BEHAVIORAL TERATOLOGY OF METHYLMERCURY

甲基汞的行为畸胎学

• 批准号: 2155314
• 负责人: Marshall CHRISTOPHER NEWLAND
• 金额: $ 11.78万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-01 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2155314
• 关键词: age difference; animal developmental psychology; behavior test; developmental neurobiology; dosage; embryo /fetus toxicology; environmental toxicology; laboratory rat; longitudinal animal study; mercury poisoning; methylmercury; neurochemistry; neurotoxins; operant conditionings; stimulus /response; teratogens

Methylmercury is neurotoxic to the developing organism. Human and animal studies concur on methylmercury's sensory, motor, and' cognitive effects after acute or transient exposure to high levels. Exposure to very low levels can produce subtle but detectable and long-lasting effects on the behavior of offspring. Studies with rodents had used exposure levels ranging from 0.5 to 10 mg/kg/day with one or a few administrations during gestation, but several investigators have reported effects on operant behavior at levels as low as 0.05 mg/kg/day. In a recent study conducted by the PI in collaboration with the Institute for Hygiene, Lund University, Sweden, monkeys showed delayed effects of prenatal methylmercury exposure in behavior maintained by concurrent schedules of reinforcement. Severe learning deficits were manifested in behavior during transition states in monkeys that appeared normal and even behaved normally on more conventional, steady-state baselines. The proposed studies build on those observations in a new species and examine low levels of exposure. Rats will be exposed to 0, 0.05, or 0.5 mg/kg/day of methylmercury during gestation. When adults, lever-pressing will be maintained under concurrent schedules of reinforcement in which a rich lever produces reinforcement at a higher rate than the lean one. When the schedules on the levers are reversed, behavior shifts to the newly rich lever but, in preliminary studies, more slowly in exposed animals. Behavior change is quantified by fitting a logistic function to measures of responding taken as the transition progresses. The resulting parameters are used in developing dose-effect relationship and identifying behavioral and neural mechanisms of neurotoxicity. The proposed studies are designed to I) replicate in rats the effects reported in monkeys 2) examine a refinement recently developed by the PI to shorten transitions from 4 weeks to I day, 3) identify environmental moderators of methylmercury's effects, 4) probe for neurochemical mechanisms of damage and 5) identify sensitivity of aged animals. This proposal is a modification of one previously submitted and the modifications entail 1) eliminating parallel studies conducted with monkeys in Lund, 2) developing rapid transitions, and 3) detailed examination of other determinants of methylmercury 's developmental neurotoxicity.

甲基汞对发育中的生物具有神经毒性。人类和动物 研究同意甲基汞的感觉，运动和认知效应 急性或短暂暴露在高水平之后。暴露于非常低的 水平可以对 后代的行为。啮齿动物的研究使用了暴露水平 范围从0.5至10 mg/kg/天，在一个或几个范围内 妊娠，但有几位调查人员报告了对操作员的影响 低至0.05 mg/kg/天的行为。 在PI与研究所合作进行的一项最新研究中 对于卫生，伦敦大学，瑞典，猴子表现出延迟的影响 通过并发维持的行为中的产前甲基汞暴露 加固的时间表。严重的学习缺陷在 在猴子中过渡状态的行为，猴子看起来正常， 甚至通常在更常规的稳态基线上行事。这 拟议的研究以新物种的观察为基础 暴露水平低。大鼠将暴露于0、0.05或0.5 mg/kg/天 妊娠期间的甲基汞。成人时，杠杆压榨将是 在同时安排的加固计划下保持富人 杠杆产生的增强速度比瘦的速度更高。什么时候 杠杆上的时间表被颠倒，行为转移到新的富人 杠杆，但在初步研究中，暴露的动物较慢。 通过将逻辑函数拟合到措施来量化行为改变 随着过渡的进展而做出的响应。结果 参数用于发展剂量效应关系和 确定神经毒性的行为和神经机制。 拟议的研究设计为i）在大鼠中复制效果 在猴子2）检查了PI最近开发的细化 要缩短从4周到我的一天，3）确定环境 甲基汞作用的主持人，4）探针对神经化学 损害的机制和5）确定年龄动物的灵敏度。这 提案是对先前提交的一个修改， 修改需要1）消除与 隆德中的猴子，2）发展快速过渡，3）详细 检查甲基汞发育的其他决定因素 神经毒性。