GESTATIONAL EXPOSURES EPIGENETICS AND RESPIRATORY HEALTH

妊娠期暴露表观遗传学和呼吸系统健康

• 批准号: 8360470
• 负责人: Curtis William Noonan
• 金额: $ 2.09万
• 依托单位: UNIVERSITY OF MONTANA
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360470
• 关键词: Adult; Adult asthma; Affect; Allergens; Animals; Applications Grants; Asthma; Biological; Biomass; Birth; Birth Weight; Blood specimen; Breathing; Cardiovascular system; Cells; Child; Childhood; Childhood Asthma; Chronic Disease; Cohort Studies; Communities; Coughing; DNA; DNA Sequence; Data; Development; Dictyoptera; Diet; Dietary Factors; Disease; Endocrine; Environment; Environmental Exposure; Environmental Health; Environmental Tobacco Smoke; Epidemiology; Epigenetic Process; Event; Exposure to; Fatty acid glycerol esters; Fetus; Frequencies; Funding; Future; Generations; Genes; Genetic; Goals; Grant; Health; Heating; Home environment; Hypertension; Infant; Infection; Investigation; Life; Maternal Exposure; Mediating; Metabolic; Metabolic syndrome; Methylation; Modification; Molds; National Center for Research Resources; National Institute of Environmental Health Sciences; Native Americans; Nature; Neonatal; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Particulate; Particulate Matter; Perinatal Exposure; Pilot Projects; Play; Population; Pregnancy; Pregnant Women; Prenatal Nutrition; Principal Investigator; Research; Research Infrastructure; Resources; Respiration Disorders; Respiratory Tract Infections; Risk; Risk Factors; Rodent; Role; Rural Community; Sampling; Smoke; Source; Supplementation; Symptoms; Tissues; Umbilical Cord Blood; United States National Institutes of Health; Wheezing; Work; cost; genome-wide; maternal cigarette smoking; pollutant; prenatal; prenatal influence; pyroglyphid; respiratory; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A. SPECIFIC AIMS The developmental origins of disease hypothesis is supported by numerous epidemiological and animal studies which suggest that adverse prenatal factors are associated with increased risk in adult life for obesity, hypertension, Type II diabetes, and metabolic syndrome (1-4). Although these cardiovascular, endocrine and metabolic outcomes are the most commonly investigated with respect to early origins of disease, asthma and other respiratory disorders are also affected by early exposures (5, 6). These prenatal influences likely exert their phenotypic effects through epigenetic changes (i.e. altered genetic expression) rather than through alteration of the primary DNA sequence (7, 8). Epigenetic factors may play an important role in mediating the environmental, genetic, and gene-environment risk factors for chronic diseases. Modifications such as DNA hypo- or hyper-methylation have been shown to occur in response to maternal exposures, and such changes are relevant to risk for chronic disease (5, 9). Although epigenetic changes can occur throughout life, they occur predominantly during gestation and shortly after birth (8). Exposure to biologics, particularly mold, dust mites, and cockroach, rodent and pet allergens, have been putatively associated with the induction of asthma in childhood (10-12). Strong evidence exists for the role of environmental tobacco smoke (ETS) in the induction of asthma (13). Importantly, cohort studies have demonstrated that in utero exposures (i.e., maternal smoking during pregnancy) are associated with subsequent asthma risk in the child (14-17). The role of ambient particulate matter (PM) or other ambient pollutants in asthma induction is less clear (13). Indoor-generated biomass smoke is an ideal particulate source for the investigation of PM-induced epigenetic changes and consequent effects on risk for chronic disease. Woodstoves are a common source of heating in many rural communities, and we have shown that such homes have moderately elevated indoor PM concentrations (18). Maternal environmental exposures to inhaled particulates should not be considered in isolation, however. Maternal diet may play a role in epigenetic modifications of the developing fetus and may also be relevant to childhood risk for asthma. Several lines of evidence, including