title: Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: role of dopamine handling in neurotoxicity.
abstract: In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson's disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH+ neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders.
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322-3090, USA. joshua.m.bradner@emory.edu
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Bradner
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Suragh
authors.forename: W Wyatt
authors.initials: WW
authors.lastname: Wilson
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Lazo
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Stout
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Kim
authors.forename: Min Z
authors.initials: MZ
authors.lastname: Wang
authors.forename: Douglas I
authors.initials: DI
authors.lastname: Walker
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Pennell
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
authors.forename: W Michael
authors.initials: WM
authors.lastname: Caudle
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055768:Halogenated Diphenyl Ethers / Q000494:pharmacology / Q000633:toxicity*; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D055768:Halogenated Diphenyl Ethers; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; C086401:pentabromodiphenyl ether; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid