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

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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.