Molecular & Behavioral Effects of Low Level Mn Exposure

项目摘要：锰是人体健康必不可少的一种金属，但暴露在过量的水平下可能会 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的神经健康产生不利影响。 汽车燃烧含甲基环戊二烯基锰三甲酰(MMT)的汽油具有 有可能显著增加使用这种燃料添加剂的人群对锰的暴露。 然而，关于长期接触低水平辐射对神经健康的影响，人们知之甚少。 锰的含量。而中到高水平的锰暴露与运动异常和认知功能障碍有关 人类和非人类灵长类动物的基底节多巴胺能功能障碍。广度 较低水平的锰暴露可能针对特定的认知领域，而改变大脑化学不是 为人所知。本申请中描述的研究是正在进行的独特和富有成效的研究的结果 拥有行为神经科学、分子成像、分子和细胞专业知识的科学家之间的合作 神经科学、神经毒理学、神经化学和神经病理学应用最新技术 行为和神经成像方法了解行为功能障碍和潜在的分子 以及在活着的非人类灵长类动物大脑中锰诱导神经疾病的细胞机制。我们最大的 最近的证据表明，非人类灵长类动物长期接触锰会在体内产生神经化学物质。 类似于精神分裂症的变化。此外，暴露于锰会产生细胞应激反应，并 额叶皮质中弥漫的淀粉样斑块，类似于老化的大脑和阿尔茨海默病的S病。 这些初步发现提供了环境毒物(锰)与精神和神经的假定联系。 疾病。拟议的研究将对这些发现进行扩展，并提供最全面的评估 到目前为止，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研究。这个 所获得的知识将有助于制定未来的公共卫生政策和指南，以限制在 对职业环境和普通民众而言，这是一项重要的工作。 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 慢性低水平锰暴露对非人类灵长类动物的神经病理影响。他们代表了最多 到目前为止，对慢性接触锰水平的神经后果进行了全面评估 人口的一部分很可能在他们的环境中遇到。所获得的知识将有助于 未来的公共卫生政策和指南，以限制职业环境和一般人群中的锰暴露 人口。

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.