title: Selective damage to dopaminergic transporters following exposure to the brominated flame retardant, HBCDD.
abstract: Over the last several decades, the use of halogenated organic compounds has become the cause of environmental and human health concerns. Of particular notoriety has been the establishment of the neurotoxicity of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). The subsequent banning of PBDEs has led to greatly increased use of 1,2,5,6,9,10-hexabromocyclododecane (HBCDD, also known as HBCD) as a flame retardant in consumer products. The physiochemical similarities between HBCDD and PBDEs suggest that HBCDD may also be neurotoxic to the dopamine system, which is specifically damaged in Parkinson disease (PD). The purpose of this study was to assess the neurotoxicity of HBCDD on the nigrostriatal dopamine system using an in vitro and in vivo approach. We demonstrate that exposure to HBCDD (0-25 μM) for 24 h causes significant cell death in the SK-N-SH catecholaminergic cell line, as well as reductions in the growth and viability of TH+ primary cultured neurons at lower concentrations (0-10 μM) after 72 h of treatment. Assessment of the in vivo neurotoxicity of HBCDD (25 mg/kg for 30 days) resulted in significant reductions in the expression of the striatal dopamine transporter and vesicular monoamine transporter 2, both of which are integral in mediating dopamine homeostasis and neurotransmission in the dopamine circuit. However, no changes were seen in the expression of tyrosine hydroxylase in the dopamine terminal, or striatal levels of dopamine. To date, these are the first data to demonstrate that exposure to HBCDD disrupts the nigrostriatal dopamine system. Given these results and the ubiquitous nature of HBCDD in the environment, its possible role as an environmental risk factor for PD should be further investigated.
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322-3090, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Genskow
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322-3090, USA; Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322-3090, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Bradner
authors.affiliation: Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School Piscataway, NJ 08854, USA.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Hossain
authors.affiliation: Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School Piscataway, NJ 08854, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322-3090, USA; Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322-3090, USA. Electronic address: william.m.caudle@emory.edu.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Caudle
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005411:Flame Retardants / Q000633:toxicity*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D005411:Flame Retardants; D050485:GABA Plasma Membrane Transport Proteins; D006842:Hydrocarbons, Brominated; C493454:Slc18a2 protein, rat; C118623:Slc32a1 protein, rat; D050496:Vesicular Glutamate Transport Proteins; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C089796:hexabromocyclododecane; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Dopamine; Dopamine transporter; Hexabromocyclododecane; Neurotoxicity; Parkinson disease; Vesicular monoamine transporter 2