Molecular & Behavioral Effects of Low Level Mn Exposure

分子

• 批准号: 6433942
• 负责人: Tomas R Guilarte
• 金额: $ 90.33万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6433942
• 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）：锰（Mn）的批准用途， 汽油添加剂可能会增加这种积累 环境中的金属。长期暴露于低水平的锰可能会造成 对人类健康的风险，但不知道这可能会发生到什么程度。一 少数研究描述了人类的急性神经系统症状， 职业暴露锰类似于帕金森？S 疾病然而，无论是作用机制还是神经系统， 长期、低水平暴露于锰的后果是已知的。的目标 这个建议是描述行为，在体内神经化学， 神经病理学变化，发生由于长期暴露于低 Mn的水平。拟议研究的结果将是基本的， 了解慢性、低水平锰神经毒性的机制。 此外，这些数据将确定用于早期检测的敏感标记物， 锰神经毒性，可用于人体体内。我们建议Mn 在非人灵长类动物猕猴（恒河猴）中研究神经毒性 猴子），通过使用 前瞻性研究设计。将用正电子扫描仪进行连续的脑部成像 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）和波谱（MRS）技术，在整个 锰暴露。进行的PET/SPECT扫描的类型将取决于分子水平。 要检查的终点。核磁共振扫描会显示 Mn的分布，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 锰暴露导致的代谢变化。结束后 行为和脑成像研究，神经病理学技术将是 在死后组织上进行，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。这个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， 与评估锰对人类健康风险直接相关的研究提案 exposure.我们的长期目标是描述神经毒性相关的 与慢性低水平锰暴露的关系，并建立其基础， 作用机制。拟议的研究使用最先进的技术 将为人类风险评估提供最佳数据 以及关于汽油中锰的监管决定。拟议的研究将有助于 我们了解暴露于环境因子之间的潜在相互作用 和神经退行性疾病。