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Molecular Mechanisms Underlying Toxicant Effects on Mast Cell Signaling and Mitochondria Juyoung Katherine Shim University of Maine, [email protected]

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Molecular Mechanisms Underlying Toxicant Effects on Mast Cell Signaling and Mitochondria Juyoung Katherine Shim University of Maine, Juyoung.Shim@Maine.Edu The University of Maine DigitalCommons@UMaine Electronic Theses and Dissertations Fogler Library Summer 8-17-2018 Molecular Mechanisms Underlying Toxicant Effects on Mast Cell Signaling and Mitochondria Juyoung Katherine Shim University of Maine, [email protected] Follow this and additional works at: https://digitalcommons.library.umaine.edu/etd Part of the Molecular Biology Commons, and the Toxicology Commons Recommended Citation Shim, Juyoung Katherine, "Molecular Mechanisms Underlying Toxicant Effects on Mast Cell Signaling and Mitochondria" (2018). Electronic Theses and Dissertations. 2909. https://digitalcommons.library.umaine.edu/etd/2909 This Open-Access Thesis is brought to you for free and open access by DigitalCommons@UMaine. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of DigitalCommons@UMaine. For more information, please contact [email protected]. MOLECULAR MECHANISMS UNDERLYING TOXICANT EFFECTS ON MAST CELL SIGNALING AND MITOCHONDRIA By Juyoung K. Shim B.A. Hankook University of Foreign Studies, 1994 B.S. Bates College, 2005 A DISSERTATION Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (in Biochemistry and Molecular Biology) The Graduate School The University of Maine August 2018 Advisory Committee: Julie A. Gosse, Associate Professor of Biochemistry; Advisor John T. Singer, Professor of Microbiology Paul J. Millard, Associate Professor of Chemical and Biological Engineering Rebecca J. Van Beneden, Professor of Biochemistry and Marine Sciences, Director for School of Marine Sciences Robert E. Gundersen, Chair of Molecular and Biomedical Sciences © 2018 Juyoung Katherine Shim All Rights Reserved ii MOLECULAR MECHANISMS UNDERLYING TOXICANT EFFECTS ON MAST CELL SIGNALING AND MITOCHONDRIA By Juyoung K. Shim Dissertation Advisor: Dr. Julie A. Gosse An Abstract of the Dissertation Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (in Biochemistry and Molecular Biology) August 2018 Mast cells contribute to numerous physiological processes and diseases including immunological and neurological roles. Mast cells degranulate, releasing potent mediators, following signal transduction initiated by receptor crosslinking. Previously, we showed that the environmental toxicant arsenic and the antibacterial agent triclosan inhibit mast cell degranulation; thus, we have investigated the mechanisms underlying their inhibitory action. We have discovered that arsenic targets early steps in the mast cell signaling pathway: it inhibits phosphorylation of early tyrosine kinase Syk and of Syk’s direct substrate PI3K. Arsenic’s tyrosine phosphorylation inhibition causes inhibition of calcium influx into the cytosol, a key event necessary for degranulation. Pharmaceutical agent triclosan also inhibits calcium influx but, in contrast to arsenic, does not inhibit early steps in the pathway. We have discovered that one of triclosan’s targets in the mast cell signaling pathway is phospholipase D (PLD): PLD activity is decreased by triclosan. Triclosan does not inhibit activity of key enzyme protein kinase C but does delay its translocation to the plasma membrane and translocation of its substrate MARCKS to the cytosol. In addition, we have shown that another mechanism of triclosan toxicity, mitochondrial uncoupling, also occurs in vivo. We developed a high-throughput assay to measure bioenergetics of living zebrafish embryos and showed that triclosan exposure decreases ATP production without causing mortality of zebrafish. Finally, in preparation for comparative studies of toxicant effects on mast cells in vivo using zebrafish and in vitro using the mast cell model RBL-2H3, we aimed to develop a tryptase assay of mast cell degranulation that could be used in both systems. However, we discovered that RBL-2H3 cells express neither mRNA nor protein of several tryptase genes. Overall, the findings in this thesis provide biochemical and cellular explanations for known human health effects of triclosan and arsenic and set the stage for future comparative toxicology studies of mast cell function. iii DEDICATION To my husband, Changsu K. Lee and my daughter, Hana “Alexa” L. Lee And to my parents and families iv ACKNOWLEDGEMENTS I feel very fortunate to have met, encountered, and acquainted myself with many amazing people during my graduate work, and though I may have missed some of the names here that deserve recognition, I would like to express my sincere thanks to all. Foremost, I cannot give enough thanks to my advisor, Dr. Julie Gosse, for her guidance throughout my