our own research in Native American communities, support an association between obesity and asthma, but the causal and mechanistic nature of this relationship is not well understood (2, 19-21). Importantly, high birth weight has been associated with both asthma and adult obesity(22). Thus, prenatal nutrition could be an important factor in subsequent development of asthma and obesity. The mechanisms by which these relationships occur are unclear, but epigenetic events in response to the gestational environment are suspected to play a role (23, 24). The central hypothesis is that in utero exposure to biomass smoke and maternal dietary factors result in epigenetic changes that are associated with increased risk for development of childhood asthma. This pilot project represents a departure from our currently funded line of research but also represents a logical transition to understanding the early life risk factors associated with the development of asthma. This project will result in the generation of preliminary data, proof of principal, and demonstration of capacity to work with and collect biological samples from pregnant women and neonatal populations. Ultimately, our goal is to continue this research by submitting an R21 or R01 to NIEHS. Specific Aim 1. Maternal and newborn blood samples will be evaluated via genome-wide methylation analysis to identify commonly methylated targets from smoke exposure and/or diet. The following descriptive analyses will be conducted: (1a) Targets of hyper- and hypo-methylation will be identified in blood samples with respect to gestational biomass smoke exposure and (1b) Targets of hyper- and hypo-methylation will be identified in blood samples with respect to maternal methyl supplementation and/or high fat maternal diet. Specific Aim 2. Infants will be prospectively followed for six months to assess early life respiratory symptoms and respiratory infections. The following hypotheses will be assessed: (2a) Frequency of infant symptoms (e.g., cough, wheeze) and infections (e.g., RSV) will be associated with gestational biomass smoke exposure; and (2b) Frequency of infant symptoms (e.g., cough, wheeze) and infections (e.g., RSV) will be associated with maternal methyl supplementation and/or high fat maternal diet. Exploratory Aim (EA). Demonstration of capacity to collect additional biological samples from these populations will provide strong support for a future grant application. The following objectives will be assessed. EA1. Placental tissue and cord blood samples will be collected for future methylation analysis. EA2. Buccal cells will be collected from maternal/infant pairs for future DNA isolation and analysis.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 A.具体目标 疾病假设的发展起源得到了许多流行病学和动物研究的支持，这些研究表明，不良产前因素与肥胖，高血压，II型糖尿病和代谢综合征的成人生活风险增加有关（1-4）。尽管这些心血管，内分泌和代谢结果是关于疾病早期起源的最常见研究，但哮喘和其他呼吸系统疾病也受到早期暴露的影响（5，6）。这些产前影响可能通过表观遗传变化（即遗传表达改变）而不是通过一级DNA序列的改变来发挥其表型作用（7，8）。表观遗传因素可能在介导慢性疾病的环境，遗传和基因环境风险因素中起重要作用。诸如DNA降低或高甲基化之类的修饰已被证明是响应母体暴露而发生的，并且这种变化与慢性疾病的风险有关（5，9）。尽管表观遗传学变化可能会在一生中发生 主要发生在妊娠期间，出生后不久（8）。 接触生物制剂，尤其是霉菌，尘螨和蟑螂，啮齿动物和宠物过敏原，与童年时期诱导哮喘的诱导性相关（10-12）。有强有力的证据证明了环境烟草烟雾（ETS）在诱导哮喘中的作用（13）。重要的是，队列研究表明，在子宫内暴露（即怀孕期间的孕产妇吸烟）与随后儿童的哮喘风险有关（14-17）。环境颗粒物（PM）或其他环境污染物在哮喘诱导中的作用尚不清楚（13）。室内生成的生物量烟雾是研究PM诱导的表观遗传变化的理想颗粒来源，并对慢性病风险产生影响。在许多农村社区中，木窝是加热的常见来源，我们已经表明，这种房屋的室内PM浓度适中升高（18）。但是，不应孤立地考虑对吸入颗粒物的孕产妇环境暴露。孕产妇饮食可能在发育中的胎儿的表观遗传修饰中起作用，并且可能与儿童哮喘的风险有关。几条证据，包括我们自己在美国原住民社区的研究，支持肥胖与哮喘之间的关联，但是这种关系的因果和机械性质尚不清楚（2，19-21）。重要的是，高出生体重与哮喘和成人肥胖都相关（22）。因此，产前营养可能是随后发展哮喘和肥胖症的重要因素。这些关系发生的机制尚不清楚，但是怀疑对妊娠环境的表观遗传事件扮演角色（23，24）。 中心假设是，在子宫内暴露于生物质烟雾中，孕产妇饮食因素会导致表观遗传变化，这与增加儿童哮喘的风险增加有关。该试点项目代表了我们目前资助的研究线的背离，但也代表了了解与哮喘发展相关的早期生命危险因素的逻辑过渡。该项目将产生初步数据，本金证明以及与之合作和收集能力的证明 来自孕妇和新生儿种群的生物样品。最终，我们的目标是通过向NIEHS提交R21或R01来继续这项研究。 具体目的1。将通过全基因组甲基化分析评估母体和新生血样品，以鉴定烟雾暴露和/或饮食中常见的甲基化靶标。将进行以下描述性分析：（1a）在血液样本中将确定高甲基化和低乙基化靶标与 在血液样本中，相对于母体补充和/或高脂肪产妇饮食，将在血液样本中鉴定出妊娠生物量烟雾和（1B）的（1B）靶标。 特定的目标2。六个月的婴儿将被前瞻性地评估生命早期呼吸道症状和呼吸道感染。将评估以下假设：（2a）婴儿症状（例如，咳嗽，喘息）和感染（例如RSV）的频率将与妊娠生物量烟雾暴露有关； （2B）婴儿症状的频率（例如，咳嗽，喘息）和感染（例如，RSV）将与母体补充剂和/或高脂肪母体饮食有关。 探索目标（EA）。从这些人群中收集其他生物样本的能力的演示将为未来的赠款应用提供大力支持。将评估以下目标。 EA1。将收集胎盘组织和脐带血样品以进行将来的甲基化分析。 EA2。颊细胞将从母体/婴儿对收集，以进行将来的DNA分离和分析。