Association between early-life submicron particulate matter exposure, inducible nitric oxide synthase methylation, and children's asthma/wheezing

The impact of PM₁ (particulate matter with aerodynamic diameter ≤ 1 μm) exposure on asthma risk during specific fetal lung development windows, and its potential mediation by DNA methylation, remains understudied. Thus, we conducted a nested case-control study from the Prenatal Environments and Offspring Health cohort with children having asthma/wheezing. The results revealed a positive correlation between average prenatal PM₁ exposure and childhood asthma/wheezing risk (HR = 1.39, 95 % CI: 1.02, 1.90), especially during the pseudoglandular period. PM₁ exposure was negatively correlated with neonatal inducible nitric oxide synthase (iNOS) methylation (IQR (interquartile range) = 4.44 µg/m³, β = -1.19 %, 95 % CI: -2.23 %, -0.15 %). Additionally, a 5.6 % increase (the interquartile range) in neonatal iNOS methylation was associated with a reduced risk of childhood asthma/wheezing (OR = 0.62, 95 % CI: 0.43, 0.88). In vitro studies showed PM₁ treatment increased nitric oxide (NO) production and iNOS expression, and reduced iNOS methylation. Moreover, PM₁ induced the accumulation of reactive oxygen species (ROS) and pro-inflammatory responses in human bronchial epithelial (HBE) cells, activating NOD-like receptor protein 3 (NLRP3) inflammasomes and caspase-1 for inflammation, caspase-3 and caspase-9 for apoptosis. NF-κB expression, crucial for NLRP3 synthesis, was also increased. In conclusion, maternal PM₁ exposure was associated with childhood asthma/wheezing, especially during the pseudoglandular stage, and this effect may relate to iNOS hypomethylation as well as the exacerbation of oxidative stress and inflammation, possibly involving the iNOS/NLRP3/NF-κB signaling pathway.