studies. She has provided tremendous support and timely (often-necessary) encouragement. She is one of the most dedicated teachers I have ever encountered and truly cares about her students’ overall wellbeing. She taught me through experimental problem solving, critical thinking, and scientific writing more than I could give her credit for here. Thank you! I would also like to thank my committee members, Drs. John Singer, Robert Gundersen, Rebecca Van Beneden, and Paul Millard for their extensive personal and professional guidance. You are the best (and the only) committee I could ever ask for. I also appreciate your congenial correspondence whenever I needed extra help. My work here would not have been possible without colleagues and collaborators who have contributed to my research. Dr. Rachel Kennedy and Dr. Lisa Weatherly have been more than officemates, and who have been my best supporters and helpers to pull through scientific problems and personal hardships. I would also like to thank Suraj Sangroula and Siham Hattab for assisting me with confocal experiments. Richard Luc assisted me tremendously in zebrafish experiments, Tyler McGathey provided much moral support during my preparations for the comprehensive exam. I thank Atefeh Rajaei for her input in writing the tryptase paper and Andrew Hart for his help on the tubulin assay. Dr. Remi Gratacap also helped me greatly with v confocal experiments, zebrafish experiments, and the comprehensive exam. I would like to thank him especially for his sympathetic ear. My collaborative works outside of my department have been successful thanks to these wonderful people: Dr. Heather Hamlin and her student Sarah Conlin (Department of Marine Biology) were a pleasure to work with. I am grateful for their part of the work to yield a publication. I also want to thank the Dr. Marie Hayes Laboratory for giving me an opportunity to work on an oxytocin project. Special thanks to Andy Neilson and Ryan Ng for providing me the equipment, reagents, and helpful advice for zebrafish bioenergetics experiments. Their assistance was indispensable to complete the project. My time in the Gosse lab provided me the opportunity to work with many wonderful undergraduate students. I am grateful to all of them for their helping hands and hard work. Molly Caron, Logan Gerchman, and Talya Briana have worked together on the PKC and PLD activity experiments, which required lots of troubleshooting. I would not have completed this project without their help. Hina Hashmi was another great undergraduate who helped me with arsenic experiments. I would also like to thank Alan Baez for information on Sucralose, Maxwell Dorman for zebrafish work, Nicholas Doucette for the Oxytocin assay, and Saige McGinnis for purified PLD assay. I thank Bailey West, Grace Bagley, and Bridget Konitzer for help with laboratory equipment and maintenance. I am very thankful for members of other labs in the department of Molecular and Biomedical Sciences. They are always willing to help me and share their resources. Thanks to Dr. Carol Kim and Dr. Con Sullivan for use of the Amaxa Nucleofector equipment, Dr. Robert Wheeler and his lab for the use of the Ibidi heating system, Dr. Melissa Maginnis and her lab for the use of refrigerated centrifuge, Dr. Joshua Kelly and his lab for the use of bacterial incubator, vi Dr. Sally Molloy and her lab for the use of electrophoresis equipment, and Dr. Timothy Bowden for gel imaging system. Especially I would like to thank and acknowledge graduate students in other labs for necessary training and willingness to accommodate me in their lab space: Brittany Seman, Allison Scherer, Linda Archambault, Collen Mayberry, Audrey Bergeron, Magdalena Blaskiewicz, and William Simke. A special thanks to Doreen Sanborn, Tammy Gosselin, and Roseann Cochrane for their administrative support and to Mark Nilan from for providing me zebrafish embryos. I would like to acknowledge the kind generosity of Drs. David Holowka and Barbara Baird for the antigen, RBL-2H3 cells, and mRFP-MARCKS-ED plasmid; Dr. Michael Frohman and Yelena Altshuller at Stony Brook University and Dr. Shamshad Cockcroft at University College London for the PLD1-EGFP construct. Thank you to the John Wiley & Sons, Journal of Applied Toxicology for permission to reuse material published in their journal. The full citation for the article in the Chapter 2 is: Shim, J., Kennedy, R. H., Weatherly, L. M., Hutchinson, L. M., Pelletier, J. H., Hashmi, H. N., Blais, K., Velez, A., and Gosse, J. A. (2016) Arsenic inhibits mast cell degranulation via suppression of early tyrosine phosphorylation events. J. Appl. Toxicol., 36: 1446–1459. doi: 10.1002/jat.3300. The full citation for the article in the Chapter 5 is: Shim, J., Weatherly, L. M., Luc, R. H., Dorman, M. T., Neilson, A., Ng, R., Kim, C. H., Millard, P. J., and Gosse, J. A. (2016) Triclosan
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