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The Effects of Propofol, Sodium Pentobarbital, and Ketamine Hydrochloride on in Vitro Mouse Embryonic Development

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The Effects of Propofol, Sodium Pentobarbital, and Ketamine Hydrochloride on in Vitro Mouse Embryonic Development Old Dominion University ODU Digital Commons Theses and Dissertations in Biomedical Sciences College of Sciences Spring 2015 The Effects of Propofol, Sodium Pentobarbital, and Ketamine Hydrochloride on In Vitro Mouse Embryonic Development Tyler C. Balak Old Dominion University Follow this and additional works at: https://digitalcommons.odu.edu/biomedicalsciences_etds Part of the Cell Biology Commons, and the Developmental Biology Commons Recommended Citation Balak, Tyler C.. "The Effects of Propofol, Sodium Pentobarbital, and Ketamine Hydrochloride on In Vitro Mouse Embryonic Development" (2015). Doctor of Philosophy (PhD), Dissertation, , Old Dominion University, DOI: 10.25777/k9ed-gn11 https://digitalcommons.odu.edu/biomedicalsciences_etds/10 This Dissertation is brought to you for free and open access by the College of Sciences at ODU Digital Commons. It has been accepted for inclusion in Theses and Dissertations in Biomedical Sciences by an authorized administrator of ODU Digital Commons. For more information, please contact [email protected]. THE EFFECTS OF PROPOFOL, SODIUM PENTOBARBITAL, AND KETAMINE HYDROCHLORIDE ON In Vitro MOUSE EMBRYONIC DEVELOPMENT by Tyler C. Balak B.S. Biology, 2004, University of North Carolina at Wilmington A Dissertation Submitted to the Faculty of Old Dominion University in Partial Fulfillment o f the Requirements for the Degree of DOCTOR OF PHILOSOPHY BIOMEDICAL SCIENCES OLD DOMINION UNIVERSITY May 2015 Approved by: James Swanson (Director) Christopher Osgood (Member) ABSTRACT THE EFFECTS OF PROPOFOL, SODIUM PENTOBARBITAL, and KETAMINE HYDROCHLORIDE ON In Vitro MOUSE EMBRYONIC DEVELOPMENT Tyler Cameron Balak Old Dominion University, 2015 Director: Dr. R. James Swanson Every year more than 75,000 pregnant women are exposed to teratogenic medications or general anesthesia during non-obstetric surgery in the US,1'4 and embryonic effects of general anesthesia are o f particular interest in laboratory research and veterinary medicine. The mouse system is used to screen potential toxic effects of anesthetics used in egg retrieval for in vitro fertilization (TVF), or those of pharmacologic agents which may come in contact with the egg or early embryo. Mouse preimplantation 2-cell embryos were exposed in vitro to incremental concentrations o f common general anesthetics within and exceeding the normal clinical dosage range for mice (propofol 50- 200mg/kg, sodium pentobarbital 50mg/kg, and ketamine hydrochloride 50-100mg/kg) for 72h to determine the effects of each anesthetic on subsequent cleavage and development during prolonged exposure. The anesthetic dosage ranges were as follows: propofol 0- 25.0|ig/mL, sodium pentobarbital 0-300pg/mL, and ketamine hydrochloride 0- 5000pg/mL, embryonic development was evaluated every 24h during the 72h mouse embryo assay culture period. Results found propofol (> 2.0pg/mL), sodium pentobarbital (>30pg/mL), and ketamine hydrochloride (>40pg/mL) to exert inhibitory effects to the in vitro development o f preimplantation mouse embryos. The percentage o f 2-cell embryos developing to more advanced stages was decreased by exposure to higher concentrations of all three compounds. By the 72h endpoint, blastomeres o f delayed and arrested embryos began to degenerate, displaying lysis and/or fragmentation; embryos exposed to lower concentrations o f each anesthetic demonstrated a significant ability to continue cleavage and differentiation towards blastocyst formation. Conclusion: Embryotoxic effects to preimplantation embryos were observed in a dose-dependent manner after 72h of in vitro culture with propofol, sodium pentobarbital, and ketamine hydrochloride. This dissertation is dedicated to the philosophy that “Wise men argue causes; fools decide them.” -Anacharsis ACKNOWLEDGMENTS There are many people who have contributed to the successful completion of this dissertation. I extend many thanks to my committee members for their patience and hours o f guidance on my research and editing o f this manuscript. The untiring efforts o f my major advisor, Dr. R. James Swanson deserve special recognition for the invaluable advice and motivation he has provided throughout my graduate education. I would also like to extend my deepest gratitude to my family for “putting up with me.” VI TABLE OF CONTENTS Page LIST OF TABLES......................................................................................................................... vii LIST OF FIGURES......................................................................................................................viii Chapter I. INTRODUCTION........................................................................................................................1 II. PROPOFOL............................................................................................................................... 34 INTRODUCTION............................................................................................................ 34 METHODS.........................................................................................................................36 RESULTS...........................................................................................................................38 DISCUSSION....................................................................................................................42 ID. SODIUM PENTOBARBITAL............................................................................................. 48 INTRODUCTION............................................................................................................ 48 METHODS.........................................................................................................................50 RESULTS...........................................................................................................................52 DISCUSSION....................................................................................................................55 IV. KETAMINE HYDROCHLORIDE......................................................................................61 INTRODUCTION............................................................................................................ 61 METHODS........................................................................................................................ 62 RESULTS...........................................................................................................................64 DISCUSSION....................................................................................................................70 V. CONCLUSIONS....................................................................................................................... 78 REFERENCES............................................................................................................................... 81 APPENDICES 1. MODIFIED KREBS MEDIUM PREPARATION.................................................95 2. TWO-DIMENSIONAL CHEMICAL STRUCTURES OF COMPOUNDS DESCRIBED IN INTRODUCTION.............................................................................96 VITA 100 LIST OF TABLES Table Page 1. Propofol 72h effects on embryonic development: percentage of embryos reaching specific stage of differentiation during preliminary experimentation....................39 2. Propofol 72h effects on embryonic development: percentage of embryos reaching specific stage of differentiation ...................................................................40 3. Sodium pentobarbital 72h effects on embryonic development: percentage of embryos reaching specific stage of differentiation...................................................53 4. Sodium pentobarbital 72h effects on embryonic development: detailed differentiation percentages...............................................................................................54 5. Ketamine hydrochloride 72h effects on embryonic development: percentage of embryos............................................................................................................................... 66 6. Ketamine hydrochloride 72h effects on embryonic development: percentage of embryos reaching specific stage of differentiation .................................................67 Vlll LIST OF FIGURES Figure Page 1. Key Targets o f Intravenous Anesthetics.......................................................................... 4 2. Summary of Preimplantation Mouse Development, 2-Cell to Morula Stage.....................................................................................................................................18 3. Normal Blastocyst Development.....................................................................................18 4. Preimplantation Mouse Embryo Development ............................................................. 19 5. Degenerating 2-Cell Mouse Embryo Following 72h o f Culture With lOOOpg/mL Ketamine Hydrochloride............................................................................25 6. 72h Differentiation o f 2-Cell Mouse Embryos Exposed to Propofol: Preliminary Results..........................................................................................................40 7. 72h Differentiation o f 2-Cell Mouse Embryos Exposed to Propofol .......................41 8. Differentiation Progress of Degenerating Embryos Following 72h Exposure to Propofol ...............................................................................................................................41
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