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Bisphenol A suppresses glucocorticoid target gene (ENaCγ) expression via a novel ERβ/NF-κB/GR signalling pathway in lung epithelial cells

  • Molecular Toxicology
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Abstract

We previously demonstrated that prenatal exposure to Bisphenol A (BPA) disrupts fetal lung maturation likely through the glucocorticoid signalling pathway, but the precise molecular mechanisms remain obscure. Given that BPA diminished the expression of epithelial sodium channel-γ (ENaCγ), a well-known glucocorticoid receptor (GR) target gene, in fetal lungs, we used this GR target gene to delineate the molecular pathway through which BPA exerts its effects on lung cells. The A549 lung epithelial cell line was used as an in vitro model system. As a first step, we validated our in vitro cell model by demonstrating a robust concentration-dependent suppression of ENaCγ expression following BPA exposure. We also showed that both dexamethasone and siRNA-mediated knockdown of GR expression blocked/abrogated the inhibitory effects of BPA on ENaCγ expression, suggesting that BPA repressed ENaCγ expression via inhibition of GR activity. Given the well-known antagonistic interactions between the pro-inflammatory transcriptional factor NF-κB and GR, we then showed that BPA inhibited GR activity through the activation of NF-κB. Lastly, since BPA is known to function as a pro-inflammatory factor via the estrogen receptor β (ERβ), we provided evidence that BPA signals through ERβ to activate the NF-κB signalling pathway. Taken together, these findings demonstrate that BPA acts on ERβ to activate the NF-κB signalling pathway, which in turn leads to diminished GR activity and consequent repression of ENaCγ expression in lung epithelial cells. Thus, our present study reveals a novel BPA signalling pathway that involves ERβ, NF-κB and GR.

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Authors and Affiliations

  1. Departments of Obstetrics & Gynaecology and Physiology & Pharmacology, Children’s Health Research Institute & Lawson Health Research Institute, Western University, 800 Commissioners Rd. E., London, ON, N6C 2V5, Canada

    Ayten Hijazi, Haiyan Guan & Kaiping Yang

  2. Children’s Health Research Institute, Room A5-132, Victoria Research Laboratories, 800 Commissioners Road East, London, ON, N6C 2V5, Canada

    Kaiping Yang

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  1. Ayten Hijazi
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  2. Haiyan Guan
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Correspondence to Kaiping Yang.

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Hijazi, A., Guan, H. & Yang, K. Bisphenol A suppresses glucocorticoid target gene (ENaCγ) expression via a novel ERβ/NF-κB/GR signalling pathway in lung epithelial cells. Arch Toxicol 91, 1727–1737 (2017). https://doi.org/10.1007/s00204-016-1807-7

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