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.

抽象的 驻扎在北卡罗来纳州莱吉恩营地的一百万个人可能被毒死 接触挥发性有机化合物（VOC），这些化合物已进入基础饮用水 从1953年至1987年。VA现在涵盖了Lejeune Camp退伍军人，平民的健康费用 员工和居民家庭在那段时间内驻扎在基地 疾病，包括帕金森氏病（PD）。尽管如此，在 毒性作用，三氯乙烯（TCE）和四氯乙烯（PCE）尚未显示 在饮酒中引起的PD以内的PD在100倍之内 水。当下给啮齿动物时，TCE可能会在很高的水平上引起PD，并且PCE 仅建议将动物模型与TCE结合时引起PD。 过去研究中使用的持续时间和TCE或PCE的剂量均未近似camp Lejeune平均暴露估计。因此，该试点项目的目标是记录 慢性TCE（有或没有PCE）暴露所必需的基本参数会导致 长期在水中递送PD神经毒性的行为和生物学体征 供应。我们的工作假设是慢性TCE+PCE从饮用水中摄入 导致行为变化，指示尼格拉统治中潜在的神经炎症 大脑的pars comcacta（SNPC），随着持续摄入，最终导致 SNPC多巴胺（DA）神经元的神经变性（即PD的发展）。测试 通过通过评估暴露大鼠的功能和神经病理学来实现这一假设 2目标。 AIM 1将集中于确定饮用水对PD的可能贡献 病理。已建立的有毒亚基剂每日粘液剂量将在6上延长 饮用水中的月期，以确定总累积暴露预测是否 如果TCE诱导PD或每日高浓度诱导PD。遵循 类似的实验设计，AIM 2将确定在TCE污染中添加PCE是否添加 饮用水潜力PD的诱导。功能评估，通过行为测试， 将在TCE或TCE+PCE暴露期间发生。在每个时间点，老鼠将是 评估了运动配位和感觉运动反应性。最后一职完成后 暴露行为测试，所有大鼠的大脑都将用于随后的大脑 评估。将对纹状体中的DA和DA-代谢物水平进行评估，并 SNPC中的神经炎症/神经病理学。这些验尸分析，结合 随着时间的推移，反复的行为测试将提供第一个证据，如果慢性饮用水 TCE或TCE+PCE污染足以引起PD样运动障碍或 彻底的PD。