Huang Min, Lou Dan, Cai Qian, Chang Xiuli, Wang Xinjin, Zhou Zhijun
School of Public Health/MOE Key Lab of Public Health Safety/WHO Collaborating Center for Occupational Health, Fudan University, Shanghai 200032, China.
Department of Occupational and Environmental Health, School of Public Health, Ningxia Medical University, Yinchuan 750000, China.
Int J Mol Sci. 2014 Oct 13;15(10):18422-36. doi: 10.3390/ijms151018422.
Aberration during the development of the central nervous system (CNS) due to environmental factors underlies a variety of adverse developmental outcomes. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. Yet, the impacts of PQ exposure on the developing CNS remain unclear. miRNAs represent a class of small non-coding RNA molecules involved in the regulation of neural development. Thus in the present study, we analyzed the impacts of PQ on the miRNome of human neural progenitor cells (hNPCs) during proliferation by using the Exiqon miRCURY™ LNA Array. A total of 66 miRNAs were identified as differentially expressed in proliferating hNPCs upon PQ treatment. miRTarBase prediction identified 1465 mRNAs, including several genes (e.g., nestin, sox1, ngn1) previously proved to be associated with the neural proliferation and differentiation, as target genes of PQ-induced differentially expressed miRNAs. The database for annotation, visualization and integrated discovery (DAVID) bioinformatics analysis showed that target genes were enriched in regulation of cell proliferation and differentiation, cell cycle and apoptosis as well as tumor protein 53 (p53), Wnt, Notch and mitogen-activated protein kinases (MAPK) signaling pathways (p < 0.001). These findings were confirmed by real-time RT-PCR. Based on our results we conclude that PQ-induced impacts on the miRNA profiling of hNPCs undergoing proliferation may underlie the developmental neurotoxicity of PQ.
中枢神经系统（CNS）发育过程中因环境因素导致的畸变是多种不良发育结局的基础。百草枯（PQ）是一种经过广泛研究的神经毒物，会扰乱成年中枢神经系统的正常结构/功能。然而，PQ暴露对发育中的中枢神经系统的影响仍不清楚。微小RNA（miRNA）是一类参与神经发育调控的小非编码RNA分子。因此，在本研究中，我们使用Exiqon miRCURY™ LNA芯片分析了PQ对人神经祖细胞（hNPCs）增殖过程中miRNome的影响。总共鉴定出66种miRNA在PQ处理后的增殖hNPCs中差异表达。miRTarBase预测将1465种mRNA鉴定为PQ诱导的差异表达miRNA的靶基因，其中包括几个先前已证明与神经增殖和分化相关的基因（如巢蛋白、sox1、ngn1）。注释、可视化和整合发现数据库（DAVID）生物信息学分析表明，靶基因在细胞增殖和分化调控、细胞周期和凋亡以及肿瘤蛋白53（p53）、Wnt、Notch和丝裂原活化蛋白激酶（MAPK）信号通路中富集（p < 0.001）。这些发现通过实时RT-PCR得到证实。基于我们的结果，我们得出结论，PQ对增殖中的hNPCs的miRNA谱的影响可能是PQ发育神经毒性的基础。
