Genskow Kelly R, Bradner Joshua M, Hossain Muhammad M, Richardson Jason R, Caudle W Michael
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322-3090, USA.
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.
Neurotoxicol Teratol. 2015 Nov-Dec;52(Pt B):162-9. doi: 10.1016/j.ntt.2015.06.003. Epub 2015 Jun 12.
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.
在过去几十年中，卤代有机化合物的使用已成为环境和人类健康问题的根源。多氯联苯（PCBs）和多溴二苯醚（PBDEs）的神经毒性已广为人知。随后PBDEs被禁用，导致1,2,5,6,9,10-六溴环十二烷（HBCDD，也称为HBCD）作为消费品中的阻燃剂使用量大幅增加。HBCDD与PBDEs在物理化学性质上的相似性表明，HBCDD可能对多巴胺系统也具有神经毒性，而多巴胺系统在帕金森病（PD）中会受到特异性损伤。本研究的目的是采用体外和体内方法评估HBCDD对黑质纹状体多巴胺系统的神经毒性。我们证明，在SK-N-SH儿茶酚胺能细胞系中，暴露于HBCDD（0-25μM）24小时会导致显著的细胞死亡，并且在较低浓度（0-10μM）下处理72小时后，TH+原代培养神经元的生长和活力会降低。对HBCDD（25mg/kg，持续30天）的体内神经毒性评估导致纹状体多巴胺转运体和囊泡单胺转运体2的表达显著降低，这两者在介导多巴胺回路中的多巴胺稳态和神经传递中都起着不可或缺的作用。然而，多巴胺末端的酪氨酸羟化酶表达或纹状体多巴胺水平未见变化。迄今为止，这些是首次证明暴露于HBCDD会破坏黑质纹状体多巴胺系统的数据。鉴于这些结果以及HBCDD在环境中的普遍存在，其作为PD环境风险因素的可能作用应进一步研究。
