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Triclosan Disrupts Thyroid Hormones: Mode-Of-Action, Developmental Susceptibility, and Determination of Human Relevance

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Triclosan Disrupts Thyroid Hormones: Mode-Of-Action, Developmental Susceptibility, and Determination of Human Relevance Triclosan Disrupts Thyroid Hormones: Mode-of-Action, Developmental Susceptibility, and Determination of Human Relevance Katie Beth Paul “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 Curriculum of Toxicology.” Chapel Hill 2011 Approved by: Kim L. R. Brouwer, Pharm.D., Ph.D. Kevin M. Crofton, Ph.D. Michael J. DeVito, Ph.D. Philip C. Smith, Ph.D James A. Swenberg, D.V.M., Ph.D. ©2011 Katie Beth Paul ALL RIGHTS RESERVED ii Abstract Katie Beth Paul Triclosan Disrupts Thyroid Hormones: Mode-of-Action, Developmental Susceptibility, and Determination of Human Relevance (Under the direction of Kevin M. Crofton, Ph.D.) Preliminary study demonstrated that triclosan (TCS), a bacteriostat in myriad consumer products, decreases serum thyroxine (T4) in rats. Adverse neurodevelopmental consequences result from thyroid hormone (TH) disruption; therefore determination of whether TCS disrupts THs during development, its mode-of-action (MOA), and the human relevance is critical. This research tested the hypothesis that TCS disrupts THs via activation of pregnane X and constitutive androstane receptors (PXR, CAR), mediating Phase I-II enzyme and hepatic transporter expression and protein changes, thereby increasing catabolism and elimination of THs, resulting in decreased TH concentrations. For Aim One, the hypothesized MOA was assessed using weanling female Long-Evans rats orally exposed to TCS (0-1000 mg/kg/day) for four days. Serum T4 decreased 35% at 300 mg/kg/day. Activity and expression of markers of Phase I (Cyp2b, Cyp3a1) and Phase II (Ugt1a1, Sult1c1) metabolism were moderately induced, consistent with PXR and/or CAR activation and increased hepatic catabolism. Susceptibility of dams and developing rats to TCS- induced hypothyroxinemia was determined for Aim Two. Long-Evans dams received TCS (0-300 mg/kg/day) orally from gestational day (GD) 6 to postnatal day (PND) 21; tissues were collected from fetuses (GD20), pups (PND4, 14, 21), and dams (GD20, PND22). iii Serum T4 decreased 30% in GD20 dams and fetuses, PND4 pups, and PND22 dams (300 mg/kg/day). Minor increases in activity and expression of markers of hepatic Phase I (Cyp2b, Cyp3a) and Phase II (T4-glucuronidation in PND22 dams) metabolism were consistent with PXR/CAR activation and concomitant minor decreases in T4. For Aim Three, cell-based rat and human PXR and CAR reporter assays were employed to evaluate the human relevance of the putative MOA. TCS (10-30 µM) demonstrated human receptor reporter activities: inverse agonism of CAR1 and agonism of CAR2 CAR3, and PXR. TCS was an inverse agonist of rat CAR, similar to compounds that increase Phase I-II metabolism downstream. Although the data indicate potential species differences in the initiating key event, downstream effects on hepatic catabolism may be similar due to overlapping transcriptional regulatory functions of PXR and CAR. These data establish a plausible MOA for TCS-induced hypothyroxinemia in rats and demonstrate initiation of the MOA in human models. iv To my uncle, Kenneth Marshall Paul (June 7, 1942 - August 21, 2010), a courier, New York City public transportation expert, lover of food and culture, and quietly hilarious friend to many. What he lacked in “book smarts” he made up for amply with his sense of humor and will (perhaps stubbornness to some). He was a testament to our shared belief that hard work and fulfilling contributions need not be limited by innate intelligence at birth. Despite his mental retardation, his efforts to survive, work, make friends, travel, attend Broadway shows, and give back, supported by the beliefs and help of my grandmother, Sophie Paul, made these things a reality. While by some unexplained event I was not born with the same disadvantage, this dissertation work is also the result of this common philosophy in my family: working hard, and even harder, makes it so. v Acknowledgements First I would like to thank Kevin M. Crofton, PhD., for his invaluable mentorship throughout this work, and hopefully in the future. The time and patience he invested in me and this project will not be forgotten. Considerable thanks are also due to my dissertation committee members: Kim L. R. Brouwer, Pharm.D., Ph.D., Michael J. DeVito, Ph.D., Philip C. Smith, Ph.D., and James A. Swenberg, D.V.M., Ph.D. for their help and guidance throughout the project. Dr. DeVito served as my laboratory co-mentor and spent extra time ensuring my success and asking helpful questions. Drs. Brouwer and Smith also hosted me in their laboratories for additional experimentation and training, which was exceedingly