CIGARETTE SMOKE IMPACTS FETAL LUNG DNA METHYLATION AND GENE EXPRESSION

香烟烟雾影响胎儿肺 DNA 甲基化和基因表达

• 批准号: 8090798
• 负责人: DAWN L DEMEO
• 金额: $ 26.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090798
• 关键词: Adult; Affect; American; Asthma; Behavior Disorders; Cessation of life; Childhood; Chronic Obstructive Airway Disease; Complex; DNA; DNA Methylation; DNA Sequence; Data; Data Set; Development; Developmental Biology; Developmental Gene; Diabetes Mellitus; Disease; Elements; Environmental Exposure; Epigenetic Process; Fetal Lung; Fetus; Future; Gene Expression; Gene Expression Alteration; Genes; Genetic; Genome; Genomics; Gestational Age; Goals; Hospitalization; Human; Human Development; Hypoxia; Infant; Lead; Life; Link; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Molecular Profiling; Morbidity - disease rate; Neonatology; Neurodevelopmental Disorder; Nicotine; Obesity; Organ; Pattern; Perinatal; Placenta; Predisposition; Pregnancy; Premature Infant; Prevalence; Regulator Genes; Research; Resources; Risk Factors; Role; Sampling; Site; Small for Gestational Age Infant; Smoke; Smoking; Source; Staging; Sudden infant death syndrome; System; Testing; Therapeutic; Time; Tissues; United States; Up-Regulation; Wheezing; Woman; Work; cigarette smoking; cigarette smoking; early onset; economic cost; epigenomics; experience; fetal; fetal programming; genome-wide; human disease; in utero; lung development; maternal cigarette smoking; mortality; novel; premature; prenatal; prenatal smoking; pulmonary function; respiratory

DESCRIPTION (provided by applicant): Prenatal smoking is one of the most common preventable causes of infant morbidity and mortality; in the United States, it is estimated that about 13.8% of women smoke during pregnancy. In utero smoke (IUS) exposure has been associated with both perinatal morbidity and the development of complex diseases in later childhood. Additionally, IUS exposure has been associated with alterations in fetal lung development and consequent decreased pulmonary function, early-onset wheeze, and asthma in childhood. DNA methylation is one type of epigenetic change that results in the alteration of gene expression without affecting DNA sequence. In adults, cigarette smoking has been associated with alterations in DNA methylation, which influences the development of adult onset lung diseases such as COPD and lung cancer. In the maternal-fetal system, placental gene expression is a critical element for guiding in utero development. Environmental exposures including nicotine have been demonstrated to cross the placental barrier and impact placental gene expression. In addition to being a source of compounds, maternal cigarette smoking impacts placental hypoxia; placental hypoxia has been associated with up-regulation of genes intrinsic to DNA methylation and epigenetic processes. The major goal of this project is to demonstrate that IUS exposure results in epigenetic changes in the placenta and developing fetus that have downstream impact on the expression of genes crucial to normal human lung development. This application specifically seeks to define the DNA methylation profile of normal early fetal lung development, its correlation with normal gene expression, its relationship to DNA methylation in the developing placenta, and how each of these is altered via IUS. To explore our global hypothesis we will: (1) examine DNA methylation status of greater than 450,000 CpG sites across the epigenome in DNA from 48 IUS-unexposed and 48 IUS-exposed fetal lung samples to identify methylation patterns critical during to the pseudoglandular and canalicular stages of lung development and altered in the setting of IUS exposure; and (2) use placental tissue from the same fetuses from which the lung samples are obtained to identify the epigenomic and genomic profiles of 48 IUS-exposed and 48 IUS-unexposed placentas. We will subsequently compare these profiles within placenta and between placenta and the developing lung. The correlation of epigenomic and genomic profiles within the developing lung will provide a direct functional link to the epigenomics of fetal IUS exposure and set the stage for future work focused on the relevance of these changes to the development of airways disease or other IUS-associated childhood diseases. Moreover, if significant, by sampling placental tissue as a marker of other fetal organs, the placental/fetal lung epigenomic correlation has direct translational implications for the field of neonatology, and efforts to link early-life fetal programming to the development of complex human disease. PUBLIC HEALTH RELEVANCE: This project seeks to identify DNA methylation marks associated with normal and in utero smoke-exposed lung development and with the genetic expression signature during those times. By demonstrating that these marks also correlate with gene expression, the marks can be inferred to have a functional role in smoking-related changes in the developing fetus. This may eventually be used to formulate novel prenatal therapeutic and preventative strategies. Since in utero smoke exposure remains a leading cause of perinatal morbidity and mortality and a major risk factor for the development of complex childhood disease, including asthma, these strategies have the potential to substantially decrease the morbidity and financial burden related to prenatal smoking.

