Aryl hydrocarbon receptor-dependent induction of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells from mouse
Aryl hydrocarbon receptor-dependent induction of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells from mouse
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DOI：
10.1111/j.1471-4159.2011.07291.x
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发表时间：
2011-07-01
影响因子：
4.7
通讯作者：
Merino, Jaime M.
中科院分区：
文献类型：
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作者：
Sanchez-Martin, Franciso J.;Fernandez-Salguero, Pedro M.;Merino, Jaime M.
2，3，7，8-四氯二苯并对二恶英（TCDD）是一种典型的环境污染物，具有神经毒性，可改变神经发育和行为。TCDD是芳烃受体（AhR）的配体，而AhR是充分了解二恶英毒性和致癌特性的关键信号分子。TCDD神经毒性的分子机制和信号通路的研究以及TCDD神经毒性的分子靶点的确定正在进行中。我们使用野生型（AhR+/+）和AhR-null（AhR-/-）小鼠的小脑颗粒细胞（CGC）来表征TCDD毒性后神经元中发生的细胞死亡。TCDD在野生型小鼠CGC培养物中诱导细胞死亡，EC 50为127 +/- 21 nM。相反，当从AhR-null小鼠CGC神经元用TCDD处理时，没有观察到显著的细胞死亡。AhR在TCDD诱导的死亡中的作用通过使用拮抗剂白藜芦醇和α-萘黄酮（alpha-naphatoflavone）进一步评估，所述拮抗剂在AhR+/+ CGC培养物中容易地保护免受TCDD毒性。AhR+/+ CGC培养物与TCDD处理显示核碎裂，DNA梯状，并增加caspase 3活性，类似于所发现的使用星形孢菌素，一个公认的诱导细胞凋亡。最后，AhR途径在CGC中是活跃的，因为TCDD可以诱导靶基因细胞色素P450 1A 2在AhR+/+ CGC培养物中的表达。所有这些结果支持的假设，TCDD在CGC神经元的毒性涉及的AhR，它主要是通过凋亡过程发生。因此，AhR可以被认为是神经毒性和神经退行性变的新靶点，其下调可以阻断CNS中某些外源性相关的不良反应。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a prototypical environmental contaminant with neurotoxic properties that alters neurodevelopment and behavior. TCDD is a ligand of the aryl hydrocarbon receptor (AhR), which is a key signaling molecule to fully understand the toxic and carcinogenic properties of dioxin. Much effort is underway to unravel the molecular mechanisms and the signaling pathways involved in TCDD-induced neurotoxicity, and to define its molecular targets in neurons. We have used cerebellar granule cells (CGC) from wild-type (AhR+/+) and AhR-null (AhR-/-) mice to characterize the cell death that takes place in neurons after TCDD toxicity. TCDD induced cell death in CGC cultures from wild-type mice with an EC50 of 127 +/- 21 nM. On the contrary, when CGC neurons from AhR-null mice were treated with TCDD no significant cell death was observed. The role of AhR in TCDD-induced death was further assessed by using the antagonists resveratrol and alpha-naphtoflavone, which readily protected against TCDD toxicity in AhR+/+ CGC cultures. AhR+/+ CGC cultures treated with TCDD showed nuclear fragmentation, DNA laddering, and increased caspase 3 activity, similarly to what was found by the use of staurosporine, a well-established inducer of apoptosis. Finally, the AhR pathway was active in CGC because TCDD could induce the expression of the target gene cytochrome P450 1A2 in AhR+/+ CGC cultures. All together these results support the hypothesis that TCDD toxicity in CGC neurons involves the AhR and that it takes place mainly through an apoptotic process. AhR could be then considered a novel target in neurotoxicity and neurodegeneration whose down-modulation could block certain xenobiotic-related adverse effects in CNS.