Molecular & Behavioral Effects of Low Level Mn Exposure

说明(由申请人提供)：批准将锰(Mn)用作 汽油添加剂可能会导致这种物质的积累增加。 环境中的金属。长期接触低水平的锰可能会造成 对人类的健康风险，但目前尚不清楚这种情况可能会在多大程度上发生。一个 少数研究描述了人类的急性神经系统症状 与帕金森病患者相似的职业性接触锰？S 疾病。然而，无论是作用机制还是神经学 慢性、低水平接触锰的后果是已知的。的目标是 这项提议是为了描述行为、体内神经化学和 慢性暴露于低氧所致的神经病理改变 锰的水平。拟议中的研究结果将是 了解慢性低水平锰神经毒性的机制(S)。 此外，这些数据将识别敏感的标记，用于早期检测 可在人体内使用的锰神经毒性。我们建议MN 非人灵长类猕猴的神经毒性研究 猴子)，通过使用一种 前瞻性研究设计。一连串的脑部成像将由正电子进行 发射断层扫描(PET)、单光子发射计算机断层扫描(SPECT)、 磁共振成像(MRI)和波谱(MRS)技术，贯穿始终 锰暴露。进行的PET/SPECT扫描的类型将取决于分子 要检查的终结点。核磁共振扫描将显示该区域的大脑 以及提供PET/SPECT的解剖模板 扫描每只猴子大脑的图像。MRS研究将提供大脑 锰暴露引起的代谢变化。在会议结束后 行为和脑成像研究，神经病理技术将是 对身体组织进行检查，以充分表征和定义 脑成像研究发现的变化并评估其他神经系统 也可能受到影响。这项建议融合了行为学的学科 毒理学、脑成像、神经科学和神经毒理学 与评估人类健康风险直接相关的研究建议 曝光。我们的长期目标是描述相关的神经毒性 与慢性、低水平的锰接触，并建立其基础 作用机制。拟议中的研究使用了最先进的技术 将提供最好的数据来进行人类风险评估 以及有关汽油中锰的监管决定。拟议的研究将会有所帮助。 美国了解接触环境制剂之间的潜在相互作用 和神经退行性疾病。

DESCRIPTION (provided by applicant): The approved use of manganese (Mn) as an additive to gasoline is likely to result in increased accumulation of this metal in the environment. Chronic exposure to low-levels of Mn may pose a health risk to humans, but it is not known to what extent this may occur. A small number of studies describe acute neurological symptoms in humans after occupational exposure to Mn which resemble those observed in Parkinson?s disease. However, neither the mechanism of action nor the neurological consequences of chronic, low-level exposure to Mn is known. The objective of this proposal is to describe behavioral, in vivo neurochemical, and neuropathological changes that occur as a result of chronic exposure to low levels of Mn. The findings from the proposed studies will be fundamental in understanding the mechanism(s) of chronic, low-level Mn neurotoxicity. Moreover, these data will identify sensitive markers for the early detection of Mn neurotoxicity that can be used in vivo in humans. We propose that Mn neurotoxicity be studied in the non-human primate, Macaca mulatta (rhesus monkey), by assessing behavioral and in vivo brain chemistry using a prospective study design. Serial brain imaging will be performed by positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques, throughout Mn exposure. The type of PET/SPECT scan performed will depend on the molecular endpoint to be examined. The MRI scans will show the regional brain distribution of Mn, as well as provide an anatomical template of the PET/SPECT scan images from each monkey brain. The MRS studies will provide brain metabolic changes resulting from Mn exposure. Following the conclusion of the behavioral and brain imaging studies, neuropathological techniques will be performed on the post-mortem tissue to fully characterize and define the changes found by the brain imaging studies and to assess other neuronal systems which may also be affected. This proposal merges the disciplines of behavioral toxicology, brain imaging, neuroscience and neurotoxicology in an innovative research proposal directly relevant to assessing human health risk to Mn exposure. Our long-term objective is to describe the neurotoxicity associated with exposure to chronic, low level Mn exposure and establish the basis for its mechanism of action. The proposed research using state-of the-art techniques will provide the best possible data with which to make human risk assessment and regulatory decisions about Mn in gasoline. The proposed studies will help us understand potential interactions between exposure to environmental agents and neurodegenerative disease.