Cytochrome P450 and metallothionein activation in human lung organoids following particulate matter exposure

Particulate matter (PM) has raised increasing concerns regarding its adverse impact on respiratory health. Although numerous studies have investigated PM effects under varying conditions, most have relied on cancer-derived cell lines or animal models that lack the cellular complexity and physiological relevance of human lung tissue. To address this limitation, we generated functional lung organoids (hLOs) derived from human embryonic stem cells to evaluate transcriptomic and toxicological responses to PM exposure. Transcriptome profiling of hLOs exposed to European Reference Material (ERM) revealed 283 differentially expressed genes, primarily enriched in xenobiotic metabolism and oxidative stress-related pathways. ERM exposure significantly upregulated CYP1A1 expression and enzymatic activity in a dose-dependent manner, while increasing reactive oxygen species production. Comparative analysis with diesel particulate matter treatment showed distinct gene expression profiles but identified a conserved subset of commonly upregulated genes, including CYP1A1, CYP1B1, and metallothionein family members (MT2A, MT1E, MT1G)—key regulators of xenobiotic metabolism and oxidative stress defense. Network analysis revealed molecular connectivity between these gene families, demonstrating that hLOs recapitulate metabolic and oxidative stress responses to compositionally distinct PMs. This study provides a physiologically relevant in vitro platform for assessing the pulmonary effects of environmental pollutants.