345 - Maternal Exposure to Polycyclic Aromatic Hydrocarbons (PAH) Exacerbates Oxygen-mediated Neonatal Lung Injury and Causes Dysbiosis of Lung and Gut microbiome: The Role of cytochrome P450 (CYP)1A2

Publication Number: 1329.345

Deven Narke, Baylor College of Medicine, Houston, TX, United States; Bhagavatula Moorthy, Baylor College of Medicine, Houston, TX, United States; Weiwu Jiang, Baylor College of Medicine, Houston, 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 often leads to preterm births (PTB), which could in turn lead to bonchopulmonary dysplasia (BPD). The trifecta of maternal PAH exposure, preterm birth, and postnatal hyperoxia is known to exacerbate lung injury in neonates, predominantly through the activation of cytochrome P450 (CYP)1A/1B1 enzymes.

Objective: In this investigation, we tested the hypothesis that mice lacking the gene for cytochrome P450 (Cyp)1a2, would be more susceptible to lung injury mediated by maternal PAH administration followed by postnatal hyperoxia, and that CYP1A2 enzyme in part protects against lung injury by maintaining gut and lung microbial eubiosis.

Design/Methods: Timed pregnant wild-type (WT) (C57BL/6J) and Cyp1a2-null mice were orally administered a mixture of PAHs 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 offspring were exposed to oxygen (>85%) or room air (control) for 14 days after birth. Mice were sacrificed on postnatal day 15 and lung injury and microbiome analysis was performed on the lung and intestinal contents using 16S rRNA gene sequencing.

Results: Prenatal PAH exposure, followed by postnatal hyperoxia caused alveolar simplification in WT and Cyp1a2-null mice, with the latter displaying a lot more injury. PAH exposure alone significantly altered lung microbial beta diversity in Cyp1a2-null mice (Bray-Curtis, p-value: 0.002) and intestinal microbial beta diversity in WT (Bray-Curtis, p-value: 0.029) as well as Cyp1a2-null mice (Bray-Curtis, p-value: 0.003). Moreover, postnatal hyperoxia alone significantly altered intestinal microbial beta diversity in WT mice (Bray-Curtis, p-value: 0.016). Prenatal PAH exposure alone also significantly decreased the relative abundance of a bacterial family – Lactobacillaceae in the intestine of WT mice (Mann-Whitney, p-value: 0.0294) and increased the same in Cyp1a2-null mice (Mann-Whitney, p-value: 0.0135).

Conclusion(s): Our study suggests that maternal PAH exposure causes alterations in the lung and gut microbiome of newborn mice in the absence of the Cyp1a2 gene, suggesting a potential protective role. Further studies are needed to understand the complex interplay (liver-gut-lung axis) between the role of the CYP1A2 enzyme, environmental exposures, and their cumulative impact on lung and intestinal microbial communities, in relation to neonatal lung injury.