Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Yang, Kaiping

Abstract

Developmental exposure to bisphenol A (BPA), a ubiquitous endocrine disrupting chemical, is associated with organ dysfunction and diseases in adulthood. However, little is known about its effects on the adrenal glands. Therefore, this thesis addresses this important question using both in vivo and in vitro approaches. BPA at environmentally relevant doses was administrated via diet to pregnant mice from embryonic day 7.5 to birth, following which mice were switched to a standard chow. At two months postnatally, adrenal glands and blood samples were collected from adult mouse offspring for structural and functional analysis. I found that: (a) BPA increased adrenal gland weight as well as plasma corticosterone levels; (b) BPA did not alter plasma levels of ACTH; and (c) BPA stimulated expression of the two key steroidogenic factors, steroidogenic acute regulatory protein (StAR) and cyp11A1 in female but not male offspring. To determine the molecular mechanisms underlying the BPA-induced StAR expression, I used human fetal adrenal cortical H295A cells as an in vitro model system, and showed that BPA increased StAR protein expression likely through an estrogen receptor (ER)-mediated mechanism independent of StAR gene transcription, translation and protein half-life. I then investigated the molecular mechanisms underlying the BPA-induced increase in adrenal gland weight using the same in vitro model system. I demonstrated that (a) BPA increased cell number and protein levels of the three universal markers of proliferation (proliferating cell nuclear antigen (PCNA), cyclin D1 and D2, as well as sonic hedgehog (shh) and its key transcriptional regulator Gli1; (b) cyclopamine, a shh pathway inhibitor, blocked these stimulatory effects of BPA on cell proliferation; (c) BPA increased the nuclear translocation of ERβ; and (d) the ERb-specific agonist DPN mimicked while the ERb antagonist PHTPP abrogated the stimulatory effects of BPA on cell proliferation, and prevented BPA-induced activation of the shh signaling. Taken together, these findings demonstrate that developmental exposure to BPA adversely affects adrenal gland development and steroidogenic function in adult mouse offspring. Furthermore, they reveal novel molecular signaling mechanisms of BPA actions in regulating adrenal steroidogenic function and adrenal cortical cell proliferation.

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