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Arsenic-Associated Diabetes: Mechanisms and the Role of Arsenic Metabolism

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Arsenic-Associated Diabetes: Mechanisms and the Role of Arsenic Metabolism ARSENIC-ASSOCIATED DIABETES: MECHANISMS AND THE ROLE OF ARSENIC METABOLISM Madelyn C. Huang A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Toxicology within the School of Medicine. Chapel Hill 2018 Approved by: Miroslav Stýblo Rebecca Fry Ilona Jaspers Eric Klett Zuzana Drobná © 2018 Madelyn C. Huang ALL RIGHTS RESERVED ii ABSTRACT Madelyn C. Huang: Arsenic-associated diabetes: mechanisms and the role of arsenic metabolism (Under the direction of Miroslav Stýblo) Inorganic arsenic (iAs) is a ubiquitous drinking water and food contaminant. Chronic exposure to iAs has been linked to diabetes mellitus in many populations. Experimental studies support these associations and suggest mechanisms, but the precise pathogenesis of iAs- associated diabetes is unclear. Efficient metabolism of iAs through methylation, catalyzed by arsenic (+3) methyltransferase (AS3MT), influences the risk of iAs-associated disease. Additionally, higher intake of methyl donor nutrients such as folate and methylcobalamin (B12) has been linked to increased efficiency of iAs metabolism and lowered disease risk. However, while metabolism of iAs facilitates its excretion from the body, iAs metabolites are more toxic than iAs itself. The role of iAs metabolism in iAs toxicity is understudied, especially in cardiometabolic disease. Understanding how iAs metabolism affects iAs-associated diabetes will help design appropriate intervention strategies and improve risk assessment. This project investigated how iAs metabolism influences iAs-associated diabetes. First, we compared metabolite profiles of C57BL6 (WT) with As3mt-KO (KO) mice, which cannot methylate iAs, with and without exposure to iAs. We found that while iAs exposure was linked to very few metabolites, knock-out of As3mt was associated with metabolites in a sex-specific manner. Second, we investigated the effect of iAs exposure at environmentally-relevant doses on glucose metabolism in mice and the role of methyl donor nutrient supplementation. Prenatal iii exposure to iAs elicited hyperglycemia and insulin resistance, particularly in males. Chronic iAs exposure in adult mice increased insulin resistance only with a low-folate, high-fat diet. Males were more insulin resistant than females; KO mice more than WT mice. In both studies, supplementation with B12 and/or folate protected against iAs-associated impairments in glucose metabolism, despite having a minimal effect on iAs metabolism. Third, we investigated how iAs and its methylated metabolites inhibit insulin secretion in pancreatic β-cells. These arsenicals may be impairing calcium influx by affecting ion channels. Interestingly, methylated metabolites appear to target different mechanisms than iAs. Taken together, this research adds novel knowledge about the effects of environmentally-relevant iAs exposures on glucose metabolism in mice, the underlying mechanisms, and the role of iAs metabolism and methyl donor nutrients in metabolic health. iv To the One who created it all for us to discover and enjoy v ACKNOWLEDGMENTS I would like to thank Mirek Stýblo for being a fantastic mentor. He has taught me much about being a scientist and has always been very supportive in all of my scientific, career, and life endeavors. I would like to thank my committee members for their thoughtful advice and for sitting through too many slides with too many bar charts. It has been an honor to learn from and work with such excellent scientists. This work could not have been completed, or as enjoyable, without other members of the Stýblo lab, both past and present. In particular, I would like to thank Dr. Christelle Douillet for being a great coworker and for teaching me everything I know about benchwork, mice, and running marathons. I would also like to thank the Nutritional Biochemistry Department for letting me in on their holiday parties and connecting me with valuable colleagues and friends. Many thanks to all the friends that I have made along the way in this adventure called graduate school. I have learned so much from every one of you, about science, about faith, about living life. To the other members of the best Tox cohort ever, for the all the study sessions, the comisery, and laughs. To my family for their unending love and continuous support throughout my life. And to my husband Shawn for his unconditional love, support, and everlasting smile. This work was supported by NIH grant R01ES022697 to M.S., the Curriculum in Toxicology training grant 5T32ES007126-32, and NIEHS F31 Fellowship Award F31ES027743 to M.H. vi PREFACE Many people have contributed to the research