Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung
Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung
复制标题
DOI：
10.1016/j.mrfmmm.2010.12.008
复制
发表时间：
2011-12-01
影响因子：
2.3
通讯作者：
De Flora, Silvio
中科院分区：
文献类型：
--
作者：
Izzotti, Alberto;Larghero, Patrizia;De Flora, Silvio
我们之前的研究表明，暴露于香烟烟雾（CS），无论是主流烟雾还是环境烟雾，都会导致小鼠和大鼠肺部的 microRNA 表达显着下调。本研究的目的是评估戒烟后对 CS 的剂量反应以及 microRNA 变化的持续性。 ICR (CD-1) 新生小鼠全身暴露于主流 CS，总颗粒物剂量为 119、292、438 和 631 mg/m(3)。出生后 12 小时内开始暴露，每天持续暴露，持续 4 周。通过 P-32 后标记程序测量大体积 DNA 加合物和 8-oxo-7,8-二氢-2'-脱氧鸟苷 (8-oxodGuo) 的水平，并通过微阵列分析 697 种小鼠 microRNA 的表达。最高的CS剂量是致命的。暴露于 CS 会导致 DNA 改变呈剂量依赖性增加。 DNA加合物，甚至更明显的是，8-oxodGuo在戒烟后1周和4周恢复。暴露于 CS 导致 microRNA 表达谱明显失调，主要是下调。两个最低剂量并不是特别有效，而最高的非致死剂量则产生了广泛的 microRNA 改变。大多数下调的 microRNA（包括 let-7 家族的 7 个成员）的表达在戒烟一周后恢复。然而，有限的 microRNA 阵列（包括 mir-34b、mir-345、mir-421、mir-450b、mir-466 和 mir-469）的恢复并不完全。因此，看来 microRNA 主要充当效应生物标志物，并且需要暴露于高剂量并持续足够长的时间才能在所用的实验动物模型中触发与 CS 相关的致癌过程。 (C) 2011 Elsevier B.V. 保留所有权利。
Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m(3) of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) were measured by P-32 postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used. (C) 2011 Elsevier B.V. All rights reserved.