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Developmental Toxicity of Polycyclic Aromatic Hydrocarbons: Defining Mechanisms with Systems-Based Transcriptional Profiling

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Developmental Toxicity of Polycyclic Aromatic Hydrocarbons: Defining Mechanisms with Systems-Based Transcriptional Profiling AN ABSTRACT OF THE DISSERTATION OF Britton C. Goodale for the degree of Doctor of Philosophy in Toxicology presented on August 12, 2013. Title: Developmental Toxicity of Polycyclic Aromatic Hydrocarbons: Defining Mechanisms with Systems-based Transcriptional Profiling Abstract approved:___________________________________________________________________________________ Robert L. Tanguay Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. Defining toxicity mechanisms for this large family of multi-ring structures and substituted derivatives is a substantial challenge. Several PAHs, such as benzo(a)pyrene (BaP), are mutagenic, toxic to wildlife, and classified as probable carcinogens to humans. PAHs are present in the environment both in the gaseous phase as well as associated with particulates, and exposures occur via complex mixtures; combustion emissions contain PAHs along with many other contaminants. Cardiac dysfunction and adverse birth outcomes associated with exposure to airborne PAHs suggest that this family of compounds may have non-mutagenic biological activities that affect human health. Some PAHs exert toxic effects via binding the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates transcription of many downstream target genes, including cytochrome P450 metabolizing enzymes. Unlike planar halogenated hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), PAHs are readily metabolized by CYP1A, CYP1B1 and other enzymes, which create reactive intermediates and/or facilitate excretion. Mechanisms of PAH toxicity therefore include canonical AHR signaling, induction of oxidative stress, and other lesser-understood activities that do not require the AHR. We employed zebrafish as a model to rapidly assess developmental toxicity, global transcriptional responses and AHR activation in embryos exposed to parent and oxygenated PAHs (OPAHs). Using comparative analysis of mRNA expression profiles from microarrays with embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR), we identified expression biomarkers and disrupted biological processes that precede developmental abnormalities. These transcriptional responses were associated with PAH body burdens in the embryos detected by GC-MS. We found that uptake data were essential for discerning molecular pathways from dose-related differences, and identified two primary toxicity profiles. While BAA disrupted transcripts involved in vasculogenesis, DBT and PYR misregulated ion homeostasis and muscle-related genes. NfKB signaling was predicted to be involved in both responses, but canonical AHR signaling was only activated by BAA. In order to study the role of the AHR in mediating toxicity of PAHs, we developed an AHR2 mutant zebrafish line, which has a mutation in the transactivation domain of AHR2. We used AHR agonists TCDD and leflunomide as toxicological probes to characterize AHR activity in the mutant line, and determined that the mutants were functionally null. Finally, we used AHR2 deficient zebrafish embryos to investigate mechanisms by which two four-ring OPAHs induced developmental effects. 1,9 benz-10-anthrone (BEZO) and benz(a)anthracene-7,12-dione (7,12-B[a]AQ) both caused malformations in developing embryos, but they differentially induced CYP1A expression. Despite this difference, the toxicity produced from both compounds was AHR2-dependent. We used mRNA-seq to compare the transcriptional profiles of BEZO and 7,12-B[a]AQ, and identified transcriptional networks that will be investigated further to determine how ligands differentially modulate AHR activity. We also discovered novel transcripts that are potentially important mediators of AHR toxic effects. Comparison across all five parent and OPAHs highlighted clusters of genes that, surprisingly, were similarly expressed in response to the OPAHs, DBT and PYR. These commonly-regulated transcripts may be important to consider when investigating toxicity of PAH mixtures. Together, these studies show that PAHs act via different transcriptional mechanisms, but can be categorized based on transcriptional profiles and differential AHR activation. The clusters of transcripts identified may be involved in common pathways; further investigation of transcription factors and coactivators that interact with mixexpressed genes is a promising area of research for elucidating diverse functions of the AHR. ©Copyright by Britton C. Goodale August 12, 2013 All Rights Reserved Developmental Toxicity of Polycyclic Aromatic Hydrocarbons: