Molecular & Behavioral Effects of Low Level Mn Exposure

描述（由申请人提供）：锰（Mn）是人类健康的必需金属，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，长期暴露于低水平的人为或环境来源的锰可能对人类神经系统健康产生有害影响。汽车燃烧含有甲基三羰基锰（MMT）的汽油有可能显著增加使用这种燃料添加剂的人群的锰暴露。然而，有一个缺乏知识的神经系统健康的影响，长期暴露于低水平的锰。而中到高水平的锰暴露与人类和非人灵长类动物的运动异常和认知功能障碍以及基底神经节多巴胺能功能障碍有关。在何种程度上较低水平的锰暴露可能针对特定的认知领域和改变脑化学尚不清楚。本申请中描述的研究是具有行为神经科学、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应用最新的国家的最先进的行为和神经影像学模式，以了解行为功能障碍和潜在的分子和细胞机制的锰，在非人类灵长类动物的大脑中诱发神经系统疾病。我们最近的证据表明，慢性低水平锰暴露在非人灵长类动物产生体内神经化学变化类似于精神分裂症患者。此外，暴露于Mn产生细胞应激反应，并在额叶皮质中扩散淀粉样蛋白-2斑块，类似于老化大脑和阿尔茨海默病中的那些。这些初步研究结果提供了一个假定的联系，暴露于环境毒物（锰）和神经化学和神经病理学变化与精神和神经系统疾病。拟议的研究将扩展这些发现，并提供迄今为止最全面的评估慢性锰暴露对非人灵长类动物大脑的神经系统后果。所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，以限制职业环境和普通人群中的锰暴露。相关性：我们在本提案中描述的工作将定义非人灵长类动物慢性锰暴露水平越来越低时的行为、体内神经化学和神经病理学效应。它们代表了迄今为止对部分人口在其环境中可能遇到的长期暴露于锰水平的神经后果的最全面的评估。这些研究已经提供了新的发现，所获得的知识将有助于制定未来的公共卫生政策和指南，以限制职业环境和普通人群中的锰暴露。公共卫生相关性：拟议研究的长期目标是确定慢性暴露于浓度越来越低的锰（Mn）的行为，神经影像学和神经病理学影响，以确定产生行为和脑化学最早变化的累积暴露水平。最终目标是确定长期暴露于环境或职业相关水平的锰对人类神经系统疾病的影响程度。我们独特的合作的一个主要优势是，前瞻性地监测行为和体内脑化学变化，并与非人灵长类动物的锰暴露平行。

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.