NEUROTOXICITY OF METHYLMERCURY ACROSS THE LIFESPAN

描述：(改编自申请者摘要)胎儿暴露于 甲基汞(MeHg)对感觉运动功能有长期影响， 时间表控制的行为、学习(不是记忆)和对某些东西的敏感度 行为活性药物。人类和动物研究现在将发育 或成年甲基汞暴露与年龄相关的某些行为下降 功能。营养影响也会改变汞的神经毒性，尽管 这些在整个生命周期中是如何相互作用的还不是很清楚。这是 这在机械上很重要，也因为人们担心甲基汞的低RfD 将减少鱼类的消费量，鱼类是硒和n-3脂肪酸的来源， 尤其是二十二碳六酸(DHA)。在以前的工作中，吃食物的老鼠 每天摄入40或500毫克/公斤汞(以甲基汞计)显示出年龄和剂量相关 高操纵性行为减少，学习迟缓和改变 对苯丙胺和戊巴比妥敏感。拟议的研究延长了这些 年龄和饮食对甲基汞神经行为影响的观察 毒性。将使用改进的程序检查高比率操作者的行为 (目标百分位数时间表)保持高响应率，但没有 如果行为恶化，则降低增强率。并发调度 过渡中的绩效，现在可以在单一的会议中进行，将 做学习的标尺。固定间隔(FI)调度性能将 检查本身并将其作为药物挑战的基线。雌性大鼠将开始 两人的三种饮食之一(改良的半纯、富DHA、富Se) 几周，然后是甲基汞暴露(0。0.5，或饮用水中的5ppm)两周， 然后它们就会交配。母鼠将继续喂食汞和 暴露于30个月龄，并在有针对性的情况下检查它们的行为 配筋的百分位表。在此期间，他们将收到 精选的毒品挑战。在死亡时血液和脑中的汞水平，硒(in 将检查DHA队列中的Se队列)和DHA队列。后代将会是 维持在不同的日粮上，用途如下：1)汞和硒或脂肪酸 简档确定PN1；2)药物过渡中的FI计划执行情况 挑战：3)目标百分比时间表性能，4)并发 在应对药物挑战的过渡中安排表演。项目2-4将是 作为成年人和3-4至30个月大的婴儿。死亡时汞和Se或 FA概况将根据队列的不同而确定。

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.