NEUROTOXICITY OF METHYLMERCURY ACROSS THE LIFESPAN

描述：（改编自申请人摘要）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 行为活性药物人类和动物研究现在将发育 或成年人接触甲基汞后，某些行为能力与年龄相关下降， 功能协调发展的营养的影响也会改变汞的神经毒性， 它们在整个生命周期中如何相互作用还不清楚。这是 这一点在机理上很重要，因为人们担心甲基汞的低参考剂量 会减少鱼的消费，而鱼是硒和n-3脂肪酸的来源， 特别是二十二碳六烯酸（DHA）。在之前的研究中， 摄入40或500毫克/千克/天的汞（以甲基汞计）显示出与年龄和剂量有关的 减少高速率操作行为，学习迟缓，改变 对安非他明和戊巴比妥敏感建议的研究扩展了这些 通过检查年龄和饮食作为甲基汞神经行为修饰剂的观察结果 毒性高率操作行为将使用一个完善的程序进行检查 （目标百分比时间表），保持高响应率，但不 如果行为恶化，则降低强化率。并发调度 过渡期的业绩，现在可以在单次会议上进行， 成为学习的衡量标准。固定间隔（FI）时间表性能将是 检查本身并作为药物挑战的基线。雌鼠会开始 三种饮食（改良半纯化、富含DHA、富硒）中的一种， 周，然后接触MeHg（0. 0.5，或饮用水中5 ppm）持续两周， 然后它们就会交配母鼠将继续饮食和汞 暴露于30个月的年龄，他们的行为检查下，有针对性的 百分强化计划在此期间，他们将收到 选择药物挑战。在死亡时，血液和大脑中的汞水平，硒（ Se组群）和DHA组群中的DHA）。后代将是 维持在不同的饮食和使用如下：1）汞和硒或FA 特征确定PN 1; 2）药物过渡期间的FI时间表性能 挑战：3）目标百分比计划绩效，以及4）并发 在药物挑战的过渡期安排表现。项目2-4将是 作为成年人和3-4至30个月的年龄进行。死亡时Hg和Se或 将根据队列确定FA特征。

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.