Impacts of Acute Ambient Air Pollution Exposure on Women's Reproductive Health: Identifying Mechanisms and Susceptible Reproductive Processes Across the Menstrual Cycle and Early Pregnancy

项目摘要/摘要 不孕不育和妊娠丢失是常见的，并与显著的发病率相关。环境空气污染可能 通过改变炎症反应和增加生殖健康来影响生殖健康 活性氧物种，导致细胞损伤、上皮功能障碍和血小板激活。之前 研究已经确定了空气污染暴露和人口水平生育率之间的联系；然而， 解释受到对潜在的病理生理过程的不完全理解的限制 生殖窗口最容易受到空气污染的影响。这种风险敞口存在错误分类的风险 低估空气污染对女性生殖健康的影响和研究改进暴露 为潜在的生物机制计时的窗口仍然是一个紧迫的需求。这种探索性/发展性 研究资助计划将利用来自完整的先入为主的时间的高质量二次数据- 妊娠队列，阿司匹林对妊娠和生殖的影响(AGER)试验(n=1,228)，以评估 急性暴露于环境空气污染对月经周期敏感窗口期和 早孕对妇女的生殖健康和实现活产的能力有影响。我们将利用社区 多尺度空气质量(CMAQ)模型，以估计参与者住宅对环境空气污染的暴露， 包括标准污染物、颗粒物成分和多环芳烃。这个 空气质量数据的精细空间和时间分辨率将允许评估在 月经周期的生物信息窗口(排卵前卵泡发育、排卵和 植入)和早孕。目标1将评估急性暴露于环境空气污染的影响 排卵和着床前后的多环芳烃与生殖激素和受精性的变化。目标 2将评估植入物对环境空气污染和多环芳烃急性暴露的影响 妊娠早期关于妊娠丢失风险的研究。为了这两个目标，我们将分析周期中期生物谱系的一个子集 参与者(n=288)评估暴露在多环芳烃和氧化环境中的代谢物 应激机制，包括氧化DNA损伤的标记物(8-羟基-2‘-脱氧鸟苷)和脂质 过氧化(F2-异前列腺素)。此外，我们还将利用急切试验的独特设计来确定 小剂量阿司匹林的抗炎和抗血小板作用是否能缓解 空气污染暴露对女性生殖健康的影响。这些发现将为以下工作提供基础 未来的工作评估急性暴露于环境空气污染可能影响 夫妇和个人实现活产的能力，为政策制定提供信息并确定 未来的干预措施旨在改善生殖健康。

PROJECT SUMMARY/ABSTRACT Infertility and pregnancy loss are common and associated with significant morbidity. Ambient air pollution may affect reproductive health through alterations in the inflammatory response and increased production of reactive oxygen species, leading to cellular damage, epithelial dysfunction and platelet activation. Prior research has identified associations between air pollution exposure and population-level fertility; however, interpretation is limited by an incomplete understanding of underlying pathophysiologic processes and the reproductive windows most susceptible to air pollution exposure. This exposure misclassification risks underestimating the impacts of air pollution on women’s reproductive health and studies refining exposure windows timed to underlying biologic mechanisms remains a pressing need. This exploratory/developmental research grant proposal will leverage high-quality secondary data from a completed preconception time-to- pregnancy cohort, the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (n=1,228), to evaluate the impact of acute exposure to ambient air pollution during susceptible windows of the menstrual cycle and in early pregnancy on women’s reproductive health and ability to achieve a live birth. We will utilize Community Multiscale Air Quality (CMAQ) models to estimate participants’ residential exposure to ambient air pollution, including the criteria pollutants, constituents of particulate matter, and polycyclic aromatic hydrocarbons. The fine spatial and temporal resolution of the air quality data will allow for assessment of acute exposure during biologically-informed windows of the menstrual cycle (preovulatory follicle development, ovulation, and implantation) and early pregnancy. Aim 1 will evaluate the impact of acute exposure to ambient air pollution and PAHs around ovulation and implantation with alterations in reproductive hormones and fecundability. Aim 2 will evaluate the impact of acute exposure to ambient air pollution and PAHs from implantation through the first trimester on risk of pregnancy loss. For both aims, we will analyze mid-cycle biospecimens in a subset of participants (n=288) to assess metabolites of exposure to polycyclic aromatic hydrocarbons and oxidative stress mechanisms, including markers of oxidative DNA damage (8-hydroxy-2’-deoxyguanosine) and lipid peroxidation (F2-isoprostanes). We will additionally leverage the unique design of the EAGeR trial to identify whether randomization to the anti-inflammatory and anti-platelet actions of low-dose aspirin mitigates the impact of air pollution exposure on women’s reproductive health. These findings will provide the foundation for future work evaluating the mechanisms through which acute exposure to ambient air pollution may impact the ability of couples and individuals to achieve a live birth, both informing policy development and identifying future intervention points to improve reproductive health.