Molecular & Behavioral Effects of Low Level Mn Exposure

分子

• 批准号: 8145618
• 负责人: Tomas R Guilarte
• 金额: $ 87.62万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-18 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145618
• 关键词: Affect; Alzheimer' s Disease; Amphetamines; Amyloid; Animals; Area; Attention; Automobiles; Basal Ganglia; Behavior; Behavior assessment; Behavioral; Brain; Brain Chemistry; Brain region; Cellular Stress Response; Chronic; Cognitive; Cognitive deficits; Collaborations; Corpus striatum structure; DRD2 gene; Data; Diffuse; Diffusion Magnetic Resonance Imaging; 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; Nerve Degeneration; Neurobiology; Neurologic; Neurologic Dysfunctions; Neurons; Neurosciences; Occupational; Output; Parietal; Parietal Lobe; Pathology; Patients; Play; Population; Positron; Progress Reports; Psyche structure; Public Health; Research Design; Resolution; Role; Sampling; Schizophrenia; Scientist; Source; Structure; Structure of subthalamic nucleus; Substantia nigra structure; 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; synuclein; tomography; tool; vigilance; visual learning; visual memory; white matter

DESCRIPTION (provided by applicant): 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 low level Mn exposure in non-human primates produces in vivo neurochemical changes resembling those in schizophrenia patients. Further, exposure to Mn produces a cellular stress response and diffuse amyloid-2 plaques in the frontal cortex resembling those in the aging brain and in Alzheimer's disease. These preliminary findings provide a putative link of exposure to an environmental toxicant (Mn) and neurochemical and neuropathological changes associated with mental and neurological diseases. 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 at increasingly lower levels of chronic 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. These studies have already provided novel findings and the knowledge gained will help set future public health policies and guidelines to limit Mn exposures in occupational settings and to the general population. PUBLIC HEALTH RELEVANCE: The long-term goal of the proposed studies is to determine the behavioral, neuroimaging and neuropathological effects of chronic exposure to increasingly lower concentrations of manganese (Mn) in order to identify the level of cumulative exposure that produces the earliest changes in behavior and brain chemistry. The ultimate goal is to determine the extent to which chronic exposure to environmentally- or occupationally- relevant levels of Mn contributes to human neurological disease. A major advantage of our unique collaboration is that behavioral and in vivo brain chemistry changes are monitored prospectively and in parallel with Mn exposure in non-human primates.

描述（由申请人提供）：锰（MN）是人类健康的必不可少的金属，但暴露于过度水平会导致神经系统疾病。新兴的证据表明，长期暴露于低水平的MN的人为或环境来源可能对人类神经健康的健康有害。含有甲基环甲基烷基三卡苯甲苯二烯基（MMT）的汽油燃烧的可能会显着增加对使用这种燃料添加剂的人群的MN暴露。但是，关于慢性暴露于Mn的慢性暴露的神经健康影响的知识很少。尽管中等至高水平的MN暴露与运动异常和认知功能障碍以及人类和非人类灵长类动物的基础神经节多巴胺能功能障碍有关。尚不清楚较低水平的MN暴露可能针对特定的认知结构域和改变脑化学的程度。本应用中描述的研究是科学家在行为神经科学，分子成像，分子和细胞神经科学，神经毒理学，神经化学和神经病理学方面具有独特而有效的持续合作的结果以及神经影像学的方式，以了解MN诱导的非人类灵长类动物大脑中MN诱导的神经系统疾病的行为功能障碍以及基本的分子和细胞机制。我们最近的证据表明，非人类灵长类动物的慢性低水平MN暴露会产生类似于精神分裂症患者的体内神经化学变化。此外，暴露于MN还会在额叶皮质中产生细胞应激反应和弥漫性淀粉样蛋白-2斑块，类似于大脑衰老和阿尔茨海默氏病中的淀粉样皮质。这些初步发现提供了与环境有毒物（MN）以及与心理和神经系统疾病相关的神经化学和神经病理学变化的推定联系。拟议的研究将扩大这些发现，并就慢性MN暴露对非人类灵长类动物大脑的神经系统后果提供最全面的评估。获得的知识将有助于制定未来的公共卫生政策和准则，以限制在职业环境和普通人群中的MN暴露。相关性：我们在该提案中描述的工作将定义非人类灵长类动物的慢性MN暴露水平越来越低的行为，体内神经化学和神经病理学效应。它们代表了迄今为止最全面的评估，即长期暴露于Mn水平的神经系统后果，即人群可能在其环境中遇到的部分。这些研究已经提供了新颖的发现，获得的知识将有助于制定未来的公共卫生政策和准则，以限制在职业环境和一般人群中的MN暴露。公共卫生相关性：拟议研究的长期目标是确定长期暴露于日益较低浓度的锰（MN）的行为，神经影像学和神经病理学的影响，以确定累积暴露水平，从而产生最早的变化行为和大脑化学。最终目标是确定长期暴露于环境或职业相关水平的MN的程度有助于人类神经疾病。我们独特的合作的一个主要优点是，行为和体内脑化学变化被前瞻性地监测，并与非人类灵长类动物的MN暴露并行。