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The Epigenetic Effects of Prenatal Alcohol Exposure in Human Autopsy Brain Tissue

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The Epigenetic Effects of Prenatal Alcohol Exposure in Human Autopsy Brain Tissue The Epigenetic Effects of Prenatal Alcohol Exposure in Human Autopsy Brain Tissue By Jessica S Jarmasz A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfilment of the requirements of the degree of DOCTOR OF PHILOSOPHY Department of Human Anatomy and Cell Science Max Rady College of Medicine Rady Faculty of Health Sciences University of Manitoba Winnipeg Copyright © 2018 by Jessica S Jarmasz ABSTRACT Fetal alcohol spectrum disorder (FASD) is 100% preventable, yet is the leading cause of developmental disability. Many in vivo studies in animals have established the effects of prenatal alcohol exposure (PNAE) on epigenetic processes in the developing brain. However, no studies directly assess epigenetic processes such as DNA and histone modifications in human brains. Therefore, I hypothesized that PNAE is associated with changes to epigenetic modifications in human brain cells. To test the hypothesis, I first identified a cohort of PNAE / FASD individuals that had undergone autopsy. Descriptive epidemiology and neuropathological findings were summarized for 174 cases. The brain abnormalities included: micrencephaly in 31, neural tube defects in 5, hydrocephalus in 6, corpus callosum defects in 6, prenatal ischemic lesions in 5, and minor subarachnoid heterotopias in 4. I then evaluated the effects of post-mortem delay (PMD) on the stability of epigenetic marks in mouse, pig, and human brain using Western blots and immunohistochemistry. I found all DNA cytosine modifications and most histone methylation marks were stable ≥72 hours. Histone acetylation marks varied, but the majority were stable ≥48 hours. A subset of the PNAE autopsy cases including fetuses and infants (21 weeks gestation to 7 months postnatal; N=18) were selected along with age-, sex- and PMD-matched controls to assess epigenetic modifications in brain previously shown in the experimental literature to be affected by PNAE. I also studied brain samples from a monkey model of PNAE. In human temporal lobe (7 specific regions), I found statistically significant increases in 5mC, 5fC, H3K27me3, H3K36me3, H3K9ac, H3K14ac and H3K27ac, decreases in 5mC, 5caC, H3K4me3, H3K27me3, H3K36me3, H3K9ac, H3K14ac, H3K27ac, H4K5ac, H4K12ac, and H4K16ac, and no change in 5hmC. Overall, H3K4me3 (active transcriptional mark) demonstrated a consistent decrease in 5 of the 7 brain regions studied. Among the macaques, the ependyma showed I statistically significant decreases among epigenetic marks 5fC, 5caC, H3K9ac, H3K9me2 / K9me3, and H3K36me3. Comparison of the human infant and macaque brain findings shows overlap in H3K9ac (ependyma- decreased in PNAE) and H3K36me3 (white matter – decreased in PNAE). In conclusion, I demonstrate that changes to specific epigenetic modifications on DNA and on histones occur in association with PNAE in the developing human brain. Human autopsy brain tissue is worth exploring in the context of epigenetics to understand the pathogenesis of FASD. II ACKNOWLEDGEMENTS As they say, it takes a village to raise a child. Therefore, I’d like to thank the following people who without their help, guidance and support, this thesis project I call my “baby” would not have come together. A big thank you to Dr. Marc Del Bigio, my supervisor, who provided the opportunity, the incredibly interesting research hypothesis, the funding and the countless hours of his time reviewing (especially towards the end). I’d like to thank the Hospital Pathology Department staff, specifically Susan Janeczko and Diane Legarta for preparing the countless samples I required to conduct my research. I’d like to thank lab members (previous and current) who taught me various methods and ordered products I so desperately needed to complete my work: Dr. Dominico DiCurzio, Dr. Xiaoyan Mao, Emily Turner-Brannen and Duaa Basalah. I’d like to thank medical students who helped me complete some of my work: Hannah Stirton and Dr. Conrad Goertz. I’d like to thank the Davie lab as a whole for providing the occasional product or reagent to support my work. I’d like to thank Dr. Shyamala Dakshinamurti and Dr. Jena Fediuk for donating the pig brains. I’d like to thank Dr. Susan Astley and Dr. Sterling Clarren for donating the macaque monkey brains. It is remarkable that research conducted before I was born inevitably contributed to my doctorate. I’d also like to thank Dr. Albert Chudley. A Special thanks to my committee members: Dr. Jim Davie, Dr. Sari Hannila, and Dr. Saeid Ghavami, Children’s Hospital Research Institute of Manitoba: Debbie Korpesho and Nichola Wigle, Department of Pathology: Marian Huebner (now retired), Dr. Cindy Ellison (previous committee