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在暴露于二氧化硅纳米颗粒的人BEAS-2B细胞中，CREB3L1和Bcl-2的DNA高甲基化与通过PI3K/Akt途径的线粒体介导的细胞凋亡相关。

DNA Hypermethylation of CREB3L1 and Bcl-2 Associated with the Mitochondrial-Mediated Apoptosis via PI3K/Akt Pathway in Human BEAS-2B Cells Exposure to Silica Nanoparticles.

作者信息

Zou Yang, Li Qiuling, Jiang Lizhen, Guo Caixia, Li Yanbo, Yu Yang, Li Yang, Duan Junchao, Sun Zhiwei

机构信息

Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, P.R. China.

Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, P.R. China.

出版信息

PLoS One. 2016 Jun 30;11(6):e0158475. doi: 10.1371/journal.pone.0158475. eCollection 2016.

DOI:10.1371/journal.pone.0158475
PMID:27362941
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4928798/
Abstract

The toxic effects of silica nanoparticles (SiNPs) are raising concerns due to its widely applications in biomedicine. However, current information about the epigenetic toxicity of SiNPs is insufficient. In this study, the epigenetic regulation of low-dose exposure to SiNPs was evaluated in human bronchial epithelial BEAS-2B cells over 30 passages. Cell viability was decreased in a dose- and passage-dependent manner. The apoptotic rate, the expression of caspase-9 and caspase-3, were significantly increased induced by SiNPs. HumanMethylation450 BeadChip analysis identified that the PI3K/Akt as the primary apoptosis-related pathway among the 25 significant altered processes. The differentially methylated sites of PI3K/Akt pathway involved 32 differential genes promoters, in which the CREB3L1 and Bcl-2 were significant hypermethylated. The methyltransferase inhibitor, 5-aza, further verified that the DNA hypermethylation status of CREB3L1 and Bcl-2 were associated with downregulation of their mRNA levels. In addition, mitochondrial-mediated apoptosis was triggered by SiNPs via the downregulation of PI3K/Akt/CREB/Bcl-2 signaling pathway. Our findings suggest that long-term low-dose exposure to SiNPs could lead to epigenetic alterations.

摘要

由于二氧化硅纳米颗粒（SiNPs）在生物医学中的广泛应用，其毒性作用引发了人们的关注。然而，目前关于SiNPs表观遗传毒性的信息并不充分。在本研究中，对人支气管上皮BEAS-2B细胞传代30次后低剂量暴露于SiNPs的表观遗传调控进行了评估。细胞活力以剂量和传代依赖的方式降低。SiNPs诱导凋亡率、caspase-9和caspase-3的表达显著增加。HumanMethylation450 BeadChip分析确定PI3K/Akt是25个显著改变的过程中主要的凋亡相关途径。PI3K/Akt途径的差异甲基化位点涉及32个差异基因启动子，其中CREB3L1和Bcl-2显著高甲基化。甲基转移酶抑制剂5-氮杂胞苷进一步证实，CREB3L1和Bcl-2的DNA高甲基化状态与其mRNA水平下调有关。此外，SiNPs通过下调PI3K/Akt/CREB/Bcl-2信号通路触发线粒体介导的凋亡。我们的研究结果表明，长期低剂量暴露于SiNPs可能导致表观遗传改变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c9/4928798/3e85606f49aa/pone.0158475.g008.jpg
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