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

PCB 和 PBDE 对反应抑制的三个不同组成部分的影响

基本信息

批准号：
8473215
负责人：
Paul A Eubig
金额：
$ 13.04万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-08 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473215
关键词：
Affect Animals Area Attention deficit hyperactivity disorder Basal Ganglia Behavioral Brain Brain region Cannulas Catecholamines Chemicals Child Childhood Clinical Cognitive Cognitive deficits Corpus striatum structure Development Disease Dopamine Dopamine D2 Receptor Dopaminergic Agents Dorsal Dose Drug usage Environment Environmental Pollution Evaluation Exhibits Exposure to Extinction (Psychology)Fishes Flame Retardants Foxes Future Goals Human Infusion procedures Laboratories Lead Learning Literature Long-Evans Rats Measures Medial Mediating Modeling Molecular Structure Neurotransmitters Norepinephrine Nucleus Accumbens Performance Pharmaceutical Preparations Polychlorinated Biphenyls Population Prefrontal Cortex Principal Investigator Problem behavior Process Psychological reinforcement Rattus Reaction Time Regulation Reporting Research Risk Estimate Rivers Rodent Model Role Series Signal Pathway Signal Transduction Synapses System Time Western Blotting discounting dopamine transporter dosage executive function frontal lobe human tissue insight neurochemistry neurotransmission noradrenaline transporter noradrenergic phenyl ether postsynaptic premature protein expression receptor research study response uptake vesicular monoamine transporter 2

项目摘要

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.

描述(由申请人提供) 尽管已不再用于商业用途，但多氯联苯仍在环境中存在，对一些人类人群来说，暴露仍然很严重。与此同时，多溴二苯醚阻燃剂(PBDEs)的环境水平呈指数级增长。多溴联苯醚在化学上类似于多氯联苯，因此潜在的相加效应是一个令人担忧的问题。多氯联苯/多溴二苯醚的不良神经发育影响正得到越来越广泛的认识，但需要更好地定义。暴露于多氯联苯的动物和儿童在需要抑制性控制的几项学习任务中表现出缺陷，但导致这些缺陷的潜在过程尚不清楚。对发育过程中多氯联苯暴露所损害的抑制控制的具体方面以及这些影响背后的神经化学机制进行更仔细的评估，将有助于更好地全面了解与多氯联苯暴露相关的认知缺陷。拟议的研究将与主要赞助商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/多溴二苯醚的认知影响。目前建议的具体目标是：1)使用啮齿动物模型来评估发育过程中暴露于多氯联苯、多溴联苯醚或两者对反应抑制的3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反应的能力，以及对强化延迟的容忍能力；2)使用全身和直接的颅内药物挑战，以更好地了解多巴胺和去甲肾上腺素神经传递的扰动在调节多氯联苯/多溴联苯醚暴露对反应抑制的这些具体方面的影响中的作用；3)用免疫印迹分析技术定量检测儿茶酚胺相关转运体和受体在特定脑区反应抑制中的表达，以进一步明确发育过程中多氯联苯/多溴二苯醚暴露所引起的突触变化。这一结果将对评估持续暴露于这些无处不在的环境污染物的人类人口的风险具有重要意义。由于抑制控制的类似问题也出现在患有注意缺陷多动障碍的儿童中，因此这一结果也可能有助于更好地理解这种常见的儿童障碍。