Immune Tolerance Dysfunction in Pregnancy due to Ambient Air Pollution Exposure

摘要 孕妇暴露在环境污染和毒物中显著增加了母亲患病的风险 出生后的健康。具体地说，污染与产妇死亡率和发病率增加有关 不孕不育，自发早产，哮喘，过敏，心血管疾病，自身免疫性疾病 为先兆子痫和子痫。母体免疫系统在建立， 维持和完成一个健康的妊娠，以及它的持续生长和扩散状态 系统使其对污染物敏感。孕期免疫适应不足与 怀孕期间和怀孕后的许多疾病。尽管流行病学研究指出了特定的 环境毒物和母亲的不良后果，到目前为止，几乎没有关于环境毒物和母亲不良后果的研究 大气污染毒物对孕期及孕后母亲免疫健康的影响我们 假设长期暴露在环境空气污染中，特别是细颗粒物PM2.5，将 增加孕妇在产中和短期内的免疫失调(产后立即，一年后 孕期(出生后3年)和长期(出生后3年)。使用之前从以下位置收集的生物样本 孕妇(n=200)和非孕妇(n=200)暴露在高水平和低水平污染(主要是PM2.5)中， 我们将1)测试怀孕和未怀孕的免疫细胞亚群在特性和功能上的不同 暴露在高污染与低污染下的女性；2)识别和验证表观遗传分子机制 使用甲基化检测PM2.5高暴露与低暴露时妊娠与非妊娠的免疫功能障碍， EpiTOF、ATAC-seq和组蛋白芯片-seq；3)T细胞受体多样性与免疫功能障碍的关系 高PM2.5暴露与低PM2.5暴露的妊娠与非妊娠。如果目标实现，这项研究将使我们能够 确定免疫功能障碍的驱动因素和未来潜在的可修改因素。我们将探讨如何 这些免疫发现与我们之前收集的疾病的结果有关 元数据：哮喘、感染、过敏、先兆子痫、子痫、早产和自身免疫性疾病。多数 重要的是，我们的发现可能会影响公众健康和有关空气污染暴露的政策决策。 在高度脆弱的人群中，如孕妇。

ABSTRACT Exposure of pregnant women to environmental pollution and toxicants significantly increase risks to mother’s health after birth. Specifically, pollution is association with increased rates of maternal mortality and morbidities of infertility, spontaneous preterm birth, asthma, allergy, cardiovascular disease, autoimmune disease, as well as pre-eclampsia and eclampsia. The maternal immune system plays a critical role in establishing, maintaining, and completing a healthy pregnancy and the constant state of growth and proliferation of this system makes it sensitive to pollutants. Insufficient immunological adaption in pregnancy is associated with many diseases during and after pregnancy. Although epidemiologic studies point to links between specific environmental toxicants and adverse outcomes in mothers, to date, there have been little to no studies of the effects of air pollution toxicants on pregnant mothers’ immune health during and after pregnancy. We hypothesize that chronic exposure to ambient air pollution, specifically fine particulate matter PM2.5, will increase immune dysregulation in pregnant women during, and in short- (immediate postpartum, 1 yr after birth) and long-term periods (3 years after birth) after pregnancy. Using previously collected biosamples from pregnant (n=200) and nonpregnant (n=200) women exposed to high and low levels of pollution (chiefly PM2.5), we will 1) test whether immune cell subsets are different in identity and function in pregnant vs. non pregnant women exposed to high vs. low pollution; 2) identify and validate epigenetic molecular mechanisms driving immune dysfunction in pregnancy vs no pregnancy with high vs low PM2.5 exposure using methylation, EpiTOF, ATAC-seq, and histone ChIP-seq; and 3) map T cell receptor diversity to immune dysfunction in pregnancy vs non pregnancy with high vs. low PM2.5 exposure. If the aims are met, this study will allow us to identify the drivers of immune dysfunction and potential modifiable factors for the future. We will explore how these immune findings are associated with the outcomes of diseases for which we have previously collected metadata: asthma, infections, allergy, pre-eclampsia, eclampsia, preterm birth, and autoimmune disease. Most importantly, our findings will likely impact public health and policy decisions surrounding air pollution exposure in a highly vulnerable population such as pregnant women.