Project 3: Molecular/Disease Consequences of Prenatal BPA, PAH Expos. Across Gene

项目 3：产前 BPA、PAH 暴露的分子/疾病后果。

• 批准号: 8890288
• 负责人: FRANCES A. CHAMPAGNE
• 金额: $ 7.82万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8890288
• 关键词: 5 year old; Adipocytes; Adipose tissue; Adolescent; Adult; Adult Children; Affect; Air Pollutants; Anxiety; Aromatic Polycyclic Hydrocarbons; Automobile Driving; B-Lymphocytes; Behavior; Behavioral; Biological; Biological Markers; Blood; Body Weight; Body fat; Body mass index; Brain; Brain region; Breathing; Breeding; Child; Child health care; Cognitive; Complement; DNA; DNA Methylation; Data; Development; Diet; Disease; Disease Outcome; Endocrine Disruptors; Endocrine disruption; Environment; Environmental Exposure; Environmental Health; Epidemiologic Studies; Epigenetic Process; Exposure to; Fatty acid glycerol esters; Female; Fetal Development; Functional disorder; Gene Expression; Generations; Genes; Health; Hereditary Disease; Hippocampus (Brain); Human; Hypothalamic structure; Immune; Immune System Diseases; Immune response; Immunoglobulins; Immunologics; Impairment; Infant; Inflammation; Intervention; Lead; Learning; Link; Long-Term Effects; Measures; Mediating; Messenger RNA; Metabolism; Methylation; Modification; Molecular; Molecular Target; Monitor; Mothers; Mus; Neurobiology; Neurocognitive; Neurodevelopmental Deficit; New York City; Obesity; Oral; Organ; Outcome; Pathway interactions; Performance; Physiological; Play; Pregnancy; Production; Publishing; RNA; Regulation; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Risk Assessment; Sampling; Simulate; Social Interaction; T-Lymphocyte; Testing; Tissues; Translations; Weaning; Weight; Work; aerosolized; base; behavior test; bisphenol A; bisulfite; brain tissue; clinical effect; clinically significant; cognitive function; cohort; cytokine; depressive symptoms; design; effective intervention; epigenetic marker; immune function; improved; lipid biosynthesis; male; mouse model; neurobehavioral; neurodevelopment; novel; novel strategies; offspring; postnatal; prenatal; prenatal environmental exposure; prenatal exposure; prevent; pyrosequencing; research study; social

The objective of this proposal is to determine the mechanism by which prenatal exposure to environmentally relevant levels of the endocrine disrupting chemicals bisphenol A (BPA) and polycyclic aromatic hydrocarbons (PAHs) exert long-term effects on neurobiology, metabolism, immune function and behavior. We propose to examine prenatal exposure to BPA (oral) and PAH (inhaled) in Balb/c mice using a transgenerational breeding design in which the effects can be examined in Fl offspring and F2 grand-offspring. This proposal intends to determine the distinct effects of prenatal BPA and PAH exposure on DNA methylation and gene expression in several tissues (hippocampus, hypothalamus, brain cortex, adipocytes and blood) and the association of these molecular changes with neurobiological and physiological outcomes. Exposure will occur throughout gestation and postnatal mother-infant interactions will be assessed as a potential modulating influence on offspring development. Assessment of male and female Fl and F2 offspring will include weight monitoring, homecage social interactions (PND 30-40), anxiety-like behavior (PND 40), and cognitive functioning (PND 44-60). Adiposity will be quantified following behavioral testing and in the case of BPA exposure, additional exposure groups will be included to examine immune function. Exposure-induced changes in brain cytoarchitecture will be quantified in Fl and F2 offspring at PND 40. The molecular mechanisms driving these effects will be assessed in offspring tissue during fetal development (GD 19) and in adulthood (PND 60). The selection of molecular targets will be based on the results of analysis of tissue collected from the Columbia Center for Children's Environmental Health (CCCEH) cohort with particular focus on genes involved in neurodevelopment and obesity. Methylation analysis will involve pyrosequencing of bisulphite treated DNA samples with mRNA analysis achieved through quantitative RT-PCR. Overall, these studies are designed to confirm and validate the biomarkers determined in the CCCEH human studies of BPA and PAH exposure and to determine the hypothesized link between epigenetic changes in blood with those determined in brain and adipose tissue to determine the possible mechanistic pathways through which long-term effects of exposure are mediated.

该提案的目的是确定产前暴露于环境的机制 内分泌干​​扰化学物质A（BPA）和多环芳烃的相关水平 （PAHS）对神经生物学，代谢，免疫功能和行为产生长期影响。我们建议 使用跨代育种检查BALB/C小鼠中BPA（口服）和PAH（吸入）的产前暴露 可以在FL后代和F2大弹簧中检查效果的设计。该提议打算 确定产前BPA和PAH暴露对DNA甲基化和基因表达的独特影响 几个组织（海马，下丘脑，脑皮质，脂肪细胞和血液），这些结合 神经生物学和生理结果的分子变化。暴露会在整个妊娠期间发生 和产后母互动将被评估为对后代的潜在调节影响 发展。对男性和女性FL和F2后代的评估将包括体重监测，归乡 社交互动（PND 30-40），焦虑般的行为（PND 40）和认知功能（PND 44-60）。 在行为测试和BPA暴露的情况下，肥胖将被量化 将包括组以检查免疫功能。暴露引起的大脑细胞结构变化将 在PND 40处用FL和F2后代进行量化。将评估驱动这些效果的分子机制 在胎儿发育期间（GD 19）和成年期（PND 60）中的后代组织中。分子的选择 目标将基于从哥伦比亚儿童中心收集的组织分析的结果 环境卫生（CCCEH）队列，特别关注与神经发育的基因和 肥胖。甲基化分析将涉及用mRNA进行双足石处理的DNA样品的旋转测序 通过定量RT-PCR实现的分析。总体而言，这些研究旨在确认和验证 在BPA和PAH暴露的CCCEH人类研究中确定的生物标志物，并确定 假设的血液表观遗传变化与脑确定的脂肪组织和脂肪组织的表观遗传变化之间的联系 确定介导的长期影响的可能机械途径。