PM exposure during pregnancy affects childhood asthma via placental epigenetic changes: Neuronal differentiation and proliferation and Notch signaling pathways.

Particulate matter (PM) exposure during pregnancy increases the risk of developing asthma in children. However, the placental mechanisms have yet to be elucidated. This study aims to evaluate the mechanisms associated with PM exposure during pregnancy and asthma susceptibility via placental epigenetic dysregulation. We analyzed data from two independent Korean birth cohorts (COCOA, 684 children; PSKC, 818 children). Physician-diagnosed current asthma and bronchial hyperresponsiveness (BHR) via methacholine challenge tests were evaluated at age seven. We estimated PM exposure with a diameter <10 μm (PM10) during pregnancy using land-use regression models. We performed genome-wide methylation profiling in the placenta of 40 samples in the COCOA study and analyzed the gene expression levels. High PM10 exposure during pregnancy increased the risk of developing current asthma and BHR in the COCOA study (aOR 2.36, 95% CI 1.06-5.22; aOR 2.14, 95% CI 1.40-3.27, respectively) and current asthma in the PSKC (aOR 2.62, 95% CI 1.35-5.09). The genes involved in neuronal differentiation and proliferation and Notch signaling pathways were significantly hypermethylated in children with high PM10-exposed asthma. The methylation and expression levels of eight genes (PAX6, REST, OLIG2, GLI1, ZBTB7A, NOTCH4, NOTCH1, and NOTCH3) in these pathways correlated with clinical parameters. This may effectively predict PM-related asthma through a prediction model using degrees of gene-based or CpG-based methylation (AUC = 0.96 and 0.93, respectively). PM10 exposure during pregnancy impacts asthma development in offspring via placental DNA hypermethylation via neuronal differentiation and proliferation and Notch signaling pathways.