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Developmental Deltamethrin: Effects on Cognition, Neurotransmitter Systems, Inflammatory Cytokines and Cell Death

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Developmental deltamethrin: Effects on cognition, neurotransmitter systems, inflammatory cytokines and cell death A dissertation submitted to the Graduate School of the University of Cincinnati In partial fulfillment of the requirements for the degree of Doctor of Philosophy In the Neuroscience Graduate Program of the College of Medicine By Emily Pitzer B.S. Westminster College April 2020 Dissertation Committee: Steve Danzer, Ph.D. Mary Beth Genter, Ph.D. Gary Gudelsky, Ph.D. Kimberly Yolton, Ph.D. Charles Vorhees, Ph.D. (Advisor) Michael Williams, Ph.D. (Chair) ABSTRACT Deltamethrin (DLM) is a Type II pyrethroid pesticide and is more widely used with the elimination of organophosphate pesticides. Epidemiological studies have linked elevated levels of pyrethroid metabolites in urine during development with neurological disorders, raising concern for the safety of children exposed to these agents. Few animal studies have explored the effects or mechanisms of DLM-induced deficits in behavior and cognition after developmental exposure. The aim of the present work is to examine the long-term effects of developmental (postnatal day (P) 3-20) DLM exposure in Sprague-Dawley rats on behavior, cognition, and cellular outcomes. First, the developmental effects of early DLM exposure on allocentric and egocentric learning and memory, locomotor activity, startle, conditioned freezing, and anxiety-like behaviors were assessed. The developmental effects of DLM on long-term potentiation (LTP) at P25-35, on adult dopamine (DA) release, monoamine levels, and mRNA levels of receptors/transporters/channels were then determined. In follow-up experiments, adult LTP, hippocampal glutamate release, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining for cell death, as well as DA and glutamate receptors, proinflammatory cytokines, and caspase-3 for protein expression were assessed. The results show that developmental DLM causes long-lasting impairments in behavior and cognition, reduced hippocampal norepinephrine, reduced DA-stimulated release in the nucleus (n.) accumbens, reduced DA D1 receptor (DRD1) mRNA in neostriatum, but no changes in biomarkers of DA synaptic function. Increased LTP at P25-35 in DLM- treated males and females was observed and persisted into adulthood in DLM-treated males, but not females. N-Methyl-D-aspartate (NMDA) receptor subunits -NR2A were ii increased and -NR2B decreased in the hippocampus of male DLM-treated rats with no change in hippocampal potassium-stimulated glutamate release. Developmental DLM resulted in a trend for reduced IL-1β primarily in the neostriatum and n. accumbens, and caspase-independent cell death in the hippocampus and striatum (neostriatum and n. accumbens), including increased TUNEL staining for apoptotic cells in the dentate gyrus. While the mechanism of the neurodevelopmental effects of DLM remains unknown, these data add new information about the effects of this prototypical pyrethroid on the developing brain and behavior. These experiments are an important step toward a better understanding of the potential risks to children from pyrethroid exposure. iii ACKNOWLEDGEMENTS I want to thank my advisor Dr. Charles Vorhees and my committee chair Dr. Michael Williams. Without them I would not have been able to complete this process. They provided me continual patience, mentorship and support through my entire graduate career. In addition, I want to thank my dissertation committee for their guidance and help throughout this project. I want to also thank my lab mates, who have been a continual source of laughs, encouragement, and feedback during this journey we call graduate school. I need to thank my mother and father who have continually supported me through every turn my life has taken; for the long-winded phone calls about graduate school, life in the lab, and everything in between. I also want to give a special thank you to my husband, who has shared this experience with me, overlooked the crazy work schedule, and was always honest when my writing could be better. His unwavering support and love through this challenging time has been a rock to which I could hold onto. And lastly, I need to say a little thank you to my two unofficial emotional support cats, Abner and Frankie, who have always provided me such joy after a long day’s work. Thank you, to everyone who made this possible. iv TABLE OF CONTENTS ABSTRACT...................................................................................................................... ii ACKNOWLEDGEMENTS .............................................................................................. iv TABLE OF CONTENTS .................................................................................................. 1 LIST OF TABLES AND FIGURES .................................................................................. 4 LIST OF SYMBOLS ........................................................................................................ 6 CHAPTER 1: The Type II Pyrethroid, Deltamethrin: Use, Mechanisms and Unintended Consequences……........................................................................................................ 11 Introduction ................................................................................................................... 12 Impact of pyrethroids in humans ................................................................................... 12 Epidemiological data ………………………………......................................................... 13 Pesticidal Actions …………………………………………………..................................... 19 Voltage-gated Sodium Channels ………………………………………............................ 21 Voltage-gated Calcium Channels ……………..………………………............................. 24 Additional targets ………………...………………………………...................................... 26 Effects on neurotransmitters ………….…...……............................................................ 29 DLM Kinetics and Metabolism ………………………………........................................... 33 DLM TK studies and development of PBPKs …………………...................................... 34 DLM Metabolism …………………………....................................................................... 38 Mechanisms of DLM induced neurotoxicity ……........................................................... 41 Effects of pyrethroids on behavior and cognition .…………………................................ 45 Developmental DLM effects on behavior and cognition ……...…….............................. 45 1 Conclusions .................................................................................................................. 49 References ................................................................................................................... 51 Figures and Legends .................................................................................................... 74 CHAPTER 2: Deltamethrin exposure daily from postnatal day 3–20 in Sprague-Dawley rats causes long-term cognitive and behavioral deficits ............................................... 79 Abstract ......................................................................................................................... 80 Introduction ................................................................................................................... 81 Materials and Methods ................................................................................................. 83 Results .......................................................................................................................... 93 Discussion .................................................................................................................... 98 Acknowledgement ………………………………………………………………………..... 105 References ................................................................................................................. 106 Figures and Legends .................................................................................................. 116 CHAPTER 3: Developmental Deltamethrin increases apoptosis in the dentate gyrus and reduces hippocampal NMDA receptor expression without affecting hippocampal glutamate release in Sprague-Dawley rats ……………….………………..................... 131 Abstract ....................................................................................................................... 132 Introduction ................................................................................................................. 134 Materials and Methods ............................................................................................... 138 Results ........................................................................................................................ 147 Discussion .................................................................................................................. 149 References ................................................................................................................. 157 Figures and Legends .................................................................................................. 174 2 CHAPTER 4: General Discussion .............................................................................. 187 Developmental DLM-induced behavioral and cognitive deficits ………………………. 188 Effects of DLM on monoamines ………………………………………………………….. 197 Role of glutamatergic systems and LTP in DLM induced cognitive deficits …………. 199 Developmental effects of
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