Molecular & Behavioral Effects of Low Level Mn Exposure

说明(申请人提供)：锰是人类健康所必需的一种金属，但暴露在过量的锰中会导致神经系统疾病。新出现的证据表明，长期接触低水平的人为或环境来源的锰可能会对人类神经健康产生有害影响。汽车燃烧含有甲基环戊二烯基锰三甲酰(MMT)的汽油，有可能显著增加使用这种燃料添加剂的人群中的锰暴露。然而，关于慢性暴露于低水平的锰对神经健康的影响的知识很少。而中到高水平的锰暴露与人类和非人类灵长类动物的运动异常和认知功能障碍以及基底节多巴胺能功能障碍有关。较低水平的锰暴露在多大程度上可能针对特定的认知领域并改变大脑化学成分尚不清楚。本申请中描述的研究是拥有行为神经科学、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专业知识的科学家不断合作的独特和富有成效的结果，他们应用最新的行为和神经成像方法，了解活着的非人类灵长类动物大脑中锰诱导的神经疾病的行为障碍和潜在的分子和细胞机制。我们最新的证据表明，在非人类灵长类动物中，长期低水平的锰暴露会在体内产生类似于精神分裂症患者的神经化学变化。此外，暴露在锰中会产生细胞应激反应和额叶皮质中弥漫的淀粉样蛋白-2斑块，类似于老化的大脑和阿尔茨海默病。这些初步发现提供了暴露于环境毒物(锰)与与精神和神经疾病相关的神经化学和神经病理变化之间的假定联系。拟议的研究将在这些发现的基础上进行扩展，并提供迄今为止关于长期接触锰对非人类灵长类动物大脑的神经学后果的最全面评估。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。相关性：我们在这项提案中描述的工作将定义在非人类灵长类动物中，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影响。它们代表了迄今为止对长期暴露于人群中可能在其环境中遇到的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，以限制职业环境中和普通人群的锰暴露。与公共健康相关：拟议研究的长期目标是确定慢性暴露于越来越低浓度的锰(Mn)对行为、神经成像和神经病理学的影响，以确定导致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接触环境或职业相关水平的锰对人类神经疾病的贡献程度。我们独特合作的一个主要优势是，在非人类灵长类动物接触锰的同时，可以前瞻性地监测行为和活体脑化学变化。

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.