Methylmercury antagonizes the survival-promoting activity of insulinlike growth factor on developing cerebellar granule neurons
Methylmercury antagonizes the survival-promoting activity of insulinlike growth factor on developing cerebellar granule neurons
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DOI：
10.1006/taap.1998.8561
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发表时间：
1998-12-01
影响因子：
3.8
通讯作者：
Cui, H
中科院分区：
文献类型：
--
作者：
Bulleit, RF;Cui, H
甲基汞是一种分布广泛的环境毒物，对发育中的中枢神经系统有深远的影响。人类在宫内暴露于甲基汞已导致儿童严重的神经异常，包括认知和运动功能障碍。这些异常似乎是由于发育中的中枢神经系统中神经元的死亡和细胞结构的改变造成的。成年和宫内暴露于甲基汞后，小脑颗粒神经元都会死亡，这表明这些细胞对甲基汞的毒性作用很脆弱。本文报道的研究使用发育中的小脑颗粒神经元的纯化培养来评估甲基汞是否直接作用于这些发育中的神经元以抑制其存活。这些实验表明，在纯化培养的小脑颗粒神经元中，只有胰岛素样生长因子I(IGF-I)作为唯一添加的营养因子，低摩尔浓度的甲基汞抑制颗粒神经元的存活。甲基汞引起的存活率下降可以通过增加IGF-I的浓度而部分逆转，这表明甲基汞和IGF-I之间存在拮抗作用。抑制IGF-I促存活作用的细胞内介质--磷脂酰肌醇3-K(PI3-K)可协同增强甲基汞的存活效应。进一步的研究表明，甲基汞对存活的抑制与颗粒神经元的凋亡有关。这种细胞凋亡似乎需要激活基因转录，并可能涉及即刻早期转录因子c-jun表达的增加。提示甲基汞可作用于发育中的颗粒神经元，增加c-jun的表达，拮抗IGF-I的促存活活性。(C)1998年学术出版社。
Methylnercury (MeHg), a widely distributed environmental toxicant, has a profound effect on the developing central nervous system. Human exposure to MeHg in utero has led to severe neurological abnormalities in children, including cognitive and motor dysfunction. The abnormalities appear to result from death of neurons and altered cytoarchitecture in the developing CNS. Death of cerebellar granule neurons occurs following both adult and in utero exposure to MeHg, indicating the vulnerability of these cells to the toxic action of MeHg. The studies reported here use purified cultures of developing mouse cerebellar granule neurons to evaluate whether MeHg directly acts on these developing neurons to inhibit their survival. These experiments show that, in purified cultures of cerebellar granule neurons maintained in medium containing insulin-like growth factor I(IGF-I) as the only added trophic factor, low micromolar concentrations of MeHg inhibit granule neuron survival. The reduction in survival produced by MeHg can be partially reversed by increasing the concentration of IGF-I, suggesting an antagonism between MeHg and IGF-I. Inhibition of phosphoinositide 3-kinase (PI3-K), an intracellular mediator of IGF-I's survival promoting action, can synergistically enhance MeHg's effect on survival. Further studies indicate that MeHg's inhibition of survival involves apoptotic death of granule neurons. This apoptosis appears to require activation of gene transcription and may involve an increase in expression of the immediate early transcription factor c-Jun. These studies suggest that MeHg can act on developing granule neurons to increase the expression of c-Jun and antagonize IGF-I's survival promoting activity. (C) 1998 Academic Press.