Archives of Toxicology

, Volume 92, Issue 4, pp 1453–1469 | Cite as

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

  • Laziyan Mahemuti
  • Qixuan Chen
  • Melanie C. Coughlan
  • Cunye Qiao
  • Nikolai L. Chepelev
  • Maria Florian
  • Dillon Dong
  • Robert G. Woodworth
  • Jin Yan
  • Xu-liang Cao
  • Kylie A. Scoggan
  • Xiaolei Jin
  • William G. Willmore
Molecular Toxicology

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.

Keywords

Bisphenol A Human fetal lung fibroblasts ATM signaling DNA double-strand breaks γ-H2AX p53 Nrf2 ROS Estradiol release CYP1B1 HSD17B14 Cell cycle arrest G1/S transition Senescence Autophagy Steroid synthesis and metabolism 

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors claim no conflict of interests related to the work described in this paper.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Laziyan Mahemuti
    • 1
    • 4
  • Qixuan Chen
    • 2
  • Melanie C. Coughlan
    • 1
  • Cunye Qiao
    • 3
  • Nikolai L. Chepelev
    • 4
    • 6
  • Maria Florian
    • 1
    • 4
  • Dillon Dong
    • 1
  • Robert G. Woodworth
    • 1
  • Jin Yan
    • 1
  • Xu-liang Cao
    • 5
  • Kylie A. Scoggan
    • 2
    • 7
  • Xiaolei Jin
    • 1
  • William G. Willmore
    • 4
  1. 1.Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food DirectorateHPFB, Health CanadaOttawaCanada
  2. 2.Nutrition Research Division, Bureau of Nutrition Sciences, Food DirectorateHPFB, Health CanadaOttawaCanada
  3. 3.Biostatistics and Modeling Division, Bureau of Food Surveillance and Science Integration, Food DirectorateHPFB, Health CanadaOttawaCanada
  4. 4.Departments of Biology and Chemistry, Institute of BiochemistryCarleton UniversityOttawaCanada
  5. 5.Food Research Division, Bureau of Chemical Safety, Food DirectorateHPFB, Health CanadaOttawaCanada
  6. 6.Mechanistic Studies Division, Environmental Health Science and Research Bureau, Environmental and Radiation Health Sciences DirectorateHECSB, Health CanadaOttawaCanada
  7. 7.Sector Strategies Division, Risk Management Bureau, Safe Environments DirectorateHECSB, Health CanadaOttawaCanada

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