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Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts

  • Molecular Toxicology
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Abstract

Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction. Exposure to 100 μM BPA had no effects on cell viability, but increased cytoplasmic expression of ERβ and release of GDF-15, as well as decreased release of IL-6, ET-1, and IP-10 through suppression of NFκB phosphorylation. By performing global gene expression and pathway analysis in this study, we identified molecular pathways, gene networks, and key molecules that were affected by 100, but not 0.01 and 1 µM BPA in HFLF. Using multiple genomic and proteomic tools, we confirmed these changes at both gene and protein levels. Our data suggest that 100 μM BPA increased CYP1B1 and HSD17B14 gene and protein expression and release of endogenous estradiol, which was associated with increased ROS production and DNA double-strand breaks, upregulation of genes and/or proteins in steroid synthesis and metabolism, and activation of Nrf2-regulated stress response pathways. In addition, BPA activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence and autophagy, and decreased cell proliferation in HFLF. The results suggest that prenatal exposure to BPA at certain concentrations may affect fetal lung development and maturation, and thereby affecting susceptibility to childhood respiratory diseases.

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Acknowledgements

This research was funded by the Chemical Management Plan Research Fund, Government of Canada, Granted to the research team; Discovery Grant (06414-2012) from the Natural Sciences and Engineering Research Council of Canada (NSERC) Granted to WGW and NLC; NSERC-CREATE-REACT (449153-2014) Granted to WGW and LM, Health Canada internal research fund to XJ; and CGS D Scholarship to NLC. The authors thank Ms. Bai Li from University of Ottawa for helping with cell plating and splitting. The authors thank Dr. Ivan Curran in RTRD, Health Canada, for sharing IPA license.

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Authors and Affiliations

  1. Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, PL2202D, 251 Sir Frederick Banting Drive Way, Ottawa, ON, K1A 0K9, Canada

    Laziyan Mahemuti, Melanie C. Coughlan, Maria Florian, Dillon Dong, Robert G. Woodworth, Jin Yan & Xiaolei Jin

  2. Nutrition Research Division, Bureau of Nutrition Sciences, Food Directorate, HPFB, Health Canada, Ottawa, ON, Canada

    Qixuan Chen & Kylie A. Scoggan

  3. Biostatistics and Modeling Division, Bureau of Food Surveillance and Science Integration, Food Directorate, HPFB, Health Canada, Ottawa, ON, Canada

    Cunye Qiao

  4. Departments of Biology and Chemistry, Institute of Biochemistry, Carleton University, Ottawa, ON, Canada

    Laziyan Mahemuti, Nikolai L. Chepelev, Maria Florian & William G. Willmore

  5. Food Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, Ottawa, ON, Canada

    Xu-liang Cao

  6. Mechanistic Studies Division, Environmental Health Science and Research Bureau, Environmental and Radiation Health Sciences Directorate, HECSB, Health Canada, Ottawa, ON, Canada

    Nikolai L. Chepelev

  7. Sector Strategies Division, Risk Management Bureau, Safe Environments Directorate, HECSB, Health Canada, Ottawa, ON, Canada

    Kylie A. Scoggan

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  1. Laziyan Mahemuti
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  2. Qixuan Chen
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  3. Melanie C. Coughlan
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  6. Maria Florian
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  9. Jin Yan
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Correspondence to Xiaolei Jin.

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Mahemuti, L., Chen, Q., Coughlan, M.C. et al. Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol 92, 1453–1469 (2018). https://doi.org/10.1007/s00204-017-2150-3

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