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Examining the Effects of Endogenous Sex Steroids and the Xenoestrogen Contaminant 17-Ethinylestradiol on Previtellogenic Coho Salmon Ovarian Growth and Function

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Examining the Effects of Endogenous Sex Steroids and the Xenoestrogen Contaminant 17-Ethinylestradiol on Previtellogenic Coho Salmon Ovarian Growth and Function Examining the effects of endogenous sex steroids and the xenoestrogen contaminant 17-ethinylestradiol on previtellogenic coho salmon ovarian growth and function Christopher A. Monson A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2018 Reading committee: Dr. Graham Young, Chair Dr. Penny Swanson Dr. Steven Roberts Program authorized to offer degree: Aquatic and Fishery Sciences ©Copyright 2018 Christopher A. Monson University of Washington Abstract Examining the effects of endogenous sex steroids and the xenoestrogen contaminant 17α- ethinylestradiol on previtellogenic coho salmon ovarian growth and function. Christopher A. Monson Chair of Supervisory Committee: Professor Graham Young School of Aquatic and Fishery Sciences In teleost fish, as in other oviparous vertebrates, the production of a fertilizable egg is a complex process driven by the specific spatiotemporal coordination of endocrine and paracrine factors in multiple tissues. Across the brain-pituitary-ovary-liver (BPOL) axis, this includes the synthesis and release of pituitary gonadrotopins, the ovarian production and release of sex steroids, and the hepatic synthesis and release of egg yolk protein precursors, as well as numerous factors that mediate these processes. The factors controlling the earliest stages of oogenesis, the loading of yolk proteins (vitellogenesis), and the final maturational stage are fairly well understood, but the control of the intermediate growth stages (primary and early secondary growth) and the developmental point analogous to the onset of mammalian puberty, the transition from primary to secondary growth, are less clear. The research described in this dissertation addresses the regulation of the ovarian transcriptome by sex steroids during the primary and early secondary growth stages in coho salmon (Oncorhynchus kisutch), and the potential disruption of normal ovarian processes during early secondary growth by a potent synthetic steroidal xenoestrogen. In the first chapter, the dramatic alterations of the primary growth ovarian transcriptome, and ovarian follicle growth following exposure to a natural steroidal androgen, 11-ketotestosterone (11-KT), are described. Potential alterations in gonadotropin signaling, growth factor signaling, and the extracellular matrix (ECM) were identified. The study described in the second chapter examines the effects of both 11-KT and the natural steroidal estrogen, estradiol-17β (E2), on the early secondary growth ovarian transcriptome. As in the study on primary growth, 11-KT dramatically altered the expression of genes involved in gonadotropin or growth factor signaling, the ECM, lipid incorporation, as well as steroidogenesis. E2 had a relatively smaller effect, but did alter the expression of nearly 100 genes. The third chapter examines the effects of the synthetic steroidal xenoestrogen 17α-ethinylestradiol (EE2) on the previtellogenic coho ovarian transcriptome. After a 1-week exposure, EE2 dramatically altered the ovarian transcriptome, impacting expression of genes involved in steroidogenesis, cell signaling, and protein synthesis/metabolism. After a 6-week exposure, the effects were less pronounced. Overall, this research identifies hundreds of ovarian transcripts and associated processes regulated by sex steroids during primary and early secondary growth, providing a basis for further targeted approaches to understand ovarian development during the onset of puberty. This research also demonstrates that EE2 can potentially disrupt normal endocrine function in fish by altering the potential for the synthesis of endogenous sex steroids. Dedication For Devrim and Nehir, who make every day a little bit brighter, and for my wife and parents, whose support has always been unwavering. Acknowledgements First and foremost, I would like to thank my advisor, Dr. Graham Young, for his mentorship, enthusiasm, and encouragement. It was his enthusiasm for my research that refocused my effort and kept me motivated on many occasions. I would also like to thank the other members of my supervisory committee: Dr. Penny Swanson, Dr. Steven Roberts, and Dr. Evan Gallagher, for their expertise and guidance. This work could not have been accomplished without the support of the National Science Foundation IOS (grant number: 0949765) and the Environmental Protection Agency STAR (grant number: 83516702-0). I am also grateful to have received a Graduate Fellowship through the School of Aquatic and Fishery Sciences. I would like to sincerely thank my many colleagues and friends in the Young lab: Anna Butte, Erica Curles, Fritzie Celino, Kristy Forsgren, Louisa Harding, Michelle Chow, Yashi Shibata; and at the NOAA-Northwest Fisheries Science Center: Abby Fuhrman, Adam Luckenbach, Brian Beckman, Giles Goetz, Irvin Schultz, Jon Dickey, Jose Guzman, Mollie Middleton, Shelly Nance. They provided technical support for the many experiments I performed, gave invaluable feedback on experimental design, presentations, and manuscripts, and made long days in cold fish hatcheries fun. TABLE OF CONTENTS Page List of Tables .......................................................................................................................... iii List of Figures ......................................................................................................................... iv Review of current knowledge and study objectives ..................................................................1 Introduction ....................................................................................................................1 Oogenesis .......................................................................................................................1 Endocrine regulation of oogenesis: the brain-pituitary-ovary axis ................................3 Gonadotropins ...................................................................................................4 Role of sex steroids in vitellogenesis and maturation/ovulation .......................5 Emerging roles of androgens and estrogens .....................................................6 Potential disruption by endocrine-disrupting chemicals ..............................................10 Models..........................................................................................................................12 Objectives ....................................................................................................................13 References ....................................................................................................................16 Chapter 1: A teleost androgen promotes development of primary ovarian follicles in coho salmon and rapidly alters the ovarian transcriptome.......................................................26 Abstract ........................................................................................................................26 Introduction ..................................................................................................................27 Methods........................................................................................................................31 Results ..........................................................................................................................38 Discussion ....................................................................................................................44 Conclusions ..................................................................................................................56 Acknowledgements ......................................................................................................56 References ....................................................................................................................57 Tables ...........................................................................................................................66 Figures..........................................................................................................................69 Supplementary Tables ..................................................................................................74 Supplementary Figure ..................................................................................................86 Chapter 2: Endogenous sex steroids rapidly alter the ovarian transcriptome of previtellogenic secondary growth coho salmon (Onchorhynchus kisutch). ............................87 Introduction ..................................................................................................................87 Methods........................................................................................................................89 Results ..........................................................................................................................94 Discussion ....................................................................................................................97 Conclusions ................................................................................................................120 References ..................................................................................................................122 Tables .........................................................................................................................134 Figures........................................................................................................................162
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