GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY

PCB 引起的发育神经毒性的遗传易感性

• 批准号: 8360118
• 负责人: Christine Perdan Curran
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360118
• 关键词: Affect; Animals; Anxiety; Aryl Hydrocarbon Receptor; Binding; Biomedical Research; Brain; Child; Control Animal; Corticosterone; Cytochrome P-450 CYP1A2; DNA; DNA Methylation; Development; Epigenetic Process; Food Chain; Funding; Gene Expression; Genes; Genetic Predisposition to Disease; Glucocorticoid Receptor; Grant; Health; Hippocampus (Brain); Hormones; Hypothalamic structure; Lactation; Learning; Memory; Memory impairment; Methylation; Methyltransferase; Mus; National Center for Research Resources; Neuraxis; Pattern; Polychlorinated Biphenyls; Predisposition; Principal Investigator; Research; Research Infrastructure; Resources; Source; Stress; Testing; United States National Institutes of Health; cost; design; developmental neurotoxicity; in utero; nervous system development; pollutant; receptor; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food chain and cause a number of adverse health effects including learning and memory deficits in children exposed in utero and during lactation. The principal investigator's previous research in mice uncovered two genes that increase susceptibility to developmental PCB exposure  the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2), a gene directly regulated by the AHR. Coplanar PCBs bind to the AHR, triggering changes in gene expression. Many of these AHR-regulated genes are involved in central nervous system development. AHR activation was also recently shown to affect the activity of DNA methylases. The glucocorticoid receptor is well known to be regulated by differential methylation, and changes in receptor levels can alter learning, memory and the response to stress. Interestingly, many pollutants that bind to the AHR produce changes in stress hormone levels or an animal's response to stress. This project was designed to test the hypothesis that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms. The specific aims were to: 1.) Compare corticosterone levels, anxiety and response to stress in PCB-treated and control animals differing at the Ahr and Cyp1a2 loci. 2.) Determine if developmental PCB exposure alters gene-specific DNA methylation patterns in the hippocampus, cortex and hypothalamus.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 多氯联苯 (PCB) 是持久性有机污染物，可在食物链中生物累积，对健康造成许多不利影响，包括子宫内和哺乳期间接触的儿童学习和记忆缺陷。首席研究员之前对小鼠的研究发现了两种增加对发育性 PCB 暴露敏感性的基因：芳基碳氢化合物受体 (Ahr) 和细胞色素 P450 1A2 (Cyp1a2)（一种由 AHR 直接调节的基因）。 共面 PCB 与 AHR 结合，引发基因表达的变化。许多 AHR 调控基因都参与中枢神经系统发育。最近还显示 AHR 激活会影响 DNA 甲基化酶的活性。众所周知，糖皮质激素受体受到差异甲基化的调节，受体水平的变化可以改变学习、记忆和对压力的反应。有趣的是，许多与 AHR 结合的污染物会导致应激激素水平或动物对应激的反应发生变化。该项目旨在验证 AHR 的持续激活会通过表观遗传机制改变正常的大脑发育和对压力的反应这一假设。具体目标是： 1.) 比较 PCB 处理动物和对照动物中 Ahr 和 Cyp1a2 位点不同的皮质酮水平、焦虑和应激反应。 2.) 确定发育过程中 PCB 暴露是否会改变海马体、皮质和下丘脑中基因特异性 DNA 甲基化模式。