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首页> 外文期刊>Brain research >Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells.
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Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells.

机译：毒死rif的发育神经毒性是否涉及神经胶质靶标？大分子合成，腺苷酸环化酶信号传导，核转录因子以及C6胶质瘤细胞中活性氧的形成。

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摘要

The widespread use of chlorpyrifos (CPF) has raised major concerns about its potential to cause fetal or neonatal neurobehavioral damage, even at doses that do not evoke acute toxicity. CPF has been shown to inhibit replication of brain cells, to elicit alterations in neurotrophic signaling governing cell differentiation and apoptosis, and to evoke oxidative stress. However, the specific cell types targeted by CPF have not been clarified, an issue of vital importance in establishing the boundaries of the critical period in which the developing brain is vulnerable. In the current study, we evaluated the effects of CPF on C6 glioma cells, a well-established glial model. In undifferentiated C6 cells, CPF inhibited DNA synthesis in a concentration-dependent manner, with greater potency than had been seen previously with neuronal cell lines. Just as found after in vivo CPF treatment or with neuronal cell lines, the effects on cell replication were independent of cholinergic stimulation, as cholinergic antagonists did not block CPF-induced inhibition. CPF interfered with cell signaling mediated through adenylyl cyclase at the level of G-protein function; the effects again were greater in undifferentiated C6 cells but were still detectable in differentiating cells. In contrast, differentiation enhanced the ability of CPF to elicit the formation of reactive oxygen species and to evoke deficits in Sp1, a nuclear transcription factor essential for differentiation. These results indicate that glial-type cells are targeted by CPF through the same multiple mechanisms that have been demonstrated for the effects of CPF on brain development in vivo. Because glial development continues long after the conclusion of neurogenesis, and given that CPF targets events in both glial cell replication and the later stages of differentiation, the vulnerable period for developmental neurotoxicity of CPF is likely to extend well into childhood.
机译：毒死rif（CPF）的广泛使用引起了人们对其潜在危害的担忧，即使其剂量不会引起急性毒性，毒死rif也可能引起胎儿或新生儿的神经行为损害。 CPF已显示可抑制脑细胞的复制，引起控制细胞分化和凋亡的神经营养信号的改变，并引起氧化应激。但是，尚不清楚CPF靶向的特定细胞类型，这对于确定发育中的大脑易受伤害的关键时期的边界至关重要。在当前的研究中，我们评估了CPF对C6胶质瘤细胞（成熟的神经胶质模型）的影响。在未分化的C6细胞中，CPF以浓度依赖性的方式抑制DNA合成，其效力比以前在神经元细胞系中所见强。正如在体内CPF治疗后或在神经元细胞系中发现的那样，对细胞复制的影响与胆碱能刺激无关，因为胆碱能拮抗剂不能阻断CPF诱导的抑制作用。 CPF在G蛋白功能水平上干扰通过腺苷酸环化酶介导的细胞信号传导;在未分化的C6细胞中，其作用再次增强，但在分化细胞中仍可检测到。相反，分化增强了CPF诱导活性氧形成并引起Sp1缺陷的能力，Sp1是分化所必需的核转录因子。这些结果表明，CPF通过与已证明CPF对体内脑发育的作用相同的多种机制，将CLP靶向神经胶质细胞。由于神经发生结束后神经胶质的发育持续很长时间，并且考虑到CPF靶向神经胶质细胞复制和分化后期的事件，因此CPF发育神经毒性的脆弱时期很可能会延伸到儿童期。

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