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The Mechanisms of BPA Exposure and in the Developing Mammary Gland

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The Mechanisms of BPA Exposure and in the Developing Mammary Gland The mechanisms of BPA exposure and in the developing mammary gland DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Andrea R. Hindman Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2017 Dissertation Committee: Craig J. Burd, Advisor Helen M. Chamberlin Ruth A. Keri (Case Western Reserve University) Thomas Ludwig Mark R. Parthun Copyrighted by Andrea R. Hindman 2017 Abstract It is estimated that greater than 40,000 women in the United States will die from breast cancer this year and over 250,000 will be newly diagnosed. Greater than 70% of these cases are attributable to environmental factors, some of which are suspected to be a consequence of extensive human exposure to estrogenic compounds, collectively known as endocrine disrupting compounds (EDCs). Significant evidence from animal models suggests that chronic and/ or early-life exposure to known EDCs, such as bisphenol A (BPA) and genistein (GEN) are linked to increased risk and mediators of epithelial transformation to impart later-life development of breast cancer. However, the consequences of vast human exposures are largely unknown, immeasurable and the molecular mechanisms are largely undefined. Herein, we have utilized two distinct models to address undefined facets of the EDC mechanism. We address molecular mechanisms of chronic exposures that are representative of observed human exposures and examine windows of differential in utero BPA exposure to narrow possible developmental mechanisms at time of exposure that may propagate EDC-mediated alterations to later-life. We emphasize the importance of understanding the transcriptional alterations and epigenetic landscape of adult mammary component cell types, given the primary focus of current work to be on embryonic manifestation of disease and susceptibility. Our analyses demonstrate sustained reprogramming of the estrogen response beyond cessation of chronic exposures. Further we attribute the well- ii characterized BPA in utero phenotype to a period in mammary gland development corresponding to discrete tissue compartment interactions, corroborating the vital paracrine signaling that occurs at this in utero time of exposure. Our analyses are the first of its kind to map transcriptional and epigenetic alterations following in utero BPA exposure in the adult mammary gland. Taken together, our findings can inform analysis of human populations, determining the mechanisms of deregulation by in utero BPA exposures that contribute to later-life breast cancer risk and encourage alternative compounds. We believe while these mechanisms have been investigated specific to BPA, our findings can be extended to and provide a basis of concern for other known and suspected EDCs. iii Dedication Dedicated, with love to my mother, Grace Ann, whom at the end of this journey I always believed I would have close to me celebrating this milestone and beyond. Throughout my life, she gave me the confidence and any and all resources she could to ensure I had the best chance of accomplishing anything I set out to do, no matter how fleeting some of those aspirations were. Only recently have I realized how much she gave me and my sister. When I had the opportunity to ask her, in the hopes I could raise my children with similar courage and confidence that she cultivated in us, she simply said ‘I just wanted to make sure you knew you could do anything. You never know until you try.’ So I continue to try without you now and hope I can come close to the example you set forth in never settling on anything less than what you believed you could do and never taking no for an answer. I also dedicate this work to my wonderfully supportive husband that I credit for my stamina towards completing my doctoral work. I could have never done it without your love and support and I look forward to our next adventure together, in happier times, welcoming our son, Evan, and pursuing the careers we both have imagined for ourselves. I love you with all my heart and I could not have asked for a better partner in life (PIL). iv Acknowledgments I am grateful to have an army of support surrounding me. My Dad - for instilling in me hard work, dedication and respect for all unless they prove otherwise. Kara Barrett – ever since that first phone call you dropped on me as I sat in my lonely apartment my first year of graduate school, you have been a constant source of empowerment. I have always counted on you to bounce off any experience I am faced with, not feel judged but rather understood and delivered with blunt-force honesty. Janelle Gabriel – through 3 years of being roommates, I am forever indebted to your friendship in science, brownies and reality television. There are too many more to thank but I will continue to hold you all close. Finally, my sister Emily Hickey and her kids - for their support whenever called upon. With love, thank you all so very much. Importantly, my advisor Craig - who took a chance on me, bestowing the highest honor of being his first graduate student. He showed me the greatest measure of compassion at a time when it was most needed. His patience, attentiveness and ongoing commitment to supporting his trainees has instilled pride in me for having worked for him and given me the confidence and tools to face the next steps in my career. Thanks. My amazing undergraduate mentees - Karen Wernke, Hannah Helber, Nanditha Ravichandran and Claire Kovalchin who I admire and have contributed to a great amount of what is presented herein. Thank you all. v Finally, I am grateful to my committee members, my program and my fellow graduate students, particularly Lindsey Anstine who provided guidance for me. Gina Sizemore - an invaluable resource in science and life. The labs of Ostrowski and Leone – they provided a vast amount of knowledge and resources among its members. Our dedicated lab technicians Alina Murphy and Ali Shapiro – both of whom, together with the Ostroiwski and Leone labs, I thank for their support and I credit with the progress I was able to make in the projects presented herein. vi Vita June 2006 Niagara Falls High School Feb 2011 B.S. Biological Sciences, B.A. Chemistry, the State University of New York at Buffalo 2012 to present Graduate Research Fellow, Molecular, Cellular and Developmental Biology Program, Department of Molecular Genetics, The Ohio State University Publications Hindman AR, Mo XM, Helber HL, Kovalchin CE, Ravichandran N, Murphy AR, Kladney RD, Fagan AM, St. John PM and Craig J. Burd. Defining the window of female mammary gland susceptibility to in utero BPA exposure. Endocrinology. (ACCEPTED. August 2017). McAdams NM, Patterson AR and Gollnick P. Identification of a residue (Glu60) in TRAP required for inducing efficient transcription termination at the trp attenuator independent of binding tryptophan and RNA. J. Bacteriol. 2017 Jan. doi: 10.1128/JB.00710-16. vii Patterson AR, Mo X, Shapiro A, Wernke KE, Archer TK, Burd CJ. Sustained reprogramming of the estrogen response following chronic exposure to endocrine disruptors. Mol Endocrinol. 2015 Jan 16:me20141237. Bayfield OW, Chen CS, Patterson AR, Luan W, Smits C, Gollnick P, Antson AA. Trp RNA-binding attenuation protein: modifying symmetry and stability of a circular oligomer. PLoS One. 2012;7(9):e44309. doi: 10.1371/journal.pone.0044309. Fields of Study Major Field: Molecular, Cellular and Developmental Biology viii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments................................................................................................................v Vita .................................................................................................................................... vii Publications ....................................................................................................................... vii Fields of Study ................................................................................................................. viii Table of Contents ............................................................................................................... ix List of Tables ................................................................................................................... xvi List of Figures ................................................................................................................. xvii Chapter 1: Introduction .......................................................................................................1 1.1 Breast cancer outlook and incidence. ........................................................................ 1 1.1.1 Statistics and factors of risk. ............................................................................... 1 1.1.2 Incidence influenced by industrialization and lifestyle. ..................................... 1 1.2 Estrogen action and its receptors. .............................................................................. 2 1.2.1 The sex hormone estrogen. ................................................................................. 2 1.2.2 Estrogen receptor alpha (α) is the key regulator of breast (mammary) development................................................................................................................
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