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Caenorhabditis Elegans As a Model to Determine the Molecular Effects of Plausible Environmental Risk Factors of Breast Cancer

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Caenorhabditis Elegans As a Model to Determine the Molecular Effects of Plausible Environmental Risk Factors of Breast Cancer CAENORHABDITIS ELEGANS AS A MODEL TO DETERMINE THE MOLECULAR EFFECTS OF PLAUSIBLE ENVIRONMENTAL RISK FACTORS OF BREAST CANCER by Elizabeth Romano A Dissertation Submitted to the Graduate Faculty of George Mason University in Partial Fulfillment of The Requirements for the Degree of Doctor of Philosophy Environmental Science and Public Policy Committee: ___________________________________ Dr. Ancha Baranova, Dissertation Director ___________________________________ Dr. Aybike Birerdinc, Committee Member ___________________________________ Dr. Cara Frankenfeld, Committee Member ___________________________________ Dr. E. Christien Parsons, Committee Member ___________________________________ Dr. Albert P. Torzilli, Graduate Program Director ___________________________________ Dr. A. Alonso Aguirre, Department Chairperson ___________________________________ Dr. Donna Fox, Associate Dean, Student Affairs & Special Programs, College of Science ___________________________________ Dr. Peggy Agouris, Dean, College of Science Date: ______________________________ Fall 2017 George Mason University Fairfax, VA CAENORHABDITIS ELEGANS AS A MODEL TO DETERMINE THE MOLECULAR EFFECTS OF PLAUSIBLE ENVIRONMENTAL RISK FACTORS OF BREAST CANCER A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at George Mason University by Elizabeth Romano Master of Science George Mason University, 2010 Bachelor of Science George Mason University, 2008 Director: Ancha Baranova, Professor School of Systems Biology Fall Semester 2017 George Mason University Fairfax, VA Copyright 2017 Elizabeth Romano All Rights Reserved iii DEDICATION This is dedicated to family. For my dog who kept me (mostly) active when I just wanted to sit and work. For my husband who surprised me with treats when I was crunched for time and pushed me to “get it done.” For my mother who always watched my children when I needed to buckle down and provided a listening ear for my frustrations. But mostly, this is for my children who are my inspiration to fulfill this dream. My time and energy became much more limited for this pipe dream once you were born, but you’ve put my world into clearer perspective, and I’ve pushed myself far beyond my comfort boundaries to get to this point. So, my loves, this is for you. However demanding and out-of-the-realm your desires, here’s your proof that they’re possible, and I’ll be your cheerleader and sounding board through it all. There have been many people in my life who have been afflicted with this dreaded “C.” My mother, my father, my grandparents, my sister-in-law, my aunts and uncles…the list continues. However, of these, my father was particularly tickled at the thought of having a “doctor” in the family. He was an advocate for women’s equality and STEM initiatives. He lost his battle to cancer a few weeks before my final defense of this work. I hope this makes him proud nonetheless. XOXO iv ACKNOWLEDGEMENTS I would like to acknowledge my committee for their useful input in the design of this project. George Mason University provided the space to conduct laboratory work, while the Governor’s School at Innovation Park provided additional resources to finish this project. Thank you to Dr. Karen Dalfrey and Dr. Jason Calhoun for allowing me to parallel student research with my doctoral aims. Thank you to Dr. James D. Willett for providing insight and direction when this project was conceived. Thank you to my student research teams who furthered my pace: Navya Annapareddy, Nitya Pandya, Isabella Posey, Chathurya Anuga, Hufsa Khan, Stephen Jones, Jaichint Hanjra, Kyle Misencik, Rohan Hosuru, Maddy Seputro, Anika Iyer, Brooke Landreaux, and Munisha Sarang. Thank you to Victoria Nohelty for assistance with data input for the 24-hour C. elegans toxicity study and Marc Romano for chauffeuring me to obtain results. During my coursework, the National Science Foundation GK-12 Fellowship, under the direction of Dr. Rajesh Ganesan and Dr. Donna Sterling, was instrumental in degree funding and scientific outreach. In addition, the Biology Department of George Mason University, under the direction of Dr. Larry Rockwood, provided financial assistance and space agreements for both coursework completion and laboratory progress. v TABLE OF CONTENTS Page List of Tables ................................................................................................................... viii List of Figures ..................................................................................................................... xi List of Equations ............................................................................................................... xiv List of Abbreviations and Symbols ................................................................................... xv Abstract ............................................................................................................................. xvi Chapter One - Background .................................................................................................. 1 Introduction to Female Breast Carcinoma ....................................................................... 1 Cancer-contributing Mutations ........................................................................................ 4 Introduction to C. elegans as a model organism for studying cancer .............................. 7 Justification for inclusion of CUG2 as breast cancer gene candidate ............................ 13 Environmental Risk Factors in Breast Cancer ............................................................... 13 The Level of Toxins in the Environment ....................................................................... 24 Epidemiological Studies ................................................................................................ 26 SPECIFIC AIM: ......................................................................................................... 30 Chapter Two - Methodology ............................................................................................. 32 Cultivation of Bacterial Feedstock and C. elegans Populations .................................... 32 24-Hour Toxicity Screening .......................................................................................... 34 Chronic Toxin Exposure ................................................................................................ 38 RNA Extraction ............................................................................................................. 39 cDNA Generation .......................................................................................................... 39 Primer Generation and Optimization ............................................................................. 40 Chronic Toxin Exposure ................................................................................................ 41 qPCR with Agilent AriaMx ........................................................................................... 42 Statistical Analysis of qPCR Data .............................................................................. 50 Pathway studio -guided analysis of the connections between toxins and genes ........ 52 Chapter Three – Results .................................................................................................... 53 vi Toxin Exposure-related Changes in the Expression Levels of C. elegans’ Orthologues of Human Genes Involved in Tumorigenesis ................................................................ 56 Bisphenol A (BPA; 4,40-dihydroxy-2,2-diphenylpropane) ....................................... 56 Atrazine ...................................................................................................................... 60 Dichlorodiphenyltrichloroethane (DDT) .................................................................... 62 17 beta-Estradiol ........................................................................................................ 65 Glyphosate (N-phosphonomethyl-glycine) ................................................................ 67 Dimethylsulfoxide (DMSO) ....................................................................................... 70 Chapter Four: Discussion .................................................................................................. 74 Bisphenol A (BPA) .................................................................................................... 77 Atrazine ...................................................................................................................... 79 Dichlorodiphenyltrichloroethane (DDT) .................................................................... 81 beta-Estradiol ............................................................................................................. 83 Glyphosate .................................................................................................................. 84 Dimethylsulfoxide (DMSO) ....................................................................................... 88 Potential Aims for Further Study ............................................................................... 90 Appendix ........................................................................................................................... 92 References ....................................................................................................................... 112 vii LIST OF TABLES
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