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: 8168298
• 负责人: Christine Perdan Curran
• 金额: $ 3.36万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168298
• 关键词: Affect; Affinity; Aryl Hydrocarbon Receptor; Attenuated; Behavioral; Brain; Breast Feeding; CYP1A2 gene; Child; Computer Retrieval of Information on Scientific Projects Database; Construction Materials; Cytochrome P-450 CYP1A2; DNA; DNA Methylation; Development; Epigenetic Process; Fishes; Food Supply; Funding; Genes; Genetic; Genetic Predisposition to Disease; Glucocorticoid Receptor; Grant; Health; Home environment; Human; Individual; Institution; Kentucky; Learning; Memory; Methyltransferase; Mus; Phenotype; Polychlorinated Biphenyls; Predisposition; Pregnancy; Research; Research Personnel; Resources; Schools; Site; Source; Stress; Testing; United States National Institutes of Health; Wood material; developmental neurotoxicity; experience; exposed human population; high risk; human population study; mouse model; novel; pollutant; prenatal stress; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that bio-accumulate in the food supply and resist environmental degradation. In September 2008, Kentucky identified numerous waterways where PCB-contaminated fish remain a human health concern. Recently, new sources of human exposure have been identified including wood treatments and construction materials used in older homes and schools. Studies of human populations near the most polluted sites have found learning, memory and behavioral abnormalities in children exposed during pregnancy and breast-feeding. Not all exposed individuals experience the same level of adverse health effects, indicating that genetic differences are important in determining who is at highest risk. The applicant previously used a novel mouse model to identify two genes which affect susceptibility to PCB exposure during brain development: the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2). PCB-treated mice with a high-affinity AHR and lacking CYP1A2 showed deficits in tests of spatial and non-spatial learning and memory and an attenuated startle response. Prenatal stress can produce a similar behavioral phenotype in conjunction with reduced expression of the glucocorticoid receptor and related genes regulated by DNA methylation. AHR activation was recently shown to increase the activity of DNA methylases. Therefore, we hypothesize that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 多氯联苯 (PCB) 是持久性有机污染物 (POP)，可在食品供应中生物累积并抵抗环境退化。 2008 年 9 月，肯塔基州确定了许多水道中受多氯联苯污染的鱼类仍然是人类健康问题。最近，已经确定了新的人类接触源，包括旧住宅和学校使用的木材处理和建筑材料。对污染最严重地点附近人群的研究发现，怀孕和哺乳期间受到污染的儿童的学习、记忆和行为异常。并非所有暴露的个体都会遭受相同程度的不良健康影响，这表明遗传差异对于确定谁的风险最高非常重要。申请人之前使用一种新型小鼠模型来鉴定两个影响大脑发育过程中对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）。经过 PCB 处理的具有高亲和力 AHR 且缺乏 CYP1A2 的小鼠在空间和非空间学习和记忆测试中表现出缺陷，并且惊吓反应减弱。产前应激可产生类似的行为表型，同时糖皮质激素受体和受 DNA 甲基化调节的相关基因的表达减少。最近显示 AHR 激活可以增加 DNA 甲基化酶的活性。因此，我们假设 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。