presented in this dissertation and their contributions are detailed below: Chapter 1: I wrote this chapter which was reviewed by Mirek Stýblo. Chapter 2: This work was published previously in Archives of Toxicology and reproduced with permission. Individuals involved include: myself, Christelle Douillet, Mingming Su, Kejun Zhou, Tao Wu, Wenlian Chen, Joseph A. Galanko, Zuzana Drobná, R. Jesse Saunders, Elizabeth Martin, Rebecca C. Fry, Wei Jia, and Miroslav Stýblo. Lipid analyses were conducted at the University of Colorado Lipidomics Core, by Dr. Robert Murphy and Karin Zemski Berry. I would like to thank Dr. David Thomas (US EPA) and Dr. Rosalind Coleman (Department of Nutrition, UNC Chapel Hill) for reviewing the data generated by metabolomic analyses and for their helpful suggestions regarding the data interpretation. I wrote this chapter with edits by Mirek Stýblo. Chapter 3: The prenatal exposure study involved the contribution of myself, Christelle Douillet, Ellen Nicole Dover, and Mirek Stýblo. Dr. Zuzana Drobná (North Carolina State University, Raleigh, NC) provided advice regarding prenatal folate and B12 supplementation. Henry Gong and Jin Chen helped with animal care and data entry. I wrote this chapter with edits by Mirek Stýblo. Chapter 4: The adult exposure study involved the contribution of myself, Christelle Douillet, Ellen Nicole Dover, Chongben Zhang, Rowan Beck, and Mirek Stýblo. Sergey Krupenko vii and Eric Klett provided valuable comments on the discussion. Ahmad Tejan-Sie and Alexis Dunlap helped with animal care and data entry. I wrote this chapter with edits by Mirek Stýblo. Chapter 5: This work was completed by myself with help from Will Ostrom conducting the MTT assay. Pablo Ariel and the UNC Microscopy Services Laboratoy provided technical assistance for monitoring calcium influx. I wrote this chapter with edits by Mirek Stýblo. Chapter 6: I wrote this chapter myself. viii TABLE OF CONTENTS ABSTRACT ................................................................................................................................... iii ACKNOWLEDGMENTS ............................................................................................................. vi PREFACE ..................................................................................................................................... vii TABLE OF CONTENTS ............................................................................................................... ix LIST OF TABLES ....................................................................................................................... xiii LIST OF FIGURES ..................................................................................................................... xiv LIST OF ABBREVIATIONS ..................................................................................................... xvii 1. CHAPTER 1- Introduction ..................................................................................................... 1 1.1 Human Exposure to iAs ........................................................................................................ 2 1.1.1 As in nature ................................................................................................................................. 2 1.1.2 Uses of As .................................................................................................................................... 3 1.1.3 Routes of exposure to As ............................................................................................................. 5 1.2 iAs Metabolism ................................................................................................................... 10 1.2.1 iAs methylation .......................................................................................................................... 10 1.2.2 Genetic modifiers of iAs methylation ........................................................................................ 13 1.2.3 Dietary modifiers of iAs methylation ......................................................................................... 15 1.2.4 iAs metabolism and toxicity/disease risk ................................................................................... 17 1.3 iAs-associated diabetes ....................................................................................................... 18 1.3.1 Diabetes: Diagnosis, Pathogenesis, and Classification ............................................................ 19 1.3.2 iAs as an environmental diabetogen.......................................................................................... 22 1.3.3 Mechanisms of iAs-associated diabetes ...................................................................................
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