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Phthalates, Embryo Development, and Sperm DNA Methylation

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Phthalates, Embryo Development, and Sperm DNA Methylation University of Massachusetts Amherst ScholarWorks@UMass Amherst Doctoral Dissertations Dissertations and Theses July 2018 Phthalates, Embryo Development, and Sperm DNA Methylation Haotian Wu University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/dissertations_2 Part of the Environmental Public Health Commons, and the Epidemiology Commons Recommended Citation Wu, Haotian, "Phthalates, Embryo Development, and Sperm DNA Methylation" (2018). Doctoral Dissertations. 1306. https://doi.org/10.7275/11928583.0 https://scholarworks.umass.edu/dissertations_2/1306 This Open Access Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks@UMass Amherst. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. Phthalates, Embryo Development, and Sperm DNA Methylation A Dissertation Presented by HAOTIAN WU Submitted to the Graduate School of the University of Massachusetts Amherst in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2018 School of Public Health Environmental Health Sciences © Copyright by Haotian Wu 2018 All Rights Reserved Phthalates, Embryo Development, and Sperm DNA Methylation A Dissertation Proposal By: Haotian Wu Approved as to style and content by: _________________________________ J. Richard Pilsner, Committee Chair _________________________________ Laura N. Vandenberg, Committee Member _________________________________ Alexander Suvorov, Committee Member _________________________________ Brian W. Whitcomb, Committee Member _____________________________________ Timothy Ford, Department Chair Department of Environmental Health Sciences DEDICATION To anyone and everyone who contributed to my education ACKNOWLEDGEMENTS I would like to first thank my advisor and chair of my dissertation committee, Dr. J. Richard Pilsner, for his wise and patient guidance, without which this would not have been possible. I owe much of my success to his mentorship. I would also like to express my immense gratitude to Dr. Alexander Suvorov, Dr. Brian W. Whitcomb, and Dr. Laura N. Vandenberg for their guidance both in and outside of the classrooms and dissertation process. Additionally, a thank you to all the faculty and staff at the UMass Amherst School of Public Health and Health Sciences who have contributed to my development as an environmental health scientist and epidemiologist. I also want to thank the research team involved in the Sperm Environmental Epigenetics and Development Study (SEEDS). Specifically, from the Pilsner lab, I would like to thank Matthew de Gannes, Gianna Luchetti, Maggie Kwong, Alexandra Huffman, Allyson Rosati, Srinihaari Josyula, Alexander Shershebnev, Bernadette Ojuku, Sam Hildebrand, and Andre Porto for their contributions; the work presented here would not have happened without this team. From the Division of Reproductive Endocrinology and Infertility at Baystate Medical Center, I would like to thank Holly Dinnie, Ellen Tougias, Lisa Ashcraft, and the embryologists, nurses, and physicians. We also like to thank all of the study participants, without whom none of this would be possible. Lastly, I want to give a special thank you for all my friends and family. Your support and help in this process is deeply appreciated. v ABSTRACT PHTHALATES, EMBRYO DEVELOPMENT, AND SPERM DNA METHYLATION MAY 2018 HAOTIAN WU B.S., UNIVERSITY OF OTTAWA M.S., UNIVERSITY OF MASSACHUSETTS AMHERST Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST Directed by: Professor J. Richard Pilsner Infertility affects 15% of all couples and presents a major public health issue. Animal and human data indicate that epigenetic dysregulation in sperm is associated with poor male reproductive health and extensive epigenetic reprogramming during spermatogenesis presents a window of vulnerability for environmentally-induced epigenetic dysregulation. Phthalates is a class of ubiquitous environmental contaminant and global health concern. Phthalate exposure in humans has been associated with diminished male fertility, adverse birth outcomes, and altered offspring development. In order to facilitate additional research on this topic, we aimed to developing a higher throughput method of sperm nucleic acid extraction. In addition, this dissertation also examined the associations of paternal phthalate exposure with sperm methylation patterns and blastocyst development. vi In order to maximize efficiency of the limited and difficult to acquire samples while increasing throughput for epidemiologic studies, we developed a novel method of sperm nucleic acid extraction that improved ease and efficiency. Compared to previously published methods, our new method has 1) increased yield of DNA per sperm cell, 2) reduced time required for DNA processing, and 3) eliminated the need for odorous sulfur-based reducing compounds. As part of the Sperm Environmental Epigenetics and Development Study (SEEDS), we recruited 50 couples from an in vitro fertilization (IVF) clinic. We observed that concentrations of select paternal urinary metabolites of phthalates or phthalate alternatives were associated with a marked decrease in blastocyst quality. With respect to sperm DNA methylation, we found that the male urinary anti-androgenic phthalate metabolite concentrations were associated with 131 differentially methylated regions in sperm DNA. Gene ontology analyses revealed that these differentially methylated regions were enriched in genes related to growth and development as well as cellular function and maintenance. Overall, the evidence presented by this dissertation show that paternal adult exposure to select phthalates and phthalate alternatives may influence both embryo development and sperm DNA methylation patterns. Additional work is required to replicate our findings as well as determine whether the observed aberrant sperm DNA methylation patterns associated with urinary metabolites of phthalates and phthalate alternatives are true biological mediators of the concurrent decrease in embryo quality. vii TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ..................................................................................... v ABSTRACT .......................................................................................................... vi LIST OF TABLES ................................................................................................. xi LIST OF FIGURES .............................................................................................. xii CHAPTER 1. INTRODUCTION .............................................................................................. 1 Summary ........................................................................................................... 1 Infertility and its implications for public health ................................................... 1 Sperm epigenetics and its implications for public health .................................. 2 Phthalates, phthalate alternatives, and their implications on fertility ................. 4 Research gaps ................................................................................................. 7 2. ENVIRONMENTAL SUSCEPTIBILITY OF THE SPERM EPIGNOME DURING WINDOWS OF MALE GERM CELL DEVELOPMENT ........................................ 9 Summary .......................................................................................................... 9 Abstract ............................................................................................................ 9 Introduction ..................................................................................................... 10 Windows of male germ cell development ....................................................... 11 In utero period and primordial germ cells ..................................................... 11 Infancy and pre-pubertal periods ................................................................ 15 Spermatogenesis in adulthood ................................................................... 18 Sperm epigenetics and offspring development ........................................... 24 Conclusions .................................................................................................... 26 3. RAPID METHOD FOR THE ISOLATION OF MAMMALIAN SPERM DNA .... 32 Summary ........................................................................................................ 32 Abstract .......................................................................................................... 32 Method summary ............................................................................................ 33 Introduction ..................................................................................................... 33 Methods ......................................................................................................... 36 Results and discussion ................................................................................... 39 viii 4. PARENTAL CONTRIBUTIONS TO EARLY EMBRYO DEVELOPMENT: INFLUENCES OF URINARY PHTHALATE AND PHTHALATE ALTERNATIVES AMONG COUPLES UNDERGOING IVF TREATMENT .................................... 51 Abstract .......................................................................................................... 51 Introduction ....................................................................................................
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