BEHAVIORAL TERATOLOGY OF METHYLMERCURY

甲基汞的行为畸胎学

• 批准号: 2377905
• 负责人: Marshall CHRISTOPHER NEWLAND
• 金额: $ 9.12万
• 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 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2377905
• 关键词: age difference; animal developmental psychology; behavior test; behavioral /social science research tag; 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.

甲基汞对发育中的有机体具有神经毒性。人类和动物 研究一致认为甲基汞对感觉、运动和认知有影响 急性或短暂接触高浓度后。暴露程度极低 水平可以对身体产生微妙但可检测且持久的影响 后代的行为。对啮齿动物的研究使用了暴露水平 范围为 0.5 至 10 mg/kg/天，期间一次或几次给药 妊娠，但一些研究人员报告了对操作的影响 低至 0.05 毫克/公斤/天的水平下的行为。 在 PI 与该研究所合作进行的一项最新研究中 瑞典隆德大学的卫生学研究显示，猴子表现出延迟效应 产前甲基汞暴露影响同时维持的行为 强化计划。严重的学习缺陷表现在 猴子在过渡状态期间的行为看似正常 甚至在更传统的稳态基线上也表现正常。这 拟议的研究以新物种的观察为基础，并检查 低水平的暴露。大鼠每天将接触 0、0.05 或 0.5 毫克/公斤 妊娠期间的甲基汞。成年后，按下杠杆会 维持在并发的强化计划下，其中丰富的 杠杆产生强化的速度比精益杠杆更高。当 杠杆上的时间表被逆转，行为转向新贵 但在初步研究中，在暴露的动物中，速度更慢。 通过将逻辑函数拟合到测量值来量化行为变化 随着过渡的进展而做出的回应。由此产生的 参数用于建立剂量效应关系和 识别神经毒性的行为和神经机制。 拟议的研究旨在 I) 在大鼠中复制效果 在猴子中报告 2) 检查 PI 最近开发的改进 为了缩短从 4 周到 I 天的过渡，3) 确定环境 甲基汞效应的调节剂，4) 神经化学探针 损伤机制；5) 确定老年动物的敏感性。这 提案是对先前提交的提案的修改，并且 修改需要 1) 消除进行的平行研究 隆德的猴子，2）发展快速转变，3）详细 甲基汞发育的其他决定因素的检查 神经毒性。