Exposure to HBCDD - a Brominated Flame Retardant - Induces Altered Synaptic Protein Expression in the Hippocampus and the Frontal Cortex of a Male Mouse Model 公开

Camp, Chad Ronald (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/th83m0006?locale=zh
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Abstract

HBCDD, a brominated flame retardant, is rapidly replacing its neurotoxic predecessor, PBDEs, in a myriad of commercial and consumer products. HBCDD is a persistent, bioaccumulative compound with a propensity to deposit in lipid-rich tissues, including the brain. Although HBCDD is structurally similar to PBDEs, its neurotoxic potential is still unclear. Rodent neurobehavioral studies have indicated that exposure to HBCDD impairs the learning and memory process, and causes increased hyperactivity. In addition, HBCDD exposure was shown to alter synaptic protein expression in the striatum of a mouse model. Given these neurobehavioral outcomes, we hypothesized that HBCDD may also be affecting the hippocampus and the frontal cortex. Accordingly, we used an in vivo male mouse model to evaluate HBCDD-mediated synaptic protein alterations in these two brain regions. In the hippocampus, we dosed male mice with 25mg/kg HBCDD for 30 days and evaluated alterations in synaptic protein expression immediately following their last exposure. Here, we found that HBCDD altered synaptic proteins vital to dopaminergic, glutamatergic, and GABAergic neurotransmission including: TH, VMAT2, mGluR1, mGluR2, NMDAR-2B, and GAT-1. Additionally, in the hippocampus, HBCDD exposure caused a decrease in tau expression while increasing several regulatory proteins involved in neurogenesis, synaptogenesis, axonal growth, and synaptic plasticity such as Ube-3A, BDNF, PSA-NCAM, and GAP43. In the frontal cortex, we used a persistent HBCDD dosing paradigm that involved dosing male mice with 25mg/kg HBCDD for 30 days then allowing them to sit for 42 days before synaptic proteins were evaluated. Using this paradigm, we found that HBCDD altered frontal cortex expression of TH and mGluR1, while mGluR2, NMDAR-2B, vGlut, and GAT-1 expression was unchanged. Additionally, HBCDD exposure induced an upregulation of frontal cortex cytoskeletal proteins including ß-actin and tau. All of these alterations can produce an additive effect, giving rise to the many neurobehavioral deficits seen following HBCDD exposure, including difficulty with learning and memory, and increased hyperactivity.

Table of Contents

Introduction.........................................................................................................................1

Materials and Methods ..........................................................................................................6

Chemicals and Reagents...........................................................................................................6

Animal Treatment............................................................................................................... .....7

Western Blot Analysis............................................................................................................... 8

Immunohistochemistry.............................................................................................................9

Statistical Analysis ..................................................................................................................10

Results.................................................................................................................................10

Hippocampus Samples......................................................................................................... ....10

Frontal Cortex Samples ............................................................................................................12

Discussion............................................................................................................................14

References............................................................................................................................27

Figures and Tables ................................................................................................................38

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