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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.

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.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Mahemuti L,Chen Q,Coughlan MC,Qiao C,Chepelev NL,Florian M,Dong D,Woodworth RG,Yan J,Cao XL,Scoggan KA,Jin X,Willmore WG

doi

10.1007/s00204-017-2150-3

subject

Has Abstract

pub_date

2018-04-01 00:00:00

pages

1453-1469

issue

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-017-2150-3

journal_volume

pub_type

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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.