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USING HIGH THROUGHPUT SCREENING FOR PREDICTIVE MODELING OF REPRODUCTIVE TOXICITY Matthew T. Martin A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Environmental Sciences and Engineering. Chapel Hill 2011 Approved by: Ivan Rusyn, M.D. Ph.D. David J. Dix, Ph.D Richard S. Judson, Ph.D. Alexander Tropsha, Ph.D. Avram Gold, Ph.D. i © 2011 Matthew T. Martin ALL RIGHTS RESERVED ii ABSTRACT MATTHEW T. MARTIN: Using High Throughput Screening For Predictive Modeling of Reproductive Toxicity (Under the direction of Dr. David J. Dix) Traditional reproductive toxicity testing is inefficient, animal intensive and expensive with under a thousand chemicals ever tested among the tens of thousands of chemicals in our environment. Screening hundreds of chemicals through hundreds high-throughput biological assays generated a validated model predictive of rodent reproductive toxicity with potential application toward large-scale chemical testing prioritization and chemical testing decision- making. Chemical classification for model development began with the uniform capturing of the available animal reproductive toxicity test information utilizing an originally developed relational database and reproductive toxicity ontology. Similarly, quantitative high- throughput screening data were consistently processed, analyzed and stored in a relational database with gene and pathway mapping information. Chemicals with high quality in vivo and in vitro data comprised the training, test, external and forward validation chemical sets used to develop and assess the predictive model based on eight selected features generally targeting known modes of reproductive toxicity action. In three case studies, the forward validated predictive model reduced the overall costs of reproductive toxicity testing by roughly twenty percent. The model provides a starting point for the future of reproductive toxicity testing. iii ACKOWLEDGEMENTS First I would like to thank my research advisor, David J. Dix, PhD., for his invaluable mentorship throughout my academic and professional career, as he has provided me countless opportunities for growth, advancement and independence while continuing to provide always needed guidance. I am also grateful to my academic advisor, Ivan Rusyn, M.D. Ph.D., for his patience, flexibility and willingness to mentor and guide me through the academic process even under somewhat unique circumstances. I would also like to thank Dr. Rusyn and the other members of my committee, Richard S. Judson, Ph.D., Alexander Tropsha, Ph.D., Avram Gold, Ph.D., for taking the time to provide knowledge, expertise and support as your involvement has helped shape my education and newly formed expertise. I would also like to thank my colleagues and managers at the U.S. Environmental Protection Agency’s National Center for Computational Toxicology as they have been a continuing source of learning, challenge, entertainment, and enlightenment. It is a true pleasure to work with such an intelligent and motivated group of public servants. The research described here has been partially supported by the U.S. Environmental Protection Agency. The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. iv TABLE OF CONTENTS LIST OF TABLES .............................................................................................................. ix LIST OF FIGURES ............................................................................................................. xi LIST OF ABBREVIATIONS .............................................................................................xiv CHAPTER 1 .........................................................................................................................1 I. INTRODUCTION ................................................................................................. 1 Reproductive Physiology .......................................................................................1 Chemically-induced Reproductive Toxicity ...........................................................3 Human Reproductive Impairment ..........................................................................5 Reproductive Toxicity Testing ...............................................................................7 Predictive Toxicology using Computational and Alternative Methods ................. 10 Toxicity Databases .............................................................................................. 11 Chemical Structure-based Modeling in Toxicology ............................................. 13 Experimental Predictive Toxicology .................................................................... 14 In Vitro Assays in Toxicology ............................................................................. 16 Reproductive Toxicity Alternative Testing Methods ............................................ 19 Tables .................................................................................................................. 21 Figures ................................................................................................................ 23 References ........................................................................................................... 26 CHAPTER 2 ....................................................................................................................... 37 v II. PROFILING PHENOTYPIC ACTIVITY OF CHEMICALS FROM MULTIGENERATION REPRODUCTION STUDIES IN TOXREFDB ................................................................................................... 37 Abstract ............................................................................................................... 37 Introduction ......................................................................................................... 38 Methods .............................................................................................................. 40 Results................................................................................................................. 44 Discussion ........................................................................................................... 49 Tables .................................................................................................................. 54 Figures ................................................................................................................ 55 References ........................................................................................................... 59 CHAPTER 3 ....................................................................................................................... 61 III. IMPACT OF ENVIRONMENTAL CHEMICALS ON KEY TRANSCRIPTION REGULATORS AND CORRELATION TO TOXICITY ENDPOINTS WITHIN EPA’S TOXCASTTM PROGRAM ......................................................................................................... 61 Abstract ............................................................................................................... 61 Introduction ......................................................................................................... 62 Methods .............................................................................................................. 64 Results................................................................................................................. 68 Discussion ........................................................................................................... 80 Tables .................................................................................................................. 85 Figures ................................................................................................................ 89 References ........................................................................................................... 99 CHAPTER 4 ..................................................................................................................... 104 IV. PREDICTIVE MODEL OF RAT REPRODUCTIVE TOXICITY FROM TOXCAST HIGH THROUGHPUT SCREENING ..................................................................................................... 104 vi Abstract ............................................................................................................. 104 Introduction ....................................................................................................... 105 Methods ............................................................................................................ 107 Results............................................................................................................... 114 Discussion ......................................................................................................... 123 Tables ................................................................................................................ 131 Figures .............................................................................................................. 138 References ........................................................................................................
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