member) and Amanda Wardekker, and finally, the Department of Human Anatomy and Cell Science: Jennifer Genest, and Dr. Hugo Bergen. It is incredibly difficult to obtain funding as a student, therefore, I’d like to personally thank the following organizations for funding my thesis work: The Liquor and Gaming Authority III of Manitoba, Canada Israel International Fetal Alcohol Consortium (CIIFAC), the Graduate Enhancement of Tri-Council Stipends (GETS) through the University of Manitoba, Children’s Hospital Research Institute of Manitoba Small Grant and Trainee Travel Awards, NeuroDevNet Trainee Travel Scholarship, University of Manitoba Graduate Student’s Association Conference Award, and the University of Manitoba Dean of Medicine Travel Award. I’d also like to thank the Manitoba Centre for Health Policy (specifically Ruth-Ann Soodeen) for providing me with a stable (yet flexible) part-time job during my studies. I was fortunate enough to learn a whole other side of the research world and work with incredible people. The skills I’ve developed during my 8 years there are most certainly invaluable. Finally, I’d also like to thank my family and friends for understanding how time consuming this feat was for me. The constant “are you almost done?” or “when do you graduate?” implied I would soon finish without hesitation, and I am grateful for that assumption. IV DEDICATION To my father – this is my “Eroica” V TABLE OF CONTENTS List of Tables and Figures............................................................................................................ XII Abbreviations ............................................................................................................................... XX CHAPTER 1: LITERATURE REVIEW ........................................................................................ 1 Human Brain Development ......................................................................................................... 3 Primary Neurulation ................................................................................................................ 3 Brain Cell Development. ............................................................................................................. 5 Specific Brain Region Development ....................................................................................... 6 The Germinal Matrix ........................................................................................................................ 8 The Blood-Brain-Barrier (BBB) ....................................................................................................... 9 The Hippocampus ........................................................................................................................... 10 The Neocortex ................................................................................................................................. 10 Abnormal Human Brain Development .................................................................................. 13 Comparative Inter-Species Brain Development .................................................................... 13 Alcohol ...................................................................................................................................... 17 What is Alcohol? ................................................................................................................... 17 Statistics on Consumption ..................................................................................................... 18 Distribution of Alcohol Throughout the Body ...................................................................... 18 Metabolism and Toxic Consequences ................................................................................... 19 Polymorphisms of Alcohol Metabolizing Enzymes .............................................................. 21 Metabolic Products of Alcohol: Direct Effects, Mitochondria and Oxidative Stress ........... 23 Behavioural Effects of Alcohol Consumption ....................................................................... 28 Reasons for Drinking ............................................................................................................. 28 Long-Term Effects of Alcohol Consumption and Associated Disorders .............................. 29 VI The Neurobiology of Addiction ............................................................................................ 32 The Dopaminergic Reward System ................................................................................................ 32 Inhibitory and Excitatory Neurons: GABAergic and Glutamatergic .............................................. 33 The Effects of Alcohol on Dopaminergic, GABAergic and Glutamatergic Neurons ..................... 35 Alcohol Use Disorder
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