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

Meng-Die Li; Li-Hong Chen; Hui-Xian Xiang; Ya-Lin Jiang; Bian-Bian Lv; De-Xiang Xu; Hui Zhao; Lin Fu

doi:10.1016/j.jhazmat.2024.134560

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. Online ahead of print.

Authors

Meng-Die Li¹, Li-Hong Chen¹, Hui-Xian Xiang², Ya-Lin Jiang³, Bian-Bian Lv¹, De-Xiang Xu⁴, Hui Zhao⁵, Lin Fu⁶

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: xudex@126.com.
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: zhaohuichenxi@126.com.
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: fulindev@126.com.

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.