Benzo[a]pyrene evokes epithelial-mesenchymal transition and pulmonary fibrosis through AhR-mediated Nrf2-p62 signaling

  • J Hazard Mater. 2024 May 8:473:134560. doi: 10.1016/j.jhazmat.2024.134560.
Meng-Die Li  1 ,  Li-Hong Chen  1 ,  Hui-Xian Xiang  2 ,  Ya-Lin Jiang  3 ,  Bian-Bian Lv  1 ,  De-Xiang Xu  4 ,  Hui Zhao  5 ,  Lin Fu  6
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
  • 2. Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Department of Respiratory and Critical Care Medicine, Chengdu Fifth People's Hospital, Chengdu, Sichuan 611130, China.
  • 3. Department of Respiratory and Critical Care Medicine, Bozhou People's Hospital, Bozhou, Anhui 236800, China.
  • 4. Department of Toxicology, Anhui Medical University, Hefei, Anhui 230032, China. Electronic address: [email protected].
  • 5. Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China. Electronic address: [email protected].
  • 6. Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China. Electronic address: [email protected].
PMID: 38759404 DOI: 10.1016/j.jhazmat.2024.134560
Abstract

Benzo[a]pyrene (BaP) and its metabolic end product benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE), are known toxic environmental pollutants. This study aimed to analyze whether sub-chronic BPDE exposure initiated pulmonary fibrosis and the potential mechanisms. In this work, male C57BL6/J mice were exposed to BPDE by dynamic inhalation exposure for 8 weeks. Our results indicated that sub-chronic BPDE exposure evoked pulmonary fibrosis and epithelial-mesenchymal transition (EMT) in mice. Both in vivo and in vitro, BPDE exposure promoted nuclear translocation of Snail. Further experiments indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) and p62 were upregulated in BPDE-exposed alveolar epithelial cells. Moreover, Nrf2 siRNA transfection evidently attenuated BPDE-induced p62 upregulation. Besides, p62 shRNA inhibited BPDE-incurred Snail nuclear translocation and EMT. Mechanically, BPDE facilitated physical interaction between p62 and Snail in the nucleus, then repressed Snail protein degradation by p62-dependent autophagy-lysosome pathway, and finally upregulated transcriptional activity of Snail. Additionally, Aryl Hydrocarbon Receptor (AhR) was activated in BPDE-treated alveolar epithelial cells. Dual-luciferase assay indicated activating AhR could bind to Nrf2 gene promoter. Moreover, pretreatment with CH223191 or α-naphthoflavone (α-NF), AhR antagonists, inhibited BPDE-activated Nrf2-p62 signaling, and alleviated BPDE-induced EMT and pulmonary fibrosis in mice. Taken together, AhR-mediated Nrf2-p62 signaling contributes to BaP-induced EMT and pulmonary fibrosis.

Keywords
AhR; Benzo[a]pyrene; Epithelial-mesenchymal transition; Nrf2-p62 signaling; Pulmonary fibrosis.
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