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Title:Defining critical windows in pituitary development and elucidating sex differences in response to bisphenoL A
Author(s):Eckstrum, Kirsten S
Director of Research:Raetzman, Lori T.
Doctoral Committee Chair(s):Raetzman, Lori T.
Doctoral Committee Member(s):Flaws, Jodi A.; Bagchi, Milan K.; Nelson, Erik R.
Department / Program:Molecular & Integrative Physl
Discipline:Molecular & Integrative Physi
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Bisphenol A
Critical windows
Abstract:Exposure to hormones or endocrine disrupting chemicals (EDCs) can have many adverse effects on the endocrine system and can potentially lead to endocrine related adverse health effects such as reproductive dysfunction, obesity, and thyroid dysfunction. The pituitary gland plays a critical role in regulation of the endocrine axes; therefore, if EDCs affect the pituitary, it could lead to the development of endocrine related health effects. Exposure to EDCs during developmental windows is often more detrimental due to the perceived higher sensitivity and the potential for exposure to have lasting effects. Pituitary development occurs during two critical windows: embryonic and neonatal. During these periods, progenitor cells proliferate and eventually differentiate to one of three lineages. One EDC, bisphenol A (BPA), has been shown to alter embryonic pituitary development in a sex specific manner, however, the effects of exposure in the neonatal period have not been examined. Before examining the potential sex specific effects of BPA exposure, we first analyzed what baseline sex differences exist in the neonatal pituitary. We found that three genes, Lhb, Fshb, and Icam5, were higher in females than males and that these genes were decreased by exposure to estradiol. All the sexually dichotomous genes were found in the gonadotrope cells of the pituitary, demonstrating that even at an early age, there are sex differences in the neonatal hypothalamic pituitary gonadal axis and estradiol can regulate these differences. Because the neonatal pituitary could be altered by the naturally circulating hormonal milieu, we hypothesized that the neonatal pituitary would be sensitive to exogenous BPA and estradiol (E2) exposure and there would be sex specific effects of this exposure. We examined the effects of exposure to BPA on the neonatal pituitary. Interestingly, BPA was able to alter gene expression in the neonatal pituitary, however, not in the same way it was able to affect the embryonic pituitary. Proliferation and the gonadotrope lineage were altered with embryonic exposure, whereas the corticotrope/melanotrope and PIT1 lineages were altered in the neonatal exposure paradigm. This suggests that there are differences between the embryonic and neonatal period, which may contribute to divergent effects of BPA during the two critical windows of development. Additionally, dose and sex specific effects were observed, which shows there may be additional sex differences in the neonatal pituitary. This also shows that BPA can alter every axis of the pituitary, though the time, dose, and sex are all contributing factors to what is altered. Due to the ability of E2 and BPA to disrupt estrogen signaling and to regulate gene transcription in the pituitary, we examined further the mechanisms by which this regulation takes place. We hypothesized that E2 and BPA would be able to regulate gene transcription directly at the pituitary and this regulation would be carried out by the most ubiquitously expressed estrogen receptor, ESR1. To test this hypothesis, we treated pituitaries in ex vivo cultures with E2, BPA, or ER-subtype selective agonists and antagonist and analyzed expression of the sexually dichotomous genes. Interestingly, sex specific effects were seen with direct stimulation of the pituitary, showing that the pituitary itself maintains sex differences. Also, regulation of the sexually dichotomous genes in vivo did not always match what was seen in the cultures demonstrating other factors may be important in gene regulation. Interestingly, all of the sexually dichotomous genes appeared to be regulated via different estrogen receptor-subtypes or combinations of subtypes, demonstrating the diversity of estrogen signaling pathways within a cell. Of particular interest, Icam5 was regulated by a combination of nuclear and membrane signaling demonstrating that this decrease may be through a multi-step process that will be analyzed further in the future. Taken together, these studies demonstrate that the neonatal pituitary is sensitive to estrogen signaling through multiple pathways and therefore, exposure to EDCs that can interfere with this process to disrupt the neonatal pituitary in sex specific ways.
Issue Date:2017-04-17
Rights Information:Copyright 2017 Kirsten Eckstrum
Date Available in IDEALS:2017-08-10
Date Deposited:2017-05

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