Weighted gene co-expression network analysis of early-life PM₂.₅-Exposed lung transcriptome identifies key gene...

Early-life exposure to fine particulate matter (PM₂.₅) is increasingly implicated in the developmental origins of chronic respiratory diseases; however, the underlying molecular mechanisms remain poorly defined. This study employed Weighted Gene Co-expression Network Analysis (WGCNA) to investigate transcriptomic alterations associated with intrauterine and early neonatal PM₂.₅ exposure in the developing murine lung. Microarray data (GSE104656) spanning embryonic (E14.5, E18.5) and postnatal (P40) stages were processed using robust normalization and variance filtering to construct a scale-free co-expression network. Principal component analysis revealed that developmental maturation was the primary driver of global transcriptional variation, with no distinct separation attributable to PM₂.₅ exposure. WGCNA identified biologically relevant gene modules involved in immune and metabolic processes as well as cell cycle regulation, that exhibited strong correlations with developmental progression. Functional enrichment analysis confirmed significant involvement in immune activation, leukocyte adhesion, DNA replication, and chromosomal organisation. Although differential expression analysis under stringent thresholds did not detect significant PM₂.₅-responsive genes, integrative network analysis identified eleven exposure-associated genes embedded within key modules. These genes, including Vnn1, Gprc6a, Mfap1a, Rgs16, and Fpr1, represent highly connected hub nodes implicated in oxidative stress regulation, extracellular matrix remodelling, metabolic signalling, and immune modulation. It was concluded that early-life PM₂.₅ exposure did not globally disrupt lung transcriptomic architecture but selectively perturbs critical hub genes within developmental networks. This targeted sub-network vulnerability provided a mechanistic basis for the developmental programming of COPD susceptibility, linking early environmental insults to long-term respiratory dysfunction.