594 - Loss of Aryl hydrocarbon receptor (AHR) Exacerbates Hyperoxia-Induced Alveolar Simplification in Neonatal Mice Exposed to Prenatal Polycyclic Aromatic Hydrocarbons (PAHs)

Poster Number: 594
Publication Number: 594.1156

Background: Pregnant women exposed to polycyclic aromatic hydrocarbons (PAHs) are at increased risk for preterm birth (PTB), which is in turn a risk factor for bronchopulmonary dysplasia (BPD) in infants. The Aryl hydrocarbon receptor (AHR) is expressed in many lung cell types, including macrophages, club cells, alveolar type II cells, and endothelial cells. Studies in adult mice have shown that AHR deficiency exacerbates inflammation and injury due to exposure to hyperoxia, while AHR activation mitigates these effects, probably via cytochrome P450 (CYP)1A enzymes.

Objective: In this investigation, we tested the hypothesis that the disruption of AHR augments neonatal hyperoxic lung injury, following prenatal exposure to polycyclic aromatic hydrocarbons (PAHs).

Design/Methods: Pregnant mice, both wild type (WT) (C57BL/6J) and AHR-null, were orally administered a mixture of PAHs, including benzo[a]pyrene (BP 7.5 mg/kg) and benzo[b]fluoranthene (BbF 7.5 mg/kg), or the vehicle corn oil (CO) once daily during gestational days 15-18. Newborn mice were subjected to hyperoxia or room air conditions for 14 days. Neonatal lung injury was assessed on postnatal day 15 (PND15) using radial alveolar count (RAC), mean linear intercept (MLI) and lung weight/body weight (LW/BW) ratio (n ≥ 6). Gene expression of CYP1 family enzymes in the lung and liver, as well as TNF-alpha expression was measured. Data were presented as means ± SE. Statistical significance was determined using ANOVA (p < 0.05).

Results: Our results showed that maternal PAH exposure potentiated alveolar simplification in neonatal mice exposed to hyperoxia. The abnormal lung maturation was further exacerbated in mice lacking the AHR gene. Inactivation of AHR signaling enhanced the injurious effects of hyperoxia, as evidenced by retarded alveolarization [WT RAC (3.43) vs AHR-null (2.53), 29.1% decrease, n=6, p < 0.05]; [WT MLI (72.17 µm vs AHR-null (85.15 µm), 18.0% increase, p < 0.05)] and increased LW/BW ratio [WT (13.4 mg/g) vs AHR-null (14.8 mg/g) 10.4% increase, p < 0.05)] in neonatal mice. Moreover, prenatal PAH exposure induced significant induction in hepatic and pulmonary CYP1 gene expression in neonatal lungs exposed to hyperoxia in WT but not AHR-null pups. Also, there was a significant augmentation of TNF-alpha gene expression in lungs of AHR-null mice compared to WT mice, which was probably due to increased lung inflammation in these mice.

Conclusion(s): Our findings indicate that AHR plays a beneficial role against neonatal lung injury, and that non-toxic AHR a could agonists could be used for prevention/treatment of BPD in infants.