Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California 95616, USA.
Environ Health Perspect. 2011 Apr;119(4):519-26. doi: 10.1289/ehp.1002728. Epub 2010 Nov 24.
Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that bioaccumulate in human tissues. Their neurotoxicity involves dysregulation of calcium ion (Ca(2+))signaling; however, specific mechanisms have yet to be defined.
We aimed to define the structure-activity relationship (SAR) for PBDEs and their metabolites toward ryanodine receptors type 1 (RyR1) and type 2 (RyR2) and to determine whether it predicts neurotoxicity.
We analyzed [3H]ryanodine binding, microsomal Ca(2+) fluxes, cellular measurements of Ca(2+) homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca(2+) dysregulation.
PBDEs possessing two ortho-bromine substituents and lacking at least one para-bromine substituent (e.g., BDE-49) activate RyR1 and RyR2 with greater efficacy than corresponding congeners with two para-bromine substitutions (e.g., BDE-47). Addition of a methoxy group in the free para position reduces the activity of parent PBDEs. The hydroxylated BDEs 6-OH-BDE-47 and 4´-OH-BDE-49 are biphasic RyR modulators. Pretreatment of HEK293 cells (derived from human embryonic kidney cells) expressing either RyR1 or RyR2 with BDE-49 (250 nM) sensitized Ca2+ flux triggered by RyR agonists, whereas BDE-47 (250 nM) had negligible activity. The divergent activity of BDE-49, BDE-47, and 6-OH-BDE-47 toward RyRs predicted neurotoxicity in cultures of cortical neurons.
We found that PBDEs are potent modulators of RyR1 and RyR2. A stringent SAR at the ortho and para position determined whether a congener enhanced, inhibited, or exerted nonmonotonic actions toward RyRs. These results identify a convergent molecular target of PBDEs previously identified for noncoplanar polychlorinated biphenyls (PCBs) that predicts their cellular neurotoxicity and therefore could be a useful tool in risk assessment of PBDEs and related compounds.
多溴联苯醚（PBDEs）是广泛使用的阻燃剂，会在人体组织中生物累积。其神经毒性涉及钙离子（Ca(2+)）信号的失调；然而，特定的机制尚未确定。
我们旨在确定 PBDEs 及其代谢物与肌浆网钙释放通道 1 型（RyR1）和 2 型（RyR2）的构效关系（SAR），并确定其是否可预测神经毒性。
我们分析了[3H]ryanodine 结合、微粒体 Ca(2+)流、细胞内 Ca(2+)稳态测量，以确定 PBDE 介导的 Ca(2+)失调的机制和特异性。
具有两个邻位溴取代基且缺乏至少一个对位溴取代基的 PBDE（如 BDE-49）比具有两个对位溴取代基的相应同系物（如 BDE-47）更有效地激活 RyR1 和 RyR2。在游离对位添加甲氧基会降低母体 PBDE 的活性。羟基化的 BDE 6-OH-BDE-47 和 4´-OH-BDE-49 是双相 RyR 调节剂。用 250 nM 的 BDE-49 预处理表达 RyR1 或 RyR2 的 HEK293 细胞（源自人胚胎肾细胞）可敏化 RyR 激动剂触发的 Ca2+流，而 250 nM 的 BDE-47 几乎没有活性。BDE-49、BDE-47 和 6-OH-BDE-47 对 RyRs 的不同活性预测了皮质神经元培养物中的神经毒性。
我们发现 PBDEs 是 RyR1 和 RyR2 的有效调节剂。邻位和对位的严格 SAR 确定了同系物是否增强、抑制或对 RyRs 产生非单调作用。这些结果确定了 PBDEs 和先前确定的非平面多氯联苯（PCBs）的共同分子靶标，该靶标可预测其细胞神经毒性，因此可能成为 PBDEs 及其相关化合物风险评估的有用工具。
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