helpful not only to this work, but also my next career steps. Drs. Swenberg and Brouwer provided much additional support by their willingness to help me pursue additional outside funding resources. Special thanks to Joan M. Hedge for her support and training during my time in the Crofton Lab at the US EPA. I benefitted greatly from her technical knowledge particularly of animal-handling, and also greatly enjoyed my time working with her on many projects. Additional thanks to Steve Simmons, Ph.D., for providing the immense opportunity to work with him in his laboratory to develop Aim Three of this work; Geremy Knapp for his technical advice on PCR applications; David Ross, Elizabeth Boykin, and Joyce Royland, Ph.D., for training on equipment; previous lab member Joshua A. Harrill, Ph.D. for his support and advice; Tracy Marion, Ph.D.. Kristina Wolf, Ph.D., and David Harbourt, Ph.D. for training in UNC labs; Mary E. Gilbert, Ph.D., William R. Mundy, Ph.D., Douglas C. Wolf, D.V.M., Ph.D., Stephanie Padilla, Ph.D., and the many, many other people at the US vi EPA who provided support and importantly access to many of the tools used in this work; the University of North Carolina at Chapel Hill Curriculum in Toxicology, particularly David J. Holbrook, Ph.D., Marila Cordeiro-Stone, Ph.D., and Julie Cannefax; Arlo Brown and Elaine Kimple of the UNC School of Pharmacy; the National Institute of Environmental Health Sciences Training Grant (T32-ES07126); the EPA/UNC Toxicology Research Program Training Agreement (CR833237); the US EPA/BASF Cooperative Research and Development Agreement (CRADA 546-09) that funded a portion of this work, as well as Robert Peter, Ph.D., Edgar Leibold, Ph.D., James Plautz, Ph.D., and Lisa Navarro, Ph.D. who enabled this agreement and provided useful discussions; the Society of Toxicology Colgate- Palmolive Award for Student Research Training in Alternative Methods; and the PhRMA Foundation Predoctoral Pharmacology/Toxicology Fellowship program. vii Table of Contents List of Tables………………………………………………………...…………………........xii List of Figures………………………………………………………...………………..........xiii List of Abbreviations and Gene Symbols……………………………………………………xv Chapter 1: Introductory Chapter…..…..……………………………………………................1 1. Overview…………………………………………………………………………...2 2. Triclosan applications in personal care and pharmaceutical products……………..4 3. Environmental occurrence…………………………………………………………5 4. Measured exposures to triclosan…………………………………………………...7 4a. Wildlife exposure…………………………………………………………7 4b. Human exposure………………………………………………………….7 5. Absorption, distribution, metabolism, and excretion (ADME) of triclosan……….9 5a. Routes of exposure and absorption……………………………………….9 5b. Distribution, metabolism, and excretion………………………………...10 6. Brief examination of toxicity in mammals……………………………………….11 6a. Dermal toxicity…………………………………………………………..12 6b. Oral toxicity……………………………………………………………..12 6c. Carcinogenicity………………………………………………………….13 6d. Reproductive and teratological toxicity…………………………………14 7. Evidence for triclosan-induced endocrine disruption and potential mechanisms………………………………………………………...14 7a. Evidence for triclosan-induced sex hormone disruption………………...14 viii 7b. Evidence for triclosan-induced thyroid hormone disruption……………16 8. Thyroid hormones regulate physiology…………………………………………..19 8a. Overview of regulation of the thyroid hormone system………………...19 8b. Physiological action of thyroid hormones in adult organisms…………..22 8c. Thyroid hormones during development…………………………………23 8d. Mechanisms of thyroid hormone disruption…………………………….25 9. Rat as a model of thyroid hormone disruption……………………………………28 9a. Potential relevance to humans: differences in thyroid hormone homeostasis between rats and humans…………….29 9b. Potential relevance to humans: evidence for thyroid disruption in humans by microsomal enzyme inducers……………...31 10. Summary and human health significance……………………………………….33 11. Experimental Design…………………………………………………………….33 12. References……………………………………………………………………….37 Chapter 2: Short-term Exposure to Triclosan Decreases Thyroxine In Vivo via Upregulation of Hepatic Catabolism in Young Long-Evans Rats ………….. ……………………………………..…………..55 1. Abstract…………………………………………………………………………...56 2. Introduction……………………………………………………………………….57 3. Methods…………………………………………………………………………...59 4. Results…………………………………………………………………………….65 5. Discussion………………………………………………………………………...68 6. Supplementary Data………………………………………………………………75 7. Funding Information……………………………………………………………...75 8. Acknowledgments………………………………………………………………...75 9. References………………………………………………………………………...86 ix Chapter 3: Developmental Triclosan Exposure Decreases Maternal and Neonatal Thyroxine in Rats …………...………………………………..92 1. Abstract…………………………………………………………………………...93 2. Introduction……………………………………………………………………….93 3. Methods…………………………………………………………………………...95
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