mechanism in numerous diseases, including various neurodegenerative diseases, it is possible that the various nanomaterials may contribute to the disease process. We have shown that the redox state (dynamic balance between reduced and oxidized components) of neurons (in vitro and in vivo) can be spatially resolved by subcellular compartment. Neurotoxicants can preferentially oxidize cytoplasmic, mitochondrial, or nuclear redox components, such as thioredoxin or GSH. We hypothesize that the overall toxicity of nanomaterials will correspond to their ability to induce oxidative stress in distinct subcellular compartments and that these measures will provide a superior means of assessing their potential toxicity. We propose a series of in vitro and in vivo experiments aimed at determining the subcellular redox state of a cellular population known to be especially vulnerable to oxidative injury, namely, the dopamine neurons in the substantia nigra pars compacta. Aim 1. To determine the ability of the manufactured nanomaterials fullerene (C60), fullerol (C60(OH)22-24), manganese oxide (MnO2), titanium dioxide (TiO2), magnetic iron oxide (FeO4), and nanoscale zero valent iron (n-ZVI) to preferentially oxidize sucellular redox components. In this aim, we will examine the ability of suspended nanoparticles to induce oxidative stress in cell cultures of neuronal origin in the absence and presence of an oxidative challenge (6-OHDA). In addition, we will assess the physico-chemical properties of the nanomaterials prior to and after exposure to the cellular model. Aim 2. To determine the ability of the manufactured nanomaterials "manganese oxide (MnO2), titanium dioxide (TiO2), magnetic iron oxide (FeO4), and nanoscale zero valent iron (n-ZVI) to induce oxidative stress in dopaminergic brain regions. This aim will examine the ability of nanomaterials to alter subcellular redox state and induce oxidative damage in dopaminergic brain regions and determine the physico-chemical state of the nanomaterials prior to administration and in the brain tissue of exposed animals. Aim 3. To determine the ability of bioavailable antioxidants to attenuate the oxidative stress induced by manufactured nanomaterials. In this aim N-acetyl cysteine and alpha tocopherol will be tested for their ability to attenuate oxidative stress in in vitro and in vivo settings. Completion of these aims will provide novel information on the ability of nanomaterials to induce oxidative stress with subcellular spatial resolution and determine if their physico-chemical state is altered after exposure to the biological system.

描述（由申请人提供） 几种人造纳米材料诱导氧化应激的能力被认为是评估人造纳米材料潜在毒性的最合适方法。由于氧化应激是许多疾病（包括各种神经退行性疾病）的常见致病机制，因此各种纳米材料可能有助于疾病进程。我们已经证明，神经元（体外和体内）的氧化还原状态（还原和氧化成分之间的动态平衡）可以通过亚细胞区室进行空间解析。神经毒剂可以优先氧化细胞质、线粒体或核氧化还原成分，例如硫氧还蛋白或谷胱甘肽。我们假设纳米材料的总体毒性将与其在不同亚细胞区室中诱导氧化应激的能力相对应，并且这些措施将提供评估其潜在毒性的优越方法。我们提出了一系列体外和体内实验，旨在确定已知特别容易受到氧化损伤的细胞群（即黑质致密部中的多巴胺神经元）的亚细胞氧化还原状态。目的 1. 确定制备的纳米材料富勒烯（C60）、富勒醇（C60(OH)22-24）、氧化锰（MnO2）、二氧化钛（TiO2）、磁性氧化铁（FeO4）和纳米零价铁（n-ZVI）优先氧化细胞内氧化还原成分的能力。为此，我们将研究悬浮纳米粒子在存在和不存在氧化挑战（6-OHDA）的情况下在神经元来源的细胞培养物中诱导氧化应激的能力。此外，我们将评估纳米材料在暴露于细胞模型之前和之后的物理化学性质。目标 2. 确定制造的纳米材料“氧化锰（MnO2）、二氧化钛（TiO2）、磁性氧化铁（FeO4）和纳米零价铁（n-ZVI）在多巴胺能脑区诱导氧化应激的能力。该目标将检查纳米材料改变亚细胞氧化还原状态并诱导氧化损伤的能力。 多巴胺能大脑区域并确定纳米材料在给药前和暴露动物脑组织中的物理化学状态。目标 3. 确定生物可利用的抗氧化剂减轻人造纳米材料引起的氧化应激的能力。在此目的中，将测试 N-乙酰半胱氨酸和 α 生育酚减轻氧化应激的能力。 体外和体内环境。这些目标的完成将为纳米材料以亚细胞空间分辨率诱导氧化应激的能力提供新的信息，并确定其物理化学状态在暴露于生物系统后是否发生改变。