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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 A. 具体目标 疾病发育起源假说得到大量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成年后肥胖、高血压、II 型糖尿病和代谢综合征的风险增加相关 (1-4)。尽管这些心血管、内分泌和代谢结果是疾病早期起源最常见的研究对象，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（即基因表达改变）而不是通过初级 DNA 序列的改变来发挥表型效应 (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-环境风险因素中发挥重要作用。 DNA 低甲基化或高甲基化等修饰已被证明是因母体暴露而发生的，此类变化与慢性病风险相关 (5, 9)。尽管表观遗传变化可能在一生中发生，但它们 主要发生在妊娠期间和出生后不久 (8)。 接触生物制品，特别是霉菌、尘螨、蟑螂、啮齿动物和宠物过敏原，已被认为与儿童期哮喘的诱发有关 (10-12)。强有力的证据表明环境烟草烟雾 (ETS) 在诱发哮喘中发挥着作用 (13)。重要的是，队列研究表明，子宫内暴露（即母亲在怀孕期间吸烟）与儿童随后的哮喘风险相关 (14-17)。环境颗粒物 (PM) 或其他环境污染物在哮喘诱发中的作用尚不清楚 (13)。室内产生的生物质烟雾是研究 PM 引起的表观遗传变化及其对慢性病风险的影响的理想颗粒源。木炉是许多农村社区的常见供暖来源，我们已经表明，此类家庭的室内 PM 浓度适度升高 (18)。然而，不应孤立地考虑母亲吸入颗粒物的环境暴露。母亲饮食可能在发育中胎儿的表观遗传改变中发挥作用，也可能与儿童哮喘风险有关。包括我们自己在美洲原住民社区中进行的研究在内的多项证据都支持肥胖与哮喘之间的关联，但这种关系的因果关系和机制性质尚不清楚 (2, 19-21)。重要的是，高出生体重与哮喘和成人肥胖有关(22)。因此，产前营养可能是随后发生哮喘和肥胖的重要因素。这些关系发生的机制尚不清楚，但响应妊娠环境的表观遗传事件被怀疑发挥了一定作用 (23, 24)。 中心假设是，在子宫内暴露于生物质烟雾和母亲饮食因素会导致表观遗传变化，而这些变化与儿童哮喘发生风险增加相关。该试点项目与我们目前资助的研究路线有所不同，但也代表了理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、委托人证明以及合作和收集能力的证明 来自孕妇和新生儿群体的生物样本。最终，我们的目标是通过向 NIEHS 提交 R21 或 R01 来继续这项研究。 具体目标 1. 将通过全基因组甲基化分析评估孕产妇和新生儿血液样本，以识别烟雾暴露和/或饮食中常见的甲基化目标。将进行以下描述性分析： (1a) 将在血液样本中确定高甲基化和低甲基化的目标 (1b) 将在血液样本中确定与母亲甲基补充和/或高脂肪母亲饮食有关的高甲基化和低甲基化目标。 具体目标 2.将对婴儿进行为期六个月的前瞻性随访，以评估生命早期的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质烟雾暴露相关； (2b) 婴儿症状（例如咳嗽、喘息）和感染（例如 RSV）的频率与母亲补充甲基和/或高脂肪母亲饮食有关。 探索性目标（EA）。展示从这些人群中收集更多生物样本的能力将为未来的拨款申请提供强有力的支持。将评估以下目标。 EA1。将收集胎盘组织和脐带血样本用于未来的甲基化分析。 EA2。将从母体/婴儿对中收集口腔细胞，用于将来的 DNA 分离和分析。