Impact of Maternal Arsenic Exposure on Offspring's Epigenetic Reprogramming of Allergic Airway Disease

母亲砷暴露对后代过敏性气道疾病表观遗传重编程的影响

基本信息

批准号：
10733607
负责人：
Wan-yee Tang
金额：
$ 45.94万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-02 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733607
关键词：
Adult Affect Allergens Allergic Animal Model Arsenic Asthma Attenuated Cells Child Child Development Child Health Communities Coupled DNA Methylation Development Disease susceptibility Documentation Early Intervention Elderly Embryo Environmental Impact Epigenetic Process Exposure to Fetal Lung Fetal health Food Functional disorder Generations Genetic Transcription Genome Germ Cells Growth Guidelines Health House Dust Mite Allergens Human Hypersensitivity Immunologic Sensitization Individual Inflammation Inflammatory Response Inherited Intervention Laboratory Study Leukocytes Life Life Cycle Stages Link Lung Maternal Exposure Maternal Health Measures Mediating Mediator Messenger RNA MicroRNAs Modification Molecular Mus Outcome Oxidative Stress Pathogenicity Pathologic Phenotype Physiological Placenta Placentation Predisposition Pregnancy Production Pulmonary Inflammation Pyroglyphidae Reactive Oxygen Species Reporting Research Respiratory Disease Respiratory Signs and Symptoms Risk Role Safety Stress Structure Testing Woman Work adverse pregnancy outcome airway hyperresponsiveness allergic airway disease asthma model bisulfite sequencing comparison control drinking water early childhood early life exposure environmental stressor epidemiology study epigenetic regulation epigenomics fetal global health improved indoor allergen insight laser capture microdissection lung development methylation pattern methylome neonate novel offspring postnatal prenatal exposure prevent programs pulmonary function respiratory health single nucleus RNA-sequencing transcriptome sequencing

项目摘要

PROJECT SUMMARY Arsenic in food and drinking water is a major global health concern. It is estimated that over 200 million individuals are exposed to inorganic arsenic (iAs) at levels above the WHO provisional guideline value of 10µg/L (ppb). Epidemiological and laboratory studies have suggested that prenatal exposure to low-to-moderate levels of inorganic arsenic (iAs) may increase the risk of adverse health effects during early childhood as well as later in life. However, there are limited research examining how arsenic exposure promotes allergic airway diseases such as asthma, although there is growing documentation that arsenic exposure is associated with respiratory symptoms. Our previous work, demonstrated in animal model, suggests that maternal exposures to house allergens affect the immunological sensitization and lung growth of the neonate through epigenetic modifications of the fetal gene transcription; which determines the offspring susceptibility to allergic airway hyperresponsiveness (AHR). Certainly, these findings point to the epigenetic mechanism a possible mediator of the multigenerational effect of environmental stressors on offspring’s asthma disease susceptibility. It has been demonstrated that in utero exposure to iAs modified the structure and function of the postnatal lungs, which may predispose the offspring to pulmonary dysfunction in adulthood. Nevertheless, less is known about how early- life exposure to iAs promotes epigenetic regulation of allergic airway disease. We hypothesize that maternal iAs exposure increases offspring asthma risk, in part through placental stress, which modulates epigenetic reprograming of fetal lung development and later-life AHR phenotypes. This novel hypothesis will be tested via two specific aims. Specific Aim 1 is: To examine the epigenetic effect of iAs exposure on offspring lung function across the life course and subsequent generations. We will define the critical window(s) of iAs exposure that results in later sensitivity in asthma via epigenetic modification at lung genome. Additionally, we propose Specific Aim 2: To investigate the influence of placental oxidative stress on epigenetic regulation of fetal lung development. In this proposal, we will assess maternal placental function throughout the gestation and offspring’s lung function across the adult life, using state-of-the-art physiological, molecular and epigenomic approaches. We will also determine if the inheritance of epigenetic changes and sensitivity in the AHR of their offspring could be attenuated by reducing placental reactive oxygen species. Taken together, our findings will allow us to not only understand the epigenetic mechanisms by which maternal exposure to iAs reprograms the lung genome, but also how these epigenetic changes are inherited by subsequent generations. We will provide a unique set of lung epigenetic signatures and placental signatures for asthma risk and iAs exposure assessment, as well as considerable insight into improving an early intervention strategy to reduce asthma risk in affected community.

项目概要据估计，食品和饮用水中的砷是全球 2 亿多人的主要健康问题。个人接触的无机砷 (iAs) 含量高于世界卫生组织临时指导值 10 微克/升 (ppb) 流行病学和实验室研究表明，产前接触低至中等水平。无机砷 (iAs) 可能会增加幼儿期及以后对健康造成不良影响的风险然而，在生活中，关于砷暴露如何促进过敏性气道疾病的研究有限。例如哮喘，尽管越来越多的文献表明砷暴露与呼吸道疾病有关我们之前的工作在动物模型中得到证实，表明母亲暴露于室内。过敏原通过表观遗传修饰影响新生儿的免疫致敏和肺部生长胎儿基因转录的变化决定了后代对气道过敏的易感性当然，这些发现表明表观遗传机制可能是高反应性的调节因素。环境压力因素对后代哮喘疾病易感性的多代影响。子宫内暴露于 iAs 表明了出生后肺部的结构和功能，这可能然而，人们对后代在成年后容易出现肺功能障碍的情况知之甚少。生活中接触 iAs 会促进过敏性气道疾病的表观遗传调节。暴露会增加后代哮喘风险，部分是通过调节表观遗传的胎盘应激胎儿肺部发育和晚年 AHR 表型的重新编程将通过这一新假设进行检验。两个具体目标。具体目标 1 是：检查 iAs 暴露对后代终生肺功能的表观遗传影响我们将定义导致以后的 iAs 暴露的关键窗口。此外，我们提出了具体目标 2：通过肺基因组的表观遗传修饰来提高哮喘的敏感性。研究胎盘氧化应激对胎儿肺发育的表观遗传调控的影响。建议，我们将评估整个妊娠期间母亲的胎盘功能以及后代的肺功能我们还将使用最先进的生理、分子和表观基因组方法来确定成年生活。是否可以减弱其后代 AHR 中表观遗传变化和敏感性的遗传总而言之，我们的发现将使我们不仅了解胎盘活性氧。母体暴露于 iAs 重新编程肺基因组的表观遗传机制，以及这些机制如何表观遗传变化由后代遗传。我们将提供一套独特的肺表观遗传。哮喘风险和 IAs 暴露评估的特征和胎盘特征，以及相当大的深入了解改善早期干预策略以降低受影响社区的哮喘风险。