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制中的作用 哮喘越来越多的证据，有些来自我们自己的研究， 芳烃（PAH），来自交通和其他燃烧源的常见城市污染物，可能是 儿童哮喘的危险因素。根据最近的一项试点研究， 当然，这项研究将确定表观遗传学变化是否与产前PAH有关 暴露参与了儿童哮喘的发病过程。第一项研究将利用银行 人类脐带白色血细胞、成对胎盘组织和来自儿童的临床结果数据，现在已经年老 9/10岁），他们是纽约市少数民族社区前瞻性队列研究的参与者 （CCCEH队列）。脐血DNA甲基化及胎盘组织基因表达分析 将用于鉴定可能参与机制途径的候选基因 产前PAH暴露与9-10岁儿童哮喘之间的关系（即，甲基化差异 并在高与低PAH暴露组中表达）。然后将测试候选基因的集合， 预测儿童哮喘的潜在生物标志物。那些被发现的基因 具有预测性的基因组将包括在紧密连锁的动物中待确认的“候选表观基因组 模型在该补充动物模型中，妊娠小鼠将暴露于类似的PAH混合物， 与来自CCCEH队列的空气样品中测量的成分相比。血液、胎盘和靶组织 (lung将检查分娩时从后代中收集的PAH相关基因变化， 甲基化和基因表达。将对一组产前暴露的后代进行4年随访 以确定哮喘样表型。选择最终生物标志物的标准将是a）高 白色血细胞中基因甲基化与靶组织中基因表达之间的一致性，和B） 与哮喘样表型显著相关。预计这项研究将提供有价值的 表观遗传学改变在儿童哮喘发病机制中作用的新数据。如果特异性甲基化 发现子宫内诱导的变化可以预测哮喘，并最终得到验证，我们将确定 用于预测儿童哮喘风险的临床相关生物标志物。