Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress.
Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress.
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DOI：
10.1016/j.taap.2015.01.014
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发表时间：
2015-03-15
影响因子：
3.8
通讯作者：
Wu, Hongmei
中科院分区：
文献类型：
--
作者：
Ren, Xuefeng;Gaile, Daniel P.;Gong, Zhihong;Qiu, Wenting;Ge, Yichen;Zhang, Chuanwu;Huang, Chenping;Yan, Hongtao;Olson, James R.;Kavanagh, Terrance J.;Wu, Hongmei
关键词：
砷暴露被认为可以改变microRNA（miRNA）的表达，导致基因表达和毒性的变化，但缺乏有关miRNA对砷暴露反应的研究，特别是在体内研究方面。我们利用高通量测序技术，从Sprague道利（SD）大鼠暴露于不同浓度的亚砷酸钠（0，0.1，1，10和100 mg/L）60天的肝组织中产生的miRNA表达谱。对miRNA表达谱的无监督分层聚类分析将SD大鼠根据砷暴露状态分为不同的组，表明砷暴露与聚类成员之间存在高度显著的关联（P值为0.0012）。砷以暴露浓度依赖的方式改变了多种miRNA的表达。在已鉴定的砷响应性miRNA中，有几种被预测靶向Nfe 2l 2调节的抗氧化剂基因，包括参与谷胱甘肽（GSH）合成的谷氨酸-半胱氨酸连接酶（GCL）催化亚基（GCLC）和修饰亚基（GCLM）。暴露于低浓度的砷增加Gclc和Gclm的mRNA表达，而高浓度显着降低其表达，这与肝GCL活性和GSH水平的变化。此外，我们的数据表明，其他机制，如miRNA，而不是Nfe 2l 2-信号通路，可能参与调节Gclc和Gclm的mRNA表达后砷暴露在体内。总之，我们的研究结果表明，砷暴露破坏了体内miRNAs的全基因组表达，这可能导致生物学后果，如抗氧化防御和氧化应激的平衡改变。
Arsenic exposure is postulated to modify microRNA (miRNA) expression, leading to changes of gene expression and toxicities, but studies relating the responses of miRNAs to arsenic exposure are lacking, especially with respect to in vivo studies. We utilized high-throughput sequencing technology and generated miRNA expression profiles of liver tissues from Sprague Dawley (SD) rats exposed to various concentrations of sodium arsenite (0, 0.1, 1, 10 and 100 mg/L) for 60 days. Unsupervised hierarchical clustering analysis of the miRNA expression profiles clustered the SD rats into different groups based on the arsenic exposure status, indicating a highly significant association between arsenic exposure and cluster membership (P-value of 0.0012). Multiple miRNA expressions were altered by arsenic in an exposure concentration-dependent manner. Among the identified arsenic-responsive miRNAs, several are predicted to target Nfe2l2-regulated antioxidant genes, including glutamate-cysteine ligase (GCL) catalytic subunit (GCLC) and modifier subunit (GCLM) which are involved in glutathione (GSH) synthesis. Exposure to low concentrations of arsenic increased mRNA expression for Gclc and Gclm, while high concentrations significantly reduced their expression, which were correlated to changes in hepatic GCL activity and GSH level. Moreover, our data suggested that other mechanisms, e.g. miRNAs, rather than Nfe2l2-signaling pathway, could be involved in the regulation of mRNA expression of Gclc and Gclm post arsenic exposure in vivo. Together, our findings show that arsenic exposure disrupts the genome-wide expression of miRNAs in vivo, which could lead to the biological consequence, such as an altered balance of antioxidant defense and oxidative stress.
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