Prenatal PAH Exposure, Epigenetic Changes, and Asthma

产前 PAH 暴露、表观遗传变化和哮喘

• 批准号: 8279275
• 负责人: FREDERICA P PERERA
• 金额: $ 55.57万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279275
• 关键词: Address; Age; Animal Model; Aromatic Polycyclic Hydrocarbons; Asthma; Biological Markers; Biological Markers; Blood; Candidate Disease Gene; Child; Childhood; Childhood Asthma; Clinical; Cohort Studies; Communities; DNA Methylation; Data; Epigenetic Process; Exposure to; Gene Expression; Genes; Human; Leukocytes; Link; Measures; Methylation; Minority; Mus; New York City; Outcome; Participant; Pathogenesis; Pathway interactions; Phenotype; Pilot Projects; Placenta; Process; Research; Risk; Risk Factors; Role; Sampling Studies; Source; Spleen; Structure of parenchyma of lung; Testing; Tissues; Umbilical Cord Blood; aged; air sampling; clinically relevant; cohort; in utero; innovation; offspring; pollutant; pregnant; prenatal; prenatal exposure; programs; prospective; trafficking

This highly innovative project addresses the role of epigenetic changes in the pathogenesis of childhood asthma. There is growing evidence, some from our own research, that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs), common urban pollutants from traffic and other combustion sources, may be a risk factor for asthma in childhood. Following up on a recent pilot study that demonstrated proof of orinciple, the proposed research will determine whether epigenetic changes related to prenatal PAH exposure are involved in the pathogenic process of childhood asthma. The first study will utilize banked human cord white blood cells, paired placental tissue, and clinical outcome data from children, now aged 9/10 years) who are participants in a prospective cohort study in minority communities in New York City (CCCEH cohort). Analysis of DNA methylation in cord blood DMA and gene expression in placental tissue from these children will be used to identify candidate genes that may be involved in the mechanistic pathway between prenatal PAH exposure and childhood asthma at age 9-10 (i.e., that are differentially methylated and expressed in the high vs. low PAH exposure groups). The set of candidate genes will then be tested as potential biologic markers predictive of childhood asthma in this study sample. Those genes that are found to be predictive will then comprise a "candidate epigenome" to be confirmed in a closely linked animal model. In this complementary animal model, pregnant mice will be exposed to a PAH mixture of similar composition to that measured in air samples from the CCCEH cohort. Blood, placenta and target tissue (lung and spleen) collected from offspring at delivery will be examined for PAH-related changes in gene methylation and gene expression, respectively. A group of offspring prenatally exposed will be followed for 4 weeks to determine asthma-like phenotype. Criteria for selecting the final biomarker(s) will be a) high concordance between gene methylation in white blood cells and gene expression in target tissue and b) significant association with asthma-like phenotype. It is anticipated that this research will provide valuable new data on the role of epigenetic changes in the pathogenesis of childhood asthma. If specific methylation changes induced in utero are found to predict asthma and ultimately validated, we will have identified clinically relevant biomarkers for predicting asthma risk in children.

这个高度创新的项目解决了表观遗传变化在儿童发病机理中的作用 哮喘。越来越多的证据是我们自己的研究，表明产前暴露于多环 芳烃（PAHS），交通和其他燃烧来源的常见城市污染物，可能是 儿童哮喘的危险因素。跟进最近的一项试点研究，该研究证明了 拟议的研究将确定表观遗传学变化是否与产前PAH有关 暴露于儿童哮喘的致病过程。第一项研究将利用储藏室 人绳白细胞，配对的胎盘组织和来自儿童的临床结果数据，现已老化 9/10年）是纽约市少数民族社区的前瞻性队列研究参与者 （CCCEH队列）。分析脐带血DMA中DNA甲基化和胎盘组织中基因表达的分析 这些孩子将用于识别可能涉及机械途径的候选基因 在9-10岁时的产前PAH暴露与儿童哮喘之间 并在高和低PAH暴露组中表达）。然后，一组候选基因将被测试为 在这项研究样本中，潜在的生物标志物可以预测儿童哮喘。那些发现的基因 然后，预测将包括一个“候选表观基因组” 模型。在这种互补的动物模型中，怀孕小鼠将暴露于类似的PAH混合物中 从CCCEH队列中的空气样品中测量的组成。血液，胎盘和靶组织 （肺和脾脏）将检查与PAH相关的基因变化，从输送后的后代收集 甲基化和基因表达。一组后代将遵循4个 确定类似哮喘的表型的几周。选择最终生物标志物的标准将为a）高 白细胞中基因甲基化与靶组织和b中基因表达之间的一致性 与哮喘样表型的显着关联。预计这项研究将提供有价值的 关于表观遗传变化在儿童哮喘发病机理中的作用的新数据。如果特定的甲基化 发现子宫内诱导的变化可以预测哮喘并最终被验证，我们将确定 临床相关的生物标志物可预测儿童哮喘风险。