Placental gene networks at the interface between maternal PM_2.5 exposure early in gestation and reduced infant birthweight

Background: A growing body of evidence links maternal exposure to particulate matter <2.5 μM in diameter (PM_2.5) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM_2.5 exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM_2.5 exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM_2.5 exposure prior to and during pregnancy and infant birthweight. Methods: We evaluated PM_2.5 exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM_2.5 levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM_2.5 weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM_2.5 levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package. Results: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM_2.5 exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM_2.5 exposure levels averaged across the identified growth restriction window. Conclusion: Our findings suggest that maternal PM_2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections.