Human neurospheres as three-dimensional cellular systems for developmental neurotoxicity testing.
Human neurospheres as three-dimensional cellular systems for developmental neurotoxicity testing.
复制标题
DOI：
10.1289/ehp.0800207
复制
发表时间：
2009-07
影响因子：
10.4
通讯作者：
Fritsche E
中科院分区：
文献类型：
--
作者：
Moors M;Rockel TD;Abel J;Cline JE;Gassmann K;Schreiber T;Schuwald J;Weinmann N;Fritsche E
环境化学物质的发育性神经毒性对人类健康构成严重威胁。目前的DNT测试指南建议在啮齿类动物中进行调查，这需要大量的动物。关于动物试验的“3r”（减少、替代和改进）和欧洲化学品法规[化学品注册、评估和授权（REACH）]，需要替代测试策略，以改进和减少动物实验，并允许更快、更便宜的筛选。本研究的目的是建立基于人胎儿脑细胞的DNT筛选三维测试系统。我们利用人类神经祖细胞（hNPCs）作为神经球生长，建立了适合检测大脑发育基本过程干扰的检测方法。此外，我们评估了汞和氧化应激对这些细胞的影响。我们发现人类神经球在体外模拟增殖、分化和迁移。暴露于促凋亡剂司陶孢素进一步表明，人类神经球具有功能性凋亡机制。发育性神经毒物甲基氯化汞和氯化汞降低了分化的hNPCs中神经元样细胞的迁移距离和数量。此外，当暴露于高量氧化应激时，hNPCs发生caspase非依赖性凋亡。人类神经球可能模仿大脑发育的基本过程，这些过程可以被发育神经毒物调节。因此，这种三维细胞系统是一种很有前途的DNT测试方法。
Developmental neurotoxicity (DNT) of environmental chemicals is a serious threat to human health. Current DNT testing guidelines propose investigations in rodents, which require large numbers of animals. With regard to the “3 Rs” (reduction, replacement, and refinement) of animal testing and the European regulation of chemicals [Registration, Evaluation, and Authorisation of Chemicals (REACH)], alternative testing strategies are needed in order to refine and reduce animal experiments and allow faster and less expensive screening. The goal of this study was to establish a three-dimensional test system for DNT screening based on human fetal brain cells. We established assays suitable for detecting disturbances in basic processes of brain development by employing human neural progenitor cells (hNPCs), which grow as neurospheres. Furthermore, we assessed effects of mercury and oxidative stress on these cells. We found that human neurospheres imitate proliferation, differentiation, and migration in vitro. Exposure to the proapoptotic agent staurosporine further suggests that human neurospheres possess functioning apoptosis machinery. The developmental neurotoxicants methylmercury chloride and mercury chloride decreased migration distance and number of neuronal-like cells in differentiated hNPCs. Furthermore, hNPCs undergo caspase-independent apoptosis when exposed toward high amounts of oxidative stress. Human neurospheres are likely to imitate basic processes of brain development, and these processes can be modulated by developmental neurotoxicants. Thus, this three-dimensional cell system is a promising approach for DNT testing.
登录
查看更多内容
影响因子：
10.4
作者：
Clarkson TW
通讯作者：
Clarkson TW
影响因子：
4.6
作者：
Campos, LS;Leone, DP;ffrench-Constant, C
通讯作者：
ffrench-Constant, C
影响因子：
21.3
作者：
Hoessel, R;Leclerc, S;Meijer, L
通讯作者：
Meijer, L
影响因子：
4.8
作者：
Cedrola, S;Guzzi, G;La Porta, CAM
通讯作者：
La Porta, CAM
影响因子：
10.4
作者：
Coecke S;Goldberg AM;Allen S;Buzanska L;Calamandrei G;Crofton K;Hareng L;Hartung T;Knaut H;Honegger P;Jacobs M;Lein P;Li A;Mundy W;Owen D;Schneider S;Silbergeld E;Reum T;Trnovec T;Monnet-Tschudi F;Bal-Price A
通讯作者：
Bal-Price A