Molecular & Behavioral Effects of Low Level Mn Exposure

分子

• 批准号: 7676600
• 负责人: Tomas R Guilarte
• 金额: $ 16.32万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676600
• 关键词: Affect; Amphetamines; Amyloid; Animals; Area; Arts; Attention; Automobiles; Basal Ganglia; Behavior; Behavior assessment; Behavioral; Brain; Brain Chemistry; Brain region; Cellular Stress Response; Chromosome Pairing; Chronic; Cognitive; Cognitive deficits; Collaborations; Corpus striatum structure; DRD2 gene; Data; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Dopamine; Dopamine Receptor; Dose; Environment; Evaluation; Evolution; Exposure to; Functional disorder; Funding; Future; Gasoline; General Population; Globus Pallidus; Glutamates; Goals; Guidelines; Head; Health; Health Policy; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Knowledge; Learning; Life; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manganese; Measures; Medial; Mediating; Memory; Metals; Modality; Molecular; Monitor; Monkeys; Motor; Neurobiology; Neurologic; Neurologic Dysfunctions; Neurons; Neurosciences; Occupational; Output; Parietal Lobe; Pathology; Play; Population; Positron-Emission Tomography; Progress Reports; Psyche structure; Public Health; Research Design; Resolution; Role; Sampling; Schizophrenia; Scientist; Source; Structure; Structure of subthalamic nucleus; Synapses; System; Temporal Lobe; Testing; Time; Toxic Environmental Substances; Toxin; United States National Institutes of Health; Work; age related; aging brain; anthropogenesis; base; behavior test; dopamine transporter; executive function; frontal lobe; improved; in vivo; molecular imaging; nervous system disorder; neurobehavioral; neurochemistry; neuroimaging; neuropathology; neurotoxicity; neurotoxicology; neurotransmission; nonhuman primate; novel; processing speed; putamen; radioligand; tool; vigilance; visual learning; white matter

Project Summary: Manganese (Mn) is an essential metal for human health, but exposure to excess levels can cause neurological disease. Emerging evidence suggests that long-term exposures to low levels of anthropogenic or environmental sources of Mn may have detrimental effects on human neurological health. Automobile combustion of gasoline containing methylcyclopentadienyl manganese tricarbonyl (MMT) has the potential to significantly increase Mn exposures to human populations where this fuel additive is used. However, there is a paucity of knowledge on the neurological health effects of chronic exposures to low-levels of Mn. While moderate to high levels of Mn exposure are associated with motor abnormalities and cognitive dysfunction as well as basal ganglia dopaminergic dysfunction in humans and non-human primates. The extent to which lower levels of Mn exposure may target specific cognitive domains and alter brain chemistry is not known. The studies described in this application are the result of a unique and productive on-going collaboration of scientists with expertise in behavioral neuroscience, molecular imaging, molecular and cellular neuroscience, neurotoxicology, neurochemistry and neuropathology applying the latest state-of-the-art behavioral and neuroimaging modalities to understand the behavioral dysfunction and underlying molecular and cellular mechanisms of Mn-induced neurological disease in the living non-human primate brain. Our most recent evidence suggests that chronic Mn exposure in non-human primates produces in vivo neurochemical changes resembling those in schizophrenia. Further, exposure to Mn produces a cellular stress response and diffuse amyloid-¿ plaques in the frontal cortex resembling those in the aging brain and in Alzheimer¿s disease. These preliminary findings provide a putative link of an environmental toxicant (Mn) to mental and neurological disease. The proposed studies will expand on these findings and provide the most comprehensive assessment to date on the neurological consequences of chronic Mn exposure on the non-human primate brain. The knowledge gained will help set future public health policies and guidelines to limit Mn exposures in occupational settings and to the general population. Relevance: The work that we describe in this proposal will define the behavioral, in vivo neurochemistry and neuropathological effects of chronic low level Mn exposure in non-human primates. They represent the most comprehensive assessment to date on the neurological consequences of chronic exposure to levels of Mn that segments of the population are likely to encounter in their environment. The knowledge gained will help set future public health policies and guidelines to limit Mn exposures in occupational settings and to the general population.

项目概要：锰（Mn）是人体健康所必需的金属，但暴露于过量水平可 导致神经系统疾病。新出现的证据表明，长期接触低水平的 锰的人为或环境来源可能对人类神经健康具有有害影响。 汽车燃烧含甲基三羰基锰（MMT）的汽油， 在使用这种燃料添加剂的情况下，可能会显著增加人群的锰暴露。 然而，关于长期接触低浓度的放射性物质对神经系统健康的影响， 的Mn。而中到高水平的锰暴露与运动异常和认知障碍有关， 功能障碍以及基底神经节多巴胺能功能障碍。程度 较低水平的锰暴露可能针对特定的认知领域并改变脑化学， 知道的本申请中描述的研究是一项独特而富有成效的持续研究的结果。 具有行为神经科学、分子成像、分子和细胞学专业知识的科学家合作 神经科学、神经毒理学、神经化学和神经病理学应用最新的最先进的 行为和神经影像学方式，以了解行为功能障碍和潜在的分子 和活的非人灵长类动物脑中Mn诱导的神经系统疾病的细胞机制。我们最 最近的证据表明，非人类灵长类动物的慢性锰暴露产生体内神经化学物质， 类似精神分裂症的变化此外，暴露于Mn产生细胞应激反应， 额叶皮质弥漫性淀粉样斑块，类似于老年大脑和阿尔茨海默病中的斑块。 这些初步发现提供了一个假定的联系，环境毒物（锰），以精神和神经 疾病拟议的研究将扩大这些调查结果，并提供最全面的评估 到目前为止，慢性锰暴露对非人类灵长类动物大脑的神经学后果。的 获得的知识将有助于制定未来的公共卫生政策和指导方针，以限制锰暴露， 职业环境和一般人群。 相关性：我们在本提案中描述的工作将定义行为、体内神经化学和 非人类灵长类动物慢性低水平锰暴露的神经病理学效应。他们代表了 迄今为止对长期暴露于锰水平的神经系统后果的全面评估， 在他们的环境中可能遇到的问题。获得的知识将有助于 未来的公共卫生政策和指导方针，以限制职业环境中的锰暴露， 人口