In Vitro Study of Mechanisms Underlying the Developmental Effects of Bisphenol A Using Human Fetal Lung Fibroblasts

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Creator: 

Laziyan, Mahemuti

Date: 

2017

Abstract: 

Both 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 study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24 h exposure to 1 and 100 µM BPA increased nuclear expression of GPR30, at 100 μM, also 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, with no effects on cell viability. By performing global gene expression and pathway analyses, 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 also activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence, and autophagy in HFLF. Fetal lung development and maturation requires paracrine interaction between fetal lung alveolar type II epithelial cells and fibroblasts. The results from our studies suggest that prenatal exposure to BPA at high enough concentrations may affect fetal lung development and maturation, by altering the release of developmental, immune, and hormonal modulators from fetal lung fibroblasts, and thereby affecting susceptibility to childhood respiratory disease.

Subject: 

Cell biology
Biology - Molecular

Language: 

English

Publisher: 

Carleton University

Thesis Degree Name: 

Doctor of Philosophy: 
Ph.D.

Thesis Degree Level: 

Doctoral

Thesis Degree Discipline: 

Biology

Parent Collection: 

Theses and Dissertations

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