223 - Disruption of CYP1A2 leads to Enhanced Lung Injury, Altered Gene expression and Metabolomic Profiles in Mice Exposed to Maternal Polycyclic Aromatic Hydrocarbons (PAHs) and Postnatal Hyperoxia

Publication Number: 223.4560

Bhagavatula Moorthy, Baylor of Medicine, Houston, TX, United States; Deven Narke, Baylor College of Medicine, Houston, TX, United States; Sandra Grimm, Baylor College of Medicine, Houston, TX, United States; Cristian Coarfa, Baylor College of Medicine, Missouri City, TX, United States

Background: Polycyclic Aromatic Hydrocarbons (PAHs) are complex chemical mixtures that are found in cigarette smoke, superfund sites, and industrial effluents. Maternal exposure to PAHs is a risk factor for preterm births and development of bronchopulmonary dysplasia (BPD) in premature infants. The liver-specific cytochrome P450 (CYP)1A2 has been shown to play a protective role against hyperoxic lung injury.

Objective: In this investigation, we tested the hypothesis that newborn mice lacking the gene for Cyp1a2 enzyme would show exacerbated lung injury, and altered transcriptomic and metabolomic profiles in response to maternal PAH exposure and postnatal hyperoxia.

Design/Methods: Timed pregnant wild-type (WT) (C57BL/6J) and Cyp1a2-null mice (n=4) were orally administered a PAH mixture of benzo[a]pyrene (BP) and benzo[b]fluoranthene (BbF) (7.5mg/kg each) or the vehicle corn oil (CO) once daily on gestational days 16-19. The newborn mice were exposed to oxygen (>85%) or room air (control) for 14 days. Mice were euthanized on postnatal day (PND) 15, and alveolar simplification was evaluated using morphometry. Gene expression and metabolomic profiling was performed using bulk RNA-sequencing and unbiased metabolomics, respectively. Data were analyzed using 2- way ANOVA with Bonferroni post-hoc pairwise comparisons, and p < 0.05 was considered was statistically significant.

Results: In comparison to WT controls, Cyp1a2-null mice exposed maternally to PAHs, followed by postnatal hyperoxia showed significantly increased alveolar simplification and exacerbated lung injury (P < 0.05). Overlapping with WT mice hyperoxia gene signature, we observed a significant increase of 20 genes, including Nmrk2, Il6, Fga, and suppression of 157 genes, including Myh4, Myh8, Defb14. We determined genes associated with differential metabolites using the MetaboAnalyst platform, and identified gene ontology enriched pathways. We found that 589, 142, and 62 enriched pathways were specific to CO + O2, common to both, and unique to PAH + O2, respectively. For PAH+O2 exposure, the loss of Cyp1a2 led to an enrichment for pathways of branched chain amino acids and TCA cycle.

Conclusion(s): This study shows that maternal PAH exposure combined with postnatal hyperoxia worsens lung injury and disrupts key developmental pathways in Cyp1a2-null mice, and inflammatory and lung development-related genes were specifically altered. Metabolomic analysis highlighted disruptions in critical pathways specific to PAH exposure. These findings underscore the protective role of Cyp1a2 enzyme in neonatal lung health under environmental stress.