NEUROTOXICITY OF METHYLMERCURY ACROSS THE LIFESPAN

甲基汞在整个生命周期中的神经毒性

• 批准号: 6518206
• 负责人: Marshall CHRISTOPHER NEWLAND
• 金额: $ 35.75万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518206
• 关键词: dietary lipid; dietary mineral; embryo /fetus toxicology; laboratory rat; learning disorders; methylmercury; neuroprotectants; neurotoxicology; neurotransmitter agonist; neurotransmitter antagonist; nutrition related tag; omega 3 fatty acid; operant conditionings; selenium

DESCRIPTION: (ADAPTED FROM APPLICANT'S ABSTRACT) Fetal exposure to methylmercury (MeHg) has long-lasting effects on sensory-motor function, schedule-controlled behavior, learning (not memory) and sensitivity to certain behaviorally active drugs. Human and animal studies now associate developmental or adult MeHg exposure with age-related declines in certain behavioral functions. Nutritional influences also modify mercury's neurotoxicity, although how these interact through the lifespan is not well understood. This is important both mechanistically and because of concerns that a low RfD for MeHg would decrease consumption of fish, a source of selenium and n-3 fatty acids, especially docosahexanoic acid (DHA). In previous work, rats on a chow diet consuming 40 or 500 mg/kg/day Hg (as MeHg) showed age- and dose-related decrements on high-rate operant behavior, retarded learning, and altered sensitivity to amphetamine and pentobarbital. Proposed studies extend these observations by examining age and diet as modifiers of MeHg's neurobehavioral toxicity. High-rate operant behavior will be examined using a refined procedure (targeted percentile schedule) that maintains high response rates but without lowering reinforcement rates if behavior deteriorates. Concurrent schedule performance in transition, which now can be conducted in single sessions, will be the measure of learning. Fixed-interval (FI) schedule performance will be examined per se and as a baseline for drug challenges. Female rats will start one of three diets (modified semipurified, DHA-enriched, Se-enriched) for two weeks, then MeHg exposure (0. 0.5, or 5 ppm in drinking water) for two weeks, then they will be mated. Maternal rats will continue the diets and mercury exposure to 30 months of age, and their behavior examined under a targeted percentile schedule of reinforcement. During this time they will receive selected drug challenges. At death mercury levels in blood and brain, Se (in the Se cohort) and DHA in the DHA cohort) will be examined. Offspring will be maintained on the different diets and used as follows: 1) Hg and Se or FA profile determination PN1; 2) FI schedule performance in transition with drug challenges: 3) Targeted percentile schdule performance, and 4) Concurrent schedule performance in transition with drug challenges. Items 2-4 will be conducted as adults and 3-4 to 30 months of age. At death Hg and either Se or FA profiles will be determined, depending on the cohort.

描述：（改编自申请人的摘要）胎儿暴露于 甲基汞（MEHG）对感觉运动功能具有长期影响， 计划控制的行为，学习（不是记忆）和对某些人的敏感性 行为活跃的药物。人类和动物研究现在使发展 或成人MEHG暴露，与年龄有关的某些行为下降 功能。营养影响还可以改变汞的神经毒性，尽管 这些在寿命中如何相互作用尚不清楚。这是 机械上的重要以及由于担心MEHG的较低RFD 将减少鱼类的消耗，这是硒和N-3脂肪酸的来源， 特别是二十六烷酸（DHA）。在以前的工作中，大鼠饮食 消耗40或500 mg/kg/day hg（如MEHG）显示与年龄和剂量有关 减少高速操作行为，学习迟缓和改变 对苯丙胺和戊巴比妥的敏感性。拟议的研究扩展了这些 通过检查年龄和饮食作为MEHG神经行为的改良剂来观察 毒性。将使用精制过程检查高速运营行为 （目标百分比时间表）保持较高的响应率但没有 如果行为恶化，则降低增强率。并发时间表 现在可以在单一会话中进行的过渡表现，将 成为学习的衡量标准。固定间隔（FI）时间表的表现将是 研究本身是毒品挑战的基准。雌鼠将开始 三种饮食之一（修改半纯化的，富含DHA的饮食），用于两种 几周，然后MEHG暴露（0。0.5或饮用水中5 ppm）持续了两个星期， 然后他们将交配。孕产妇将继续饮食和汞 暴露于30个月大，其行为在有针对性的情况下检查 增强百分比时间表。在此期间，他们会收到 选定的毒品挑战。在血液和大脑中死亡的汞水平，se（在 将检查DHA队列中的SE COHORT）和DHA）。后代将是 维持不同的饮食，使用如下：1）HG和SE或FA 轮廓确定PN1; 2）FI使用药物过渡时表现表现 挑战：3）针对性的百分比schdule性能，4）并发 安排在过渡中与毒品挑战的表现。项目2-4将是 作为成年人和3-4至30个月大。在死亡HG和SE或 根据队列，将确定FA轮廓。