The aryl hydrocarbon receptor is involved in the pathogenesis of congenital diaphragmatic hernia
Introduction: Environmental factors may contribute to 70% of CDH cases. A specific class of environmental chemicals can activate the transcription factor aryl hydrocarbon receptor (AHR) to change gene expression. We hypothesize that activation of AHR by these chemicals is involved in the pathogenesis of CDH.
Methods: Ethical approval was obtained prior to experiments (19-010 (AC11436)). We compared the response of AHR to nitrofen to known ligands - benzo[α]pyrene and resveratrol - in the BEAS-2B human epithelial cell line (n=3). AHR activity within a 24 hour exposure period was assessed with immunocytochemistry (ICC/IF). We compared the abundance of AHR in saccular lung sections (n=3) from human CDH patients (Week 39-40) and nitrofen-treated rat pups (E21) to age-matched controls using immunofluorescence.
Results: AHR activation was induced in BEAS-2B cells within six hours of treatment. We observed all ligands to induce the translocation of AHR fluorescence signal from the cytoplasm (inactive) to nucleus (active), suggesting nitrofen activates AHR. After 24 hours of treatment, the AHR signal was strictly cytoplasmic and diminished. CDH patients and rat lung sections have increased AHR abundance in the mesenchyme and airways compared to controls.
Conclusion: We observed nuclear translocation of AHR indicating activation of the receptor. We saw similar changes in AHR abundance in both human CDH and nitrofen rat lungs; suggesting that similar pathological mechanisms are involved. This dysregulated expression of AHR may contribute to abnormal lung development in babies born with CDH. The results suggest that environmental chemicals structurally similar to nitrofen may activate AHR to induce CDH.