BEHAVIORAL TERATOLOGY OF METHYLMERCURY

甲基汞对发育中的生物体具有神经毒性。人类和动物 关于甲基汞的感觉、运动和认知影响的研究一致 急性或短暂暴露于高浓度后。暴露于极低 水平可以产生微妙的，但可检测和持久的影响， 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 - 10 mg/kg/天，在给药期间给药一次或几次 妊娠，但一些研究人员报告了对操作性 在低至0.05 mg/kg/天的剂量水平下的行为。 在最近由PI与研究所合作进行的一项研究中， 瑞典隆德大学的卫生学研究，猴子表现出 产前甲基汞暴露对行为的影响 强化计划。严重的学习障碍表现在 猴子在过渡期的行为表现正常， 甚至在更传统的稳态基线上表现正常。的 拟议的研究建立在对一个新物种的观察基础上， 低暴露水平。大鼠将暴露于0、0.05或0.5 mg/kg/天 甲基汞中毒当成年人， 在同时进行的强化计划下， 杠杆产生强化的速度比瘦的快。当 杠杆上的时间表被颠倒了，行为转向了新富阶层 但在初步研究中，在暴露的动物中更慢。 行为变化通过将逻辑函数拟合到测量值来量化 在过渡过程中采取的应对措施所得 参数用于建立剂量-效应关系， 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 2）检查PI最近开发的改进 将过渡期从4周缩短到1天，3）确定环境 甲基汞效应的调节剂，4）神经化学物质的探针 损伤机制; 5）识别老龄动物的敏感性。这 提案是对以前提交的提案的修改， 修改包括：1）取消与下列研究进行的平行研究： 隆德的猴子，2）发展快速转变，3）详细 对甲基汞发育的其他决定因素的研究 神经毒性

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.