Effects of PCBs and PBDEs on Three Distinct Components of Response Inhibition

描述（由申请人提供） 虽然多氯联苯已不再用于商业用途，但它仍存在于环境中，对某些人群来说，接触多氯联苯的情况仍然很严重。 与此同时，多溴二苯醚阻燃剂（PBDEs）的环境水平呈指数级增长。 多溴二苯醚在化学上与多氯联苯相似，因此可能产生叠加效应，这是一个令人关切的问题。多氯联苯/多溴二苯醚对神经发育的不利影响正得到越来越广泛的认识，但需要更好地界定。 接触多氯联苯的动物和儿童在几项需要抑制控制的学习任务上表现出缺陷，但导致这些缺陷的基本过程还不清楚。 更密切的评价的具体方面的抑制控制受损的发展PCB暴露和神经化学机制，这些影响将导致更好地全面了解与PCB暴露的认知缺陷。拟议的研究将与主要赞助者实验室正在进行的研究同时进行，这些研究的重点是了解多氯联苯/多溴二苯醚对认知的影响。目前建议的具体目标是：1）使用啮齿动物模型评估发育过程中接触多氯联苯、多溴二苯醚或两者对反应抑制的三个不同方面的影响-抑制不必要或过早反应的能力、一旦反应开始就停止的能力以及容忍延迟强化的能力; 2）使用全身和直接颅内药物激发，以更好地了解多巴胺和去甲肾上腺素神经传递中的扰动在介导多氯联苯/多溴二苯醚暴露对这些特定反应抑制方面的影响方面的作用;以及3）使用蛋白质印迹分析来量化对于反应抑制重要的特定脑区域中的儿茶酚胺相关转运蛋白和受体的表达，以便进一步确定发育中暴露于PCB/PBDE时发生的突触变化。 这些结果对于估计持续暴露于这些无处不在的环境污染物的人群的风险将是重要的。由于在注意缺陷多动障碍儿童中也发现了类似的抑制控制问题，因此该结果也有助于更好地理解这种常见的儿童疾病。

DESCRIPTION (provided by applicant) Although no longer used commercially, polychlorinated biphenyls (PCBs) persist in the environment and exposure is still significant for some human populations. Meanwhile, the environmental levels of polybrominated diphenyl ether flame retardants (PBDEs) are increasing exponentially. PBDEs are chemically similar to PCBs, making the potential for additive effects a concern. The adverse neurodevelopmental effects of PCBs/PBDEs are becoming more widely recognized, but need to be better defined. Animals and children exposed to PCBs exhibit deficits on several learning tasks that require inhibitory control, but the underlying processes responsible for these deficits are not well understood. Closer evaluation of the specific aspects of inhibitory control impaired by developmental PCB exposure and the neurochemical mechanisms underlying these effects will lead to a better overall understanding of the cognitive deficits associated with PCB exposure. The proposed studies will be conducted in parallel with ongoing studies in the primary sponsor's laboratory which focus on understanding the cognitive effects of PCBs/PBDEs. The specific aims of the current proposal are 1) to use a rodent model to assess the effects of developmental exposure to PCBs, PBDEs or both on 3 distinct aspects of response inhibition - the ability to inhibit unnecessary or premature responding, the ability to stop a response once it has been initiated, and the ability to tolerate a delay in reinforcement; 2) to use systemic and direct intracranial drug challenges to gain a better understanding of the role of perturbations in dopamine and norepinephrine neurotransmission in mediating the effects of PCB/PBDE exposure on these specific aspects of response inhibition; and 3) to use western blot analysis to quantify expression of catecholamine-related transporters and receptors in specific brain regions important for response inhibition in order to further define the synaptic changes that occur with developmental PCB/PBDE exposure. The results will be important in estimating risk to human populations that have ongoing exposure to these ubiquitous environmental contaminants. Because similar problems with inhibitory control are seen in children with attention deficit hyperactivity disorder, the results may also contribute to a better understanding of this common childhood disorder.