Molecular & Behavioral Effects of Low Level Mn Exposure

分子

• 批准号: 6995360
• 负责人: Tomas R Guilarte
• 金额: $ 108.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6995360
• 关键词: Macaca mulatta; behavioral /social science research tag; brain imaging /visualization /scanning; brain metabolism; chronic disease /disorder; environmental toxicology; magnetic resonance imaging; manganese; metal poisoning; neural degeneration; neurochemistry; neurons; neuropathology; neuropsychology; neurosciences; neurotoxicology; nuclear magnetic resonance spectroscopy; pathologic process; performance; petroleum oil; positron emission tomography; postmortem; short term memory; single photon emission computed tomography; tissue /cell culture

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.

描述（由申请人提供）：批准使用锰（Mn）作为 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。长期接触低浓度的锰可能会导致 对人类健康构成风险，但尚不清楚这种风险会发生到什么程度。一个 少数研究描述了人类急性神经系统症状 锰的职业接触与帕金森病中观察到的情况相似 疾病。然而，无论是作用机制还是神经系统 长期、低水平接触锰的后果是众所周知的。的目标 该提案旨在描述行为、体内神经化学和 由于长期暴露于低浓度环境而发生的神经病理变化 锰含量。拟议研究的结果将是基础 了解慢性、低水平锰神经毒性的机制。 此外，这些数据将识别敏感标记，以便及早发现 锰的神经毒性可用于人体体内。我们建议锰 在非人类灵长类动物猕猴（恒河猴）中研究神经毒性 猴子），通过使用 前瞻性研究设计。正电子将进行串行脑成像 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) 和光谱 (MRS) 技术，贯穿始终 锰暴露。进行 PET/SPECT 扫描的类型取决于分子 要检查的终点。核磁共振扫描将显示区域大脑 Mn 的分布，并提供 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。得出结论后 行为和脑成像研究、神经病理学技术将 在死后组织上进行，以充分表征和定义 大脑成像研究发现的变化并评估其他神经系统 这也可能受到影响。该提案融合了行为学科 毒理学、脑成像、神经科学和神经毒理学的创新 与评估锰对人类健康风险直接相关的研究提案 接触。我们的长期目标是描述相关的神经毒性 长期、低水平的锰暴露并为其奠定基础 作用机制。拟议的研究使用最先进的技术 将提供进行人类风险评估的最佳数据 以及有关汽油中锰的监管决定。拟议的研究将有助于 我们了解接触环境因素之间的潜在相互作用 和神经退行性疾病。