Background Prenatal air pollution exposure (PAPE) may have programming effects on offspring health. Placental epigenetic modifications are hypothesised to mediate this relationship, but evidence remains limited. We investigated the mediating role of placental DNA methylation (DNAm) in the association between prenatal exposure to NO 2 , PM 2.5 and PM 2.5 oxidative potential (OP) and newborn lung function. Methods Placental DNAm was measured using the Infinium HumanMethylationEPIC BeadChip in 395 participants from the French cohort SEPAGES. PAPE was estimated via personal sensors. Lung function (6 parameters) was measured at two months through tidal breathing analysis and nitrogen multiple breath washout test. We conducted adjusted epigenome-wide mediation analyses to identify genomic loci (CpGs and aggregated methylated regions; AMRs) that explain the association between PAPE and offspring lung function. Findings Thirty CpGs and 166 AMRs significantly mediated the PAPE-lung function relationship. Most mediators were involved in the effect of P M 2.5 OP on the functional residual capacity (FRC) and the lung clearance index (LCI). While most DNAm changes mediated adverse effects, several loci—especially within imprinted genes—were associated with potentially adaptive responses. Mediating loci mapped to genes involved in lung development, immunity, inflammation and oxidative stress. Expression quantitative trait methylation (eQTM) analyses revealed that nearly one quarter of the mediating CpGs and one half of the AMRs may regulate gene expression. Interpretation Our findings provide insights into the epigenetic pathways linking PAPE to early-life lung function. They highlight the placenta as a critical interface, where both detrimental and compensatory epigenetic modifications may shape newborn lung function. Funding French Agency for National Research.
Broséus et al. (Wed,) studied this question.