Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation
Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation
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DOI：
10.1016/j.mrfmmm.2003.12.016
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发表时间：
2004-04-14
影响因子：
2.3
通讯作者：
Pogribny, I
中科院分区：
文献类型：
--
作者：
Kovalchuk, O;Burke, P;Pogribny, I
近年来，慢性低剂量辐射（LDR）暴露的生物学和遗传效应及其与致癌的关系受到广泛关注。例如，辐射引起的基因组不稳定性被认为是肿瘤发生的先兆，但已被证明具有跨代性质。这表明表观遗传机制可能参与 LDR 诱导的基因组不稳定。基因组DNA甲基化是最重要的表观遗传机制之一。现有关于辐射对 DNA 甲基化模式影响的数据有限，而且没有人专门研究过 LDR 的影响。我们报告了第一项关于全身 LDR 暴露对雄性和雌性小鼠肌肉和肝脏组织中整体基因组甲基化影响的研究。同时，我们评估了肿瘤抑制基因 p16 (INKa) 和 DNA 修复基因 O-6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 的启动子甲基化和表达的变化。我们观察到受辐射的男性和女性的肝脏和肌肉中辐射诱导的全基因组 DNA 甲基化的不同模式。我们还发现 LDR 暴露后 p16(INKa) 启动子甲基化存在性别和组织特异性差异。在男性肝组织中，p16(INKa)启动子甲基化比女性组织中更明显。相比之下，在暴露的雄性和雌性的肌肉组织中，没有发现明显的辐射引起的 p16(INKa) 启动子甲基化变化。辐射也没有显着影响 MGMT 启动子的甲基化状态。我们还观察到急性和慢性辐射诱导的 p16(INKa) 和 MGMT 基因表达存在显着的性别差异。我们研究的另一个重要结果是，事实证明，长期低剂量辐射暴露比急性暴露更能诱导表观遗传效应。这支持了之前的发现，即慢性暴露比急性暴露会导致更大的基因组不稳定。 (C) 2004 Elsevier B.V. 保留所有权利。
The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16(INKa) and DNA repair gene O-6-methylguanine-DNA methyltransferase (MGMT).We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16(INKa) promoter methylation upon LDR exposure. In male liver tissue, p16(INKa) promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16(INKa) promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16(INKa) and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure. (C) 2004 Elsevier B.V. All rights reserved.