Rotenone exerts developmental neurotoxicity in a human brain spheroid model.
Rotenone exerts developmental neurotoxicity in a human brain spheroid model.
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DOI：
10.1016/j.taap.2018.02.003
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发表时间：
2018-09-01
影响因子：
3.8
通讯作者：
Hogberg HT
中科院分区：
文献类型：
--
作者：
Pamies D;Block K;Lau P;Gribaldo L;Pardo CA;Barreras P;Smirnova L;Wiersma D;Zhao L;Harris G;Hartung T;Hogberg HT
人们日益担忧一些化学物质具有（发育性）神经毒性（DNT和NT），并且与自闭症、注意力缺陷与多动障碍发病率的上升有关。用于DNT和NT评估的常规检测成本高昂，使得对大量现有化学物质进行检测变得困难。因此，需要更具成本效益的神经发育模型。诱导多能干细胞（iPSC）与新兴的人类3D组织培养平台相结合，提供了一种预测和研究人类毒性的新工具。通过将这些技术相结合，我们从人类iPSC中生成了多细胞脑球体（BrainSpheres）。该模型先前已被证明具有可重复性，并重现了若干神经发育特征。我们的研究结果表明，鱼藤酮的毒性效力因细胞的分化状态而异，在分化早期比后期显示出更高的活性氧（ROS）和更高的线粒体功能障碍。鱼藤酮暴露后的免疫荧光形态分析表明，在非细胞毒性浓度（1μM）下存在多巴胺能神经元选择性毒性，而在（一般）细胞毒性浓度（25μM）下，星形胶质细胞和其他神经元细胞类型受到影响。组学分析显示了大脑发育所必需的关键途径发生了变化，表明鱼藤酮是一种发育性神经毒物，并显示出先前所示的对神经突生长的影响与目前观察到的对Ca2 +重吸收、突触发生和PPAR途径破坏的影响之间可能存在联系。总之，我们的BrainSpheres模型已被证明是一种可重复的研究神经毒性和发育性神经毒性的新工具。此处呈现的结果支持鱼藤酮可能是一种发育性神经毒物这一观点。
Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and NT assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predict and study human toxicity. By combining these technologies, we generated multicellular brain spheroids (BrainSpheres) from human iPSC. The model has previously shown to be reproducible and recapitulates several neurodevelopmental features. Our results indicate, rotenone’s toxic potency varies depending on the differentiation status of the cells, showing higher reactive oxygen species (ROS) and higher mitochondrial dysfunction during early than later differentiation stages. Immunofluorescence morphology analysis after rotenone exposure indicated dopaminergic-neuron selective toxicity at non-cytotoxic concentrations (1 μM), while astrocytes and other neuronal cell types were affected at (general) cytotoxic concentrations (25 μM). Omics analysis showed changes in key pathways necessary for brain development, indicating rotenone as a developmental neurotoxicant and show a possible link between previously shown effects on neurite outgrowth and presently observed effects on Ca2+ reabsorption, synaptogenesis and PPAR pathway disruption. In conclusion, our BrainSpheres model has shown to be a reproducible and novel tool to study neurotoxicity and developmental neurotoxicity. Results presented here support the idea that rotenone can potentially be a developmental neurotoxicant.
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影响因子：
6.1
作者：
Balmer, Nina V.;Klima, Stefanie;Rempel, Eugen;Ivanova, Violeta N.;Kolde, Raivo;Weng, Matthias K.;Meganathan, Kesavan;Henry, Margit;Sachinidis, Agapios;Berthold, Michael R.;Hengstler, Jan G.;Rahnenfuhrer, Jorg;Waldmann, Tanja;Leist, Marcel
通讯作者：
Leist, Marcel
影响因子：
--
作者：
Dubovický M
通讯作者：
Dubovický M
DOI：
10.1073/pnas.1507125112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Darmanis S;Sloan SA;Zhang Y;Enge M;Caneda C;Shuer LM;Hayden Gephart MG;Barres BA;Quake SR
通讯作者：
Quake SR
影响因子：
11
作者：
Brumback AC;Ellwood IT;Kjaerby C;Iafrati J;Robinson S;Lee AT;Patel T;Nagaraj S;Davatolhagh F;Sohal VS
通讯作者：
Sohal VS
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