Protection from the toxicity of diisopropylfluorophosphate by adeno-associated virus expressing acetylcholinesterase.
Protection from the toxicity of diisopropylfluorophosphate by adeno-associated virus expressing acetylcholinesterase.
复制标题
通过表达乙酰胆碱酯酶的腺相关病毒来防止二异丙基氟磷酸盐的毒性。
DOI：
10.1016/j.taap.2005.12.008
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Lockridge,Oksana
中科院分区：
文献类型：
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作者：
Li,Bin;Duysen,EllenG;Poluektova,LarisaY;Murrin,LCharles;Lockridge,Oksana
有证据表明，儿童广泛暴露于有机磷农药（OP），OP在动物模型中引起发育神经毒性，这引起了人们对这些化合物对发育中的人类神经系统构成的风险的严重关切。评估这种风险的关键是确定OP针对的特定神经发育事件。OPs改变发育中啮齿类动物的脑形态，并抑制神经细胞系中的神经突生长，这表明OPs扰乱神经元形态发生。然而，一个重要的问题还有待回答的是，是否dysmorphogenic影响OP反映扰动轴突或树突生长。我们解决了这个问题，通过定量轴突和树突生长的原代培养的胚胎大鼠交感神经元来自上级颈神经节（SCG）在体外暴露于毒死蜱（CPF）或其代谢产物CPF-oxon（CPFO）和三氯吡啶醇（TCP）。在浓度分别≥0.001 μM或0.001 nM时，CPF或CPFO显著抑制轴突生长，但TCP不抑制轴突生长。相反，所有三种化合物均增强BMP诱导的树突状生长。仅最高浓度的CPF（≥1 μM）和CPFO（≥1 nM）可抑制乙酰胆碱酯酶; TCP对该参数无影响。总之，这些化合物通过对轴突和树突生长的相反作用扰乱神经元形态发生，并且这两种作用都不依赖于乙酰胆碱酯酶抑制。这些发现对目前使用乙酰胆碱酯酶抑制作为OP神经毒性生物标志物的风险评估实践具有重要意义，并表明OP可能会破坏发育中神经系统神经元连接的正常模式。
Evidence that children are widely exposed to organophosphorus pesticides (OPs) and that OPs cause developmental neurotoxicity in animal models raises significant concerns about the risks these compounds pose to the developing human nervous system. Critical to assessing this risk is identifying specific neurodevelopmental events targeted by OPs. Observations that OPs alter brain morphometry in developing rodents and inhibit neurite outgrowth in neural cell lines suggest that OPs perturb neuronal morphogenesis. However, an important question yet to be answered is whether the dysmorphogenic effect of OPs reflects perturbation of axonal or dendritic growth. We addressed this question by quantifying axonal and dendritic growth in primary cultures of embryonic rat sympathetic neurons derived from superior cervical ganglia (SCG) following in vitro exposure to chlorpyrifos (CPF) or its metabolites CPF-oxon (CPFO) and trichloropyridinol (TCP). Axon outgrowth was significantly inhibited by CPF or CPFO, but not TCP, at concentrations ≥0.001 μM or 0.001 nM, respectively. In contrast, all three compounds enhanced BMP-induced dendritic growth. Acetylcholinesterase was inhibited only by the highest concentrations of CPF (≥1 μM) and CPFO (≥1 nM); TCP had no effect on this parameter. In summary, these compounds perturb neuronal morphogenesis via opposing effects on axonal and dendritic growth, and both effects are independent of acetylcholinesterase inhibition. These findings have important implications for current risk assessment practices of using acetylcholinesterase inhibition as a biomarker of OP neurotoxicity and suggest that OPs may disrupt normal patterns of neuronal connectivity in the developing nervous system.