Perfluoroalkyl and Polyfluoroalkyl Substances and Women’s Health: A Possible Etiology for Earlier Menopause and Accelerated Reproductive Aging by Ning Ding A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Epidemiological Science) in The University of Michigan 2020 Doctoral Committee: Associate Professor Sung Kyun Park, Chair Professor Stuart Batterman Professor Siobán D. Harlow Professor Bhramar Mukherjee Professor John F. Randolph Jr. Ning Ding [email protected] ORCID iD: 0000-0001-5244-2909 © Ning Ding 2020 Dedication This work is wholeheartedly dedicated to my mother and father, Hong Wang and Zhili Ding, who are always positive role models in my life. They have not lived in the easiest of lives. And yet in the face of challenges and difficulties along the way, they have always pushed through and did what they had to do to make things work. They have taught me the importance of hard work, honesty and integrity, and always being humble in every situation, and never giving up. ii Acknowledgements First, I would like to sincerely thank my committee chair and lifelong mentor, Dr. Sung Kyun Park, whose encouragement, guidance and support from the initial to the final level of doctoral education. Dr. Park’s mentorship continuously inspires me to ask exciting research questions and pursue collaborative opportunities. I am sure it would have not been possible without his help. I am honestly thankful to my mentors, Dr. Siobán D. Harlow and Dr. John F. Randolph Jr., for their patient instructions, insightful comments, and strong support at every stage of my doctoral career. I am also grateful for my mentors, Dr. Stuart Batterman and Dr. Bhramar Mukherjee, who consistently helps me apply my research through an interdisciplinary lens. I would also like to acknowledge and extend my heartfelt gratitude to my peer students, staff in the Center for Midlife Science, and faculty at the University of Michigan School of Public Health who have made the completion of this dissertation possible. Finally, I must express my extreme gratitude to Xin Wang, my boyfriend and my colleague, who always gives me unlimited braveness and strength. I am so fortunate to have him by my side for the past seven years. Without him I can hardly overcome the obstacles I have met on my journey to the final degree. There are numerous funding sources that have been instrumental in supporting my doctoral studies which include grants from the National Institute of Environmental Health Sciences (NIEHS) R01-ES026578, R01-ES026964 and P30-ES017885, and by the Center for Disease Control and Prevention (CDC)/National Institute for Occupational Safety and Health (NIOSH) grant T42-OH008455. iii The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women’s Health (ORWH) (Grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH. The SWAN Repository (U01AG017719). This publication was supported in part by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 RR024131. Clinical Centers: University of Michigan, Ann Arbor – Siobán Harlow, PI 2011 – present, MaryFran Sowers, PI 1994-2011; Massachusetts General Hospital, Boston, MA – Joel Finkelstein, PI 1999 – present; Robert Neer, PI 1994 – 1999; Rush University, Rush University Medical Center, Chicago, IL – Howard Kravitz, PI 2009 – present; Lynda Powell, PI 1994 – 2009; University of California, Davis/Kaiser – Ellen Gold, PI; University of California, Los Angeles – Gail Greendale, PI; Albert Einstein College of Medicine, Bronx, NY – Carol Derby, PI 2011 – present, Rachel Wildman, PI 2010 – 2011; Nanette Santoro, PI 2004 – 2010; University of Medicine and Dentistry – New Jersey Medical School, Newark – Gerson Weiss, PI 1994 – 2004; and the University of Pittsburgh, Pittsburgh, PA – Karen Matthews, PI. NIH Program Office: National Institute on Aging, Bethesda, MD – Chhanda Dutta 2016- present; Winifred Rossi 2012–2016; Sherry Sherman 1994 – 2012; Marcia Ory 1994 – 2001; National Institute of Nursing Research, Bethesda, MD – Program Officers. iv Central Laboratory: University of Michigan, Ann Arbor – Daniel McConnell (Central Ligand Assay Satellite Services). SWAN Repository: University of Michigan, Ann Arbor – Siobán Harlow 2013 - Present; Dan McConnell 2011 - 2013; MaryFran Sowers 2000 – 2011. Coordinating Center: University of Pittsburgh, Pittsburgh, PA – Maria Mori Brooks, PI 2012 - present; Kim Sutton-Tyrrell, PI 2001 – 2012; New England Research Institutes, Watertown, MA - Sonja McKinlay, PI 1995 – 2001. Steering Committee: Susan Johnson, Current Chair Chris Gallagher, Former Chair We thank the study staff at each site and all the women who participated in SWAN. We also thank Drs. Antonia Calafat and Xiaoyun Ye at Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, for their support in PFAS assessment. v Table of Contents Dedication ....................................................................................................................................... ii Acknowledgements ........................................................................................................................ iii List of Tables ................................................................................................................................. ix List of Figures .............................................................................................................................. xiv Abstract ....................................................................................................................................... xvii Chapter I. Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS) and Their Effects on the Ovary ......................................................................................................................................................... 1 Abstract ....................................................................................................................................... 2 1. Introduction ............................................................................................................................. 4 2. Methods ................................................................................................................................... 6 3. Basic principles of PFAS ........................................................................................................ 7 3.1 Nomenclature ..................................................................................................................... 7 3.2 Sources of human exposure ............................................................................................... 8 3.3 Transport and clearance of PFAS in the human body ..................................................... 11 4. Mechanistic evidence for ovarian toxicity of PFAS ............................................................. 13 4.1 Effects of PFAS on folliculogenesis ................................................................................ 13 4.2 Effects of PFAS on ovarian steroidogenesis ................................................................... 17 5. Epidemiologic evidence linking PFAS exposure and ovarian outcomes .............................. 20 5.1 Sex hormones .................................................................................................................. 21 5.2 Onset age of menarche .................................................................................................... 22 5.3 Menstrual cycle characteristics ........................................................................................ 23 5.4 Ovarian aging .................................................................................................................. 24 5.5 Other conditions .............................................................................................................. 26 6. Discussion ............................................................................................................................. 27 7. Conclusions ........................................................................................................................... 29 8. Specific aims ......................................................................................................................... 29 References ................................................................................................................................. 31 vi Chapter II. Longitudinal Trends in Perfluoroalkyl and Polyfluoroalkyl Substances among Midlife Women from 1999 to 2011: the Study of Women’s Health Across the Nation ........................... 75 Abstract ..................................................................................................................................... 76 1. Introduction ..........................................................................................................................