Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. Kaiping Yang

Abstract

Prenatal exposure to bisphenol A (BPA), one of the most prevalent endocrine disrupting chemicals, is associated with lung dysfunction and diseases in later life. However, it is unknown if this association has a fetal origin. In this thesis, a series of in vivo and in vitro experiments were conducted to determine the effects of prenatal exposure to BPA on fetal lung development, and define the underlying molecular mechanisms. Environmentally relevant doses of BPA were administered to pregnant mice via diet from embryonic day (E) 7.5 to 18.5. Fetal lungs were analyzed at E18.5 for changes in structure and expression of key molecular markers of lung maturation. My main findings were: (a) BPA severely retards fetal lung maturation as evidenced by diminished alveolar airspace and thickened septa, hallmarks of lung immaturity; (b) this immaturity is characterized by aberrant alveolar epithelial type I cell differentiation; and (c) the effects of BPA are likely mediated through the glucocorticoid signaling pathway, because the expression of epithelial sodium channel g (ENaCγ), a well-known glucocorticoid receptor (GR) target gene, is down-regulated in BPA-exposed fetal lungs. Moreover, maternal administration of dexamethasone rescues the lung immaturity phenotype. However, the precise molecular mechanisms by which BPA represses ENaCγ in lung cells were unknown. This important question was addressed using the A549 human lung epithelial cell line as an in vitro model system. I found that that (d) both dexamethasone and siRNA-mediated knockdown of GR expression blocked the inhibitory effects of BPA on ENaCγ expression, indicating that BPA suppresses ENaCγ via inhibition of GR activity. Given that BPA is known to function as a pro-inflammatory factor via the estrogen receptor b (ER b), and a mutual antagonism exists between the pro-inflammatory transcriptional factor NF-κB and GR, I then explored and provide evidence supporting the notion that (e) BPA acts on ER-β to activate the NF-κB signaling pathway, which in turn leads to diminished GR activity and consequent repression of ENaCγ expression in lung cells. Taken together, these findings demonstrate that prenatal exposure to BPA disrupts fetal lung maturation, and suggest a fetal origin for BPA-induced lung dysfunction and diseases.