描述（由申请人提供）：产前吸烟是婴儿发病率和死亡率最常见的原因之一；在美国，据估计，怀孕期间约有13.8％的女性吸烟。在子宫内烟雾（IUS）暴露与围产期发病率和童年后期复杂疾病的发展有关。此外，IUS暴露与胎儿肺发育的改变有关，随之而来的肺部功能，早发喘息和儿童哮喘。 DNA甲基化是一种表观遗传变化，导致基因表达改变而不影响DNA序列。在成年人中，吸烟与DNA甲基化的改变有关，这会影响成年肺部疾病（例如COPD和肺癌）的发展。在母亲狂热系统中，胎盘基因表达是指导子宫内发育的关键要素。已证明包括尼古丁在内的环境暴露术可以越过胎盘屏障和撞击胎盘基因表达。除了成为化合物的来源外，孕产妇吸烟还会影响胎盘缺氧。胎盘缺氧与DNA甲基化和表观遗传过程的基因上调有关。该项目的主要目的是证明IUS暴露会导致胎盘的表观遗传变化和发展对正常人肺发育至关重要的基因表达的胎儿的表观遗传变化。该应用专门旨在定义正常早期胎儿肺发育的DNA甲基化谱，其与正常基因表达的相关性，其与发育中胎盘中DNA甲基化的关系以及如何通过IUS改变。为了探索我们的全球假设，我们将：（1）检查DNA的DNA甲基化状况超过45万CpG位点，从48个IUS尚不公开的DNA中的表观基因组大于48个IUS和48个IUS暴露的胎儿肺样品，以鉴定甲基化模式在伪域和肺部开发和更改的肺活量阶段至关重要的甲基化模式。 （2）使用从同一胎儿那里获得胎盘组织，从中获得肺样品的胎儿，以鉴定48个IUS暴露和48个IUS无暴露的胎盘的表观基因组和基因组谱。随后，我们将比较胎盘内以及胎盘和发育中的肺部之间的这些特征。发育中的肺部表观基因组和基因组谱的相关性将提供与胎儿IUS暴露的表观基因组学的直接功能联系，并为未来的工作奠定了阶段，该工作侧重于这些变化与气道疾病或其他IUS相关儿童疾病的发展的相关性。此外，如果很重要，则通过将胎盘组织作为其他胎儿器官的标记来取样，胎盘/胎儿肺表观基因组相关性具有直接的转化对新生儿学领域的影响，以及将早期胎儿编程与复杂人类疾病的发展联系起来的努力。 公共卫生相关性：该项目旨在确定与正常和子宫烟雾暴露的肺发育以及与那段时间的遗传表达信号相关的DNA甲基化标记。通过证明这些标记也与基因表达相关，可以推断出标记在与吸烟相关的胎儿变化中具有功能性作用。最终可以用来制定新型的产前治疗和预防策略。由于在子宫内烟雾仍然是围产期发病率和死亡率的主要原因，以及包括哮喘在内的复杂儿童疾病发展的主要风险因素，因此这些策略有可能大大减轻与产前吸烟有关的发病率和财务负担。