The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH-BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH-BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK-ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand-protein docking suggested that 6-OH-BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH-BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH-BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β-lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK-ERK signaling, and axonal guidance.

中文翻译：

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某些邻羟基化溴化醚是混杂的激酶抑制剂，会损害神经元信号传导和神经发育过程。

发育中的神经系统对环境信号非常敏感，包括破坏性毒素，例如多溴二苯醚（PBDEs）。多溴二苯醚是一类遍及环境的溴化阻燃剂，其神经发育毒性机制仍不清楚。使用分离的胚胎大鼠褐家鼠的皮层神经元，我们在这里发现长期暴露于6-OH-BDE-47（最普遍的羟基化PBDE代谢物之一）会抑制自发和诱发的神经元电活动。根据我们先前对促分裂原活化蛋白激酶（MAPK）/细胞外信号相关激酶（ERK）（MEK）生物学的研究，以及我们对6-OH-BDE-47在结构上类似于激酶抑制剂的观察，我们假设某些羟基化的多溴二苯醚至少部分介导神经毒性，通过损害MAPK信号转导的MEK-ERK轴。我们在三个实验平台上测试了这一假设：1）在计算机上，对配体-蛋白质对接建模表明6-OH-BDE-47是混杂的ATP竞争性激酶抑制剂；2）在离体神经元的体外，其中6-OH-BDE-47和另一种特定的羟基化BDE代谢物同样损害了MEK / ERK1 / 2的磷酸化和活性诱导的神经元立即早期基因的转录；3）在果蝇的体内，那里发育暴露于6-OH-BDE-47和MAPK抑制剂导致后代显示出类似的蘑菇体β瓣中线交叉频率增加，这是轴突指导的度量。在一起