Defining Mechanisms with Systems-based Transcriptional Profiling by Britton C. Goodale A DISSERTATION submitted to Oregon State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Presented August 12, 2013 Commencement June 2014 Doctor of Philosophy dissertation of Britton C. Goodale presented on August 12, 2013. APPROVED: _________________________________________________________________________________________________________ Major Professor, representing Toxicology _________________________________________________________________________________________________________ Head of the Department of Environmental and Molecular Toxicology _________________________________________________________________________________________________________ Dean of the Graduate School I understand that my dissertation will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my dissertation to any reader upon request. _______________________________________________________________________________________________________ Britton C. Goodale, Author ACKNOWLEDGEMENTS The completion of this dissertation has by no means been a solitary effort, and I am grateful to the many people who made it possible. I would like to express my sincere gratitude to my graduate mentor, Robert Tanguay, for giving me the opportunity to join the lab and pursue what were, five years ago, fairly specific interests in toxicology. Thank you for sharing your endless excitement about new ideas, and for broadening my perspective and enthusiasm for this field of research more than I could have imagined. None of the work presented here would have been possible without the support I had during my time at OSU, and I am appreciative of the excellent resources that the Tanguay lab has provided. I would like to thank the many members of the Tanguay lab who have helped me over the years: Jane La Du, for her humor and for always being there to help in a pinch; Kate Saili, Tamara Tal, Lisa Truong, Galen Miller and Sumitra Sengupta for providing training in the lab, and for their mentorship and friendship; Andrea Knecht, Mike Simonich, and Annika Swanson for their help and patience with the OPAH studies; Leah Wehmas, Derik Haggard, Siba Das and Cory Gerlach for editing, experiment assistance, and helping me through this final year with excellent company in the lab; Sean Bugel for sharing the office with the window and the challenge assay, providing thoughtful answers to my many questions, and for the excellent discussions; Jill Franzosa for encouragement and advice, both in the lab and on the climbing wall; and Margaret Corvi for helping me keep perspective, making the OPAH body burden studies possible, and being an inspiration to work with. All of the studies in this dissertation were truly made possible by the SARL staff, and I am thankful to Carrie Barton and Cari Buchner for their dedication to the zebrafish colony, particularly the AHR2 mutants (they will some day express their gratitude, too, I’m sure). Thank you to Greg Gonnerman, Chapell Miller for screening help, and to all of the other staff who have kept SARL running. I would like to thank others at OSU for their support; I am grateful to my committee members Daniel Sudakin, Michael Freitag, Kim Anderson, Barbara Taylor and Jeffrey Greenwood for their wisdom and guidance of this project. The Anderson lab welcomed me to OSU, and I can’t imagine my time here without them. Thank you to the many folks who helped me with chemistry questions, compound requests, advised me on environmental relevance for my studies, and gave me good excuses to go to campus. I thank the EMT department for making my graduate work possible, especially department head Craig Marcus for helping me accomplish many goals, and all of the EMT office staff for making things run smoothly. I am especially grateful to my friends who, from near and far, supported me through every step of graduate school. Thank you for being my family when I arrived, exploring the west coast with me, and making Oregon home. Since graduate work feels, much of the time, like a process of many failures, successes in other arenas were an essential part of life the past five years. Thank you to everyone who buoyed my sanity with triumphant climbs, bikes, and foraging adventures. I am so thankful to Erik Endrulat, for his support through this endeavor, and for gently reminding me to think about balance. I was unable to conduct a controlled study on the topic, but nevertheless attribute my perplexing decrease in flu susceptibility the past two years to the good food and abundance of laughter I’ve enjoyed with him. Most of all, I am forever grateful to my family, for their love and support through this entire journey, especially when I chose to move across the country. To my sister, Jane: thank you for your
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