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

项目摘要 食物和饮用水中的砷是一个主要的全球健康问题。据估计， 个人暴露于无机砷（iAs）的水平高于WHO暂定指南值10µg/L （ppb）。流行病学和实验室研究表明，产前接触低至中等水平的 无机砷（iAs）可能会增加儿童早期和后期不良健康影响的风险。 生活中然而，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系统疾病有关， 症状我们以前的工作，在动物模型中证明，表明母亲暴露于房子， 过敏原通过表观遗传修饰影响新生儿的免疫致敏和肺生长 胎儿基因转录;决定后代对过敏性气道的易感性 高反应性（AHR）。当然，这些发现指出了表观遗传机制，这是一个可能的调解人， 环境压力对后代哮喘病易感性的多代效应。已经 表明在子宫内暴露于iAs改变了出生后肺的结构和功能，这可能 使后代在成年后易患肺功能障碍。然而，我们对它的早期- 终生暴露于iAs促进过敏性气道疾病的表观遗传调节。我们假设母体iAs 暴露增加了后代哮喘的风险，部分原因是通过胎盘应激，调节表观遗传 胎儿肺发育和后期AHR表型的重编程。这一新的假设将通过以下方式进行检验： 两个具体目标。 具体目的1：研究iAs暴露对后代肺功能的表观遗传效应 过程和后代。我们将定义iAs暴露的关键窗口， 通过肺基因组的表观遗传修饰提高哮喘的敏感性。此外，我们提出具体目标2： 探讨胎盘氧化应激对胎肺发育表观遗传调控的影响。在这 我们将在整个妊娠期评估母体胎盘功能，并在整个妊娠期评估后代的肺功能。 成年生活，使用最先进的生理学，分子和表观基因组学方法。我们还将确定 如果他们后代的表观遗传变化和AHR敏感性的遗传可以通过以下方式减弱， 减少胎盘活性氧。综合起来，我们的发现将使我们不仅能够了解 母体暴露于iAs的表观遗传机制重新编程了肺基因组，但也研究了这些机制如何改变肺基因组。 表观遗传变化会遗传给后代。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，以及相当多的 提高早期干预策略，以减少受影响社区的哮喘风险。

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.