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.

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