Time series of transcriptome analysis in entire lung development stages provide insights into the origin of NO₂ related lung diseases

Lung growth is a critical window, when exposure to various pollutants can disturb the finely-tuned lung development and enhance risk of long-term structural and functional sequelae of lung. In this study, pregnant C57/6 mice were treated with NO₂, and lungs of fetus/offspring were collected at different developmental windows and dynamic lung development was determined. The results showed that maternal NO₂ exposure suppressed fetal weight, implying that fetal development can be disturbed. The time-series RNA-seq analysis of lungs showed that maternal NO₂ exposure induced significant time-dependent changes in the expression profiles of genes associated with lung vein myocardium development in fetus/offspring. Most of these genes in NO₂ exposure group were suppressed at middle gestation and at birth. Our results also indicated that the gene expressions of Nkx2.5 in NO₂ exposure were suppressed to 0.27- and 0.44-fold of the corresponding Air group at E13.5 and PND1, and restored at later time points. This indicated that the transcription factor Nkx2.5 played an important role in abnormal lung development in fetus/offspring caused by maternal NO₂ exposure. Importantly, gene expressions of lung vein myocardium development were related to transcription factors (TFs) and lung functions, and TFs showed similar trends with lung function. These results provide a comprehensive view of the adverse effects of maternal NO₂ exposure on fetal lung development by uncovering molecular targets and related signaling pathways at the transcriptional level.