Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers.
Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers.
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DOI：
10.1093/eep/dvx020
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发表时间：
2018-01
影响因子：
3.8
通讯作者：
Saha RN
中科院分区：
文献类型：
--
作者：
Poston RG;Dunn CJ;Sarkar P;Saha RN
多溴联苯醚(PBDEs)是一类普遍存在的溴化阻燃剂，在环境中的含量特别高，特别是在美国。它们的环境稳定性、生物蓄积倾向和已知的神经毒性潜力引起了人们对它们对发育中的神经系统的影响的兴趣。接触多溴二苯醚与神经发育障碍密切相关。然而，它们在这类疾病中的机械性作用的细节还不完全清楚。在这里，我们报告了最普遍的同系物之一，BDE-47，及其羟化代谢产物对胚胎大鼠皮质神经元成熟和功能的影响。长期接触6OH-BDE-47会在母体BDE-47同系物及其测试的羟化代谢物中产生最强的影响。这些效应包括：i)对神经元活动的转录反应的破坏，ii)与神经发育障碍相关的多个基因的失调，以及有趣的是，iii)与发育相关的BAF(BRG1相关因子)染色质重塑复合体的几个亚单位的表达改变，包括关键亚单位BAF170。综上所述，我们的数据表明，持续暴露于6OH-BDE-47可能会干扰神经发育染色质重塑机制和基因转录程序，进而可能干扰神经元的突触发育和整体功能成熟等下游过程。这项研究的结果发现了6OH-BDE-47毒性的一个新方面，并开辟了新的途径来探索无处不在的环境毒素对神经元成熟和功能的表观遗传调节的影响。
Polybrominated diphenyl ethers (PBDEs) are a pervasive class of brominated flame retardants that are present in the environment at particularly high levels, especially in the United States. Their environmental stability, propensity for bioaccumulation, and known potential for neurotoxicity has evoked interest regarding their effects on the developing nervous system. Exposure to PBDEs has been strongly associated with neurodevelopmental disorders. However, the details of their mechanistic roles in such disorders are incompletely understood. Here, we report the effects of one of the most prevalent congeners, BDE-47, and its hydroxylated metabolites on the maturation and function of embryonic rat cortical neurons. Prolonged exposure to 6OH-BDE-47 produces the strongest effects amongst the parent BDE-47 congener and its tested hydroxylated metabolites. These effects include: i) disruption of transcriptional responses to neuronal activity, ii) dysregulation of multiple genes associated with neurodevelopmental disorders, and intriguingly, iii) altered expression of several subunits of the developmentally-relevant BAF (Brg1-associated factors) chromatin remodeling complex, including the key subunit BAF170. Taken together, our data indicate that persistent exposure to 6OH-BDE-47 may interfere with neurodevelopmental chromatin remodeling mechanisms and gene transcription programs, which in turn are likely to interfere with downstream processes such as synapse development and overall functional maturity of neurons. Results from this study have identified a novel aspect of 6OH-BDE-47 toxicity and open new avenues to explore the effects of a ubiquitous environmental toxin on epigenetic regulation of neuronal maturation and function.