Volatile organic compound effects on brain and behavior

挥发性有机化合物对大脑和行为的影响

• 批准号: 10118080
• 负责人: Kevin D. Beck
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118080
• 关键词: 3-nitrotyrosine; Address; Affect; Aging; Animal Model; Area; Autopsy; Behavior; Behavior assessment; Behavioral; Biological; Brain; Chronic; Corpus striatum structure; Detection; Development; Dopamine; Dorsal; Dose; Exhibits; Experimental Designs; Exposure to; Face; Family; Goals; Gulf War; Harvest; Health; Health Care Costs; High Pressure Liquid Chromatography; Individual; Ingestion; Knowledge; Longitudinal Studies; Measures; Medical; Medical center; Methods; Microglia; Modeling; Molecular Analysis; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Nitrates; Ohio; Olive oil preparation; Oranges; Parkinson Disease; Pathology; Pilot Projects; Poison; Poisoning; Pollution; Proteins; Public Health; Publishing; Rattus; Recording of previous events; Research; Research Design; Research Personnel; Rodent; Signal Transduction; Source; Stains; Stress; Substantia nigra structure; Testing; Tetrachloroethylene; Time; Tissues; Toxic effect; Toxicology; Trichloroethylene; Tyrosine 3-Monooxygenase; Universities; Veterans; Water; Water Supply; Work; base; behavior test; brain behavior; brain tissue; contaminated drinking water; contaminated water; disease registry; dopaminergic neuron; dosage; drinking water; exposed human population; ground water; health assessment; motor impairment; neurobehavioral; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; nigrostriatal pathway; pars compacta; programs; response; volatile organic compound

Abstract Up to one million individuals stationed at Camp Lejeune, NC may have been poisoned by exposure to volatile organic compounds (VOCs) that had leached into the base drinking water from 1953 – 1987. The VA is now covering the health costs for Camp Lejeune veterans, civilian staff, and the resident families stationed at the base during that time for a variety of health conditions, including Parkinson's Disease (PD). Still, two of the main contaminants implicated in the toxic effects, trichloroethylene (TCE) and tetrachloroethylene (PCE), have yet to be shown to cause PD at the levels within 100-fold of those documented to have existed in the drinking water. TCE can cause PD at very high levels when given sub-chronically to rodents, and PCE has only been suggested to elicit PD in the animal models when it is combined with TCE. Neither the duration nor the dose of TCE or PCE used in past studies approximated the Camp Lejeune average exposure estimates. Therefore, the goal of this pilot project is to document the basic parameters necessary for chronic TCE (with and without PCE) exposure to cause behavioral and biological signs of PD neurotoxicity when delivered chronically in the water supply. Our working hypothesis is that chronic TCE+PCE ingestion through drinking water leads to behavioral changes indicative of underlying neuroinflammation in the substantia nigra pars compacta (SNPC) of the brain that, with continued ingestion, eventually leads to neurodegeneration of the SNPC dopamine (DA) neurons (i.e. development of PD). The testing of this hypothesis will occur by assessing function and neuropathology in exposed rats through 2 aims. Aim 1 will focus upon determining the possible contribution of drinking water TCE to PD pathology. An established toxic sub-chronic daily gavage TCE dose will be extended over a 6 month period in the drinking water to determine if the total cumulative exposure predicts the induction of PD or if daily high concentrations are necessary for TCE to induce PD. Following a similar experimental design, Aim 2 will determine if the addition of PCE to TCE-contaminated drinking water potentiates the induction of PD. Functional assessments, via behavioral testing, will occur during and following TCE or TCE+PCE exposure. At each time-point, rats will be assessed for motor coordination and sensorimotor reactivity. Upon completion of the last post- exposure behavioral test, all rats will have their brains harvested for subsequent brain assessments. The brains will be assessed for DA and DA-metabolite levels in the striatum and neuroinflammation/neuropathology in the SNPC. These post-mortem analyses, combined with the repeated behavioral testing over time, will provide the first evidence if chronic drinking water contamination by TCE or TCE+PCE are sufficient to cause a PD-like motor impairments or outright PD.

摘要 驻扎在北卡罗来纳州勒琼营地的多达100万人可能被 接触渗入基础饮用水的挥发性有机化合物(VOCs) 从1953年到1987年。退伍军人管理局现在为勒琼营地的老兵、平民支付医疗费用 工作人员，以及在此期间驻扎在基地的居民家庭的各种健康 疾病，包括帕金森氏病(PD)。尽管如此，牵涉到的两种主要污染物 三氯乙烯(TCE)和四氯乙烯(PCE)的毒性作用尚未显示出来 导致帕金森病的水平是记录在案的饮酒中帕金森病患者的100倍 水。当亚慢性给予啮齿动物时，TCE可导致非常高的PD水平，以及PCE 只有当它与三氯乙烯联合使用时，才被建议在动物模型中诱发帕金森病。 过去研究中使用的TCE或PCE的持续时间和剂量都与Camp相似 Lejeune平均风险敞口估计。因此，该试点项目的目标是记录 慢性接触三氯乙烯(有无四氯乙烯)所需的基本参数 钯在水中慢性中毒的行为和生物迹象 供给。我们的工作假设是通过饮用水慢性摄入TCE+PCE 导致行为改变，表明黑质潜在的神经炎症 大脑的致密部(SNPC)，随着持续的摄入，最终导致 SNPC多巴胺(DA)神经元的神经变性(即发展为帕金森病)。测试 通过评估暴露大鼠的功能和神经病理来实现这一假说 2目标。目标1将重点确定饮用水中三氯乙烯对帕金森病的可能贡献 病理学。已建立的毒性亚慢性每日灌胃TCE剂量将延长至6 在饮用水中的一个月期间，以确定总累积暴露是否预测 诱导帕金森病或如果每天的高浓度是三氯乙烯诱发帕金森病所必需的。在此之后 类似的实验设计，目标2将确定在三氯乙烯污染中添加四氯乙烯 饮用水可增强帕金森病的诱发作用。功能评估，通过行为测试， 将发生在TCE或TCE+PCE暴露期间和之后。在每个时间点，老鼠都会被 评估运动协调性和感觉运动反应性。在完成最后一个帖子后- 暴露行为学测试，所有大鼠的大脑将被采集用于后续的大脑 评估。将评估大脑纹状体和大脑中DA代谢物的水平。 SNPC的神经炎症/神经病理学。这些尸检分析结合了 随着时间的推移，反复的行为测试，将提供第一个证据，如果长期饮用 TCE或TCE+PCE的污染足以导致帕金森病样运动障碍或 彻头彻尾的警察。