Department of Molecular Biosciences, University of California, Davis, CA, USA.
Toxicol Sci. 2013 Mar;132(1):196-210. doi: 10.1093/toxsci/kfs339. Epub 2013 Jan 3.
Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether [BDE-47] and 2,2',4,5'-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50) = 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain.
多溴联苯醚（PBDEs）是一组重要的阻燃剂，广泛应用于环境中，其在过去 25 年中的使用量一直在稳步增加。PBDEs 或其代谢产物可以通过多种机制诱导神经毒性和线粒体功能障碍（MD）。最近，具有 < 5 个 Br 取代基的 PBDEs（即 2,2',4,4'-四溴二苯醚[BDE-47]和 2,2',4,5'-四溴二苯醚[BDE-49]）引起了人们的兴趣，因为它们具有高生物蓄积性。特别是，BDE-49 等同类物是最具生物活性的一种，其浓度通常低于生物组织中观察到的 BDE-47 浓度；然而，其在生物相关浓度下引起 MD 的潜力尚不清楚。为此，研究了 BDE-49 对脑线粒体和神经元祖细胞纹状体细胞（NPC）的影响。BDE-49 在浓度 < 0.1 nM 时使线粒体解偶联，而在浓度 > 1 nM 时，它抑制了复合物 V（混合抑制类型；IC50 = 6 nM）和复合物 IV（非竞争性抑制；IC50 = 40 nM）的电子传递。考虑到 BDE-49（本研究中为 400 倍）和其他 PBDEs 在细胞中积累 1-3 个数量级，特别是在线粒体和微粒体中，很容易在血浆浓度中达到这些浓度。在 NPC 中观察到类似的效果，并在 PTEN（PI3K/Akt 途径的负调节剂）缺陷的背景下加剧，这种缺陷与自闭症样行为、精神分裂症和癫痫有关。PBDE 介导的 MD 本身或由赋予对这种暴露易感性的背景增强，可能对大脑的能量平衡产生深远影响。
