Preterm birth and low birthweight are associated with increased morbidity and mortality in infancy and are risk factors for chronic disease across the life course. Maternal exposure to particulate air pollution during pregnancy has been associated with these adverse pregnancy outcomes. Although exposure to air pollution varies on a daily basis, the majority of studies have focused on the effects of cumulative exposure averaged across pregnancy. The underlying pathways linking air pollution with adverse pregnancy outcomes are incompletely understood, however, growing evidence supports epigenetic dysregulation, including altered microRNA (miRNA) expression, as one putative mechanism. During pregnancy, miRNAs of placental origin can be packaged into vesicles and trafficked to distant targets in the maternal and fetal systems, where they are thought to play a key role in cellular communication. However, the potential role of placental miRNAs in air pollution-pregnancy outcome relationships is unknown. The goals of the proposed research are to 1) investigate windows of prenatal susceptibility to particulate air pollution exposure, and 2) examine whether altered extracellular vesicle (EV) encapsulated miRNAs of placental origin and placenta tissue miRNAs play a role in these relationships. During the mentored K99 phase, Dr. Cowell will leverage data from 800 mother- newborn pairs enrolled in the urban, predominantly minority PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort to investigate spatially (1x1 km) and temporally (daily) resolved fine particulate matter (PM2.5) exposure in relation to fetal growth, birthweight, and gestational age. To accomplish this, Dr. Cowell will train in methods for identifying windows of susceptibility, including distributive lag models (DLMs) and recently developed DLM extensions for examining interactions (e.g., PM2.5 ? sex). She will also train in computational methods for analyzing transcriptomic data, which she will apply in the R00 phase. During this phase, Dr. Cowell will investigate whether placental miRNAs, measured using RNA-seq, serve as a link between air pollution exposure and pregnancy outcomes using mediation analysis and will examine effects on the placental miRNA-mRNA regulatory network. She will also characterize changes in placental EV miRNAs across pregnancy and examine PM2.5 exposure in relation to change. Results from this research will inform public health strategies for reducing exposure and mitigating its impact during the most sensitive developmental periods. The proposed studies will also provide insight on how PM2.5 operates at the biological level and may contribute to the identification of early and informative biomarkers of pregnancy risk. Dr. Cowell's mentoring team has expertise in air pollution exposure, susceptibility modeling, transcriptomics, placental signaling and neonatology. This team will provide on-site training tailored to the proposed research aims and will guide Dr. Cowell's transition to independence and her establishment of a research program that integrates `big data' analytics into children's environmental health and molecular epidemiology research.
This proposal will identify windows of fetal susceptibility to particulate air pollution exposure and characterize how air pollution impacts placenta signaling and regulatory mechanisms during mid-pregnancy and at term. Findings will advance our understanding of molecular pathways linking air pollution exposure with adverse pregnancy outcomes, including poor fetal growth, low birthweight and preterm delivery. This significant research advance has the potential to improve pregnancy outcomes by informing interventions focused on reducing exposure during vulnerable developmental windows and identifying early and relatively non-invasive placental biomarkers of air pollution exposure and pregnancy health.
