高能电粒子辐射引起的机体氧化应激反应及其作用机制的研究

发布时间：2018-06-18 13:36

本文选题：太空射线 + 高能电粒子　；参考：《武汉大学》2014年博士论文

【摘要】：背景高能量带电荷(high charge and energy, HZE)的粒子(以下简称高能电粒子)是构成宇宙射线的重要组成成分。高能电粒子由于其对机体不确定的生物学效应,成为阻碍人类进行太空探索的主要因素之一。高能电粒子通过少量射线即能传递巨大的能量,这种巨大的能量会对受辐射机体造成复杂而且难以修复的损伤。有研究表明高能电粒子辐射在啮齿类动物中会引起肿瘤性病变。另有研究发现高能电粒子辐射也会在啮齿类动物中引起一系列非肿瘤性病变,这类非肿瘤性病变包括认知和行为的改变、神经炎性病变、骨密度降低、慢性血管性损伤,以及肠道中的持续性氧化应激反应。针对这些辐射造成的肿瘤和非肿瘤性病变,目前还没有一个简单明了的解释。虽然与太空探索任务相关的高能电粒子辐射剂量较低,仅为0.3Gy或更少,然而由于缺乏有效的解释,对太空探索任务相关的辐射剂量可能引起的机体病变也无法预测。目的本研究通过利用一种小型实验动物—青溕(Oryzias latipes,俗称稻田鱼),进行一个大规模、终身观察的实验。通过实验,本研究将观察高能电粒子辐射引起的机体内持续终身的生物学效应,同时试图探索其发生发展的可能机制。方法本研究将分化处于22-34阶段(stage22-34)的青溕鱼鱼卵接受1GeV/nucleon56Fe粒子的辐射。辐射剂量从0.1Gy到9Gy,按照3倍剂量递增,共分为5组,分别是0.1Gy、0.3Gy、1Gy、3Gy和9Gy。每个剂量组含有约250枚鱼卵。同时,本研究也做了相似规模的伽马射线辐射组,辐射剂量为0.1Gy到27Gy,共分为6组,分别是0.1Gy、0.3Gy、1Gy、3Gy、9Gy和27Gy。本研究对两类辐射组分别设立了不接受辐射的对照组,对照组所有处理方式与辐射组相同。本研究选取接受辐射后250天、400天、500天和600天四个观察时间点,对实验组和对照组进行生存率、发育水平、组织形态学、线粒体功能和转录组水平的观察,并对实验结果进行相关性分析,从而试图对高能电粒子辐射的生物学作用及其机制进行探讨和说明。结果本研究仅在250天以内观察到最高辐射剂量组内青淩的急性死亡。直到辐射后600天,其余剂量组的生存率与对照组比较并无显著差异。辐射组与对照组之间个体发育水平也无显著差异。本研究于辐射后250天进行第一批标本观察,发现高辐射剂量组内,青淩肝脏出现肝脏细胞脂肪样变、海绵样变和气球样变。之前研究表明,肝脏细胞的脂肪样变、海绵样变和气球样变与青淩的自然老龄化高度相关,这些变化多出现于“老年”青淩体内(年龄大于24个月)。因此,本研究将接受辐射后青淩肝脏出现的上述各种变性定义为老龄化相似组织学变化。本研究针对老龄化相似组织学变化,进一步研究了辐射后青淩肝脏内的氧化应激反应。4-羟基—2一壬烯醛(4-hydroxy-2-nonenal,4-HNE)是一种脂质过氧化产物,与机体内的氧化应激反应高度相关。本研究发现4-HNE在接受高能电粒子辐射的青淩肝脏内有大量聚积(比对照组高1.8-5倍),而接受伽马射线辐射后的青溕肝脏内4-HNE的聚积程度仅轻度升高,与对照组无显著性差异。线粒体DNA在自然老龄化过程中会显著减少。本研究发现线粒体DNA在辐射组与对照组之间并无显著差异,但当观察转录组基因表达水平时,本研究发现线粒体调节因子过氧化物酶体增殖活化受体γ共激活因子-1α(PGC-1α)的mRNA在高能电粒子辐射组中显著降低,接受PGC-1α调控的雌激素受体相关蛋白α(ERRα)和依赖于烟酰胺腺嘌呤二核苷酸的去乙酰化酶Sirtuin-3(Sirt3)的mRNA也都有相应降低。细胞周期蛋白依赖性激酶抑制剂1A(CDKN1A)、前列腺素E合酶(PTGES)、超氧化物歧化酶2(SOD2)和过氧化氢酶(CAT)也有改变。这些改变在接受伽马射线辐射组中均不明显。结论本研究的观察结果支持了一种假设：在发育阶段接受太空探索任务相关剂量的高能电粒子辐射会引起机体长期的氧化应激反应和相关的改变,这些改变最终导致机体肝脏提前出现老龄化相似的变化。
[Abstract]:background
High charge and energy (HZE) particles (hereinafter referred to as high-energy particles) constitute an important component of cosmic rays. High energy particles, due to their indeterminate biological effects on the body, become one of the main factors that impede human exploration in space. High energy particles can transmit huge amounts of radiation through a small amount of radiation. Energy, such a huge energy, can cause complex and difficult repair damage to the irradiated body. Studies have shown that high energy particle radiation can cause tumorous lesions in rodents. And other studies have found that high-energy particles radiation also causes a non tumor disease in rodents, such as non tumor lesions. It includes cognitive and behavioral changes, neuritis, bone density reduction, chronic vascular injury, and continuous oxidative stress in the intestine. There is no simple and clear explanation for the tumor and non tumor lesions caused by these radiation. Low, only 0.3Gy or less. However, due to lack of effective explanation, it is impossible to predict the body lesions that may be caused by radiation doses related to space exploration missions.
objective
In this study, a small experimental animal, Oryzias latipes, is used to carry out a large-scale, lifelong observation experiment. Through the experiment, this study will observe the biological effects of continuous lifetime in the body caused by high energy particles radiation, and try to explore the possible mechanism of its development.
Method
In this study, the 22-34 phase (stage22-34) of the blue fish eggs received radiation from the 1GeV/nucleon56Fe particles. The radiation dose increased from 0.1Gy to 9Gy at a dose of 3 times, which were divided into 5 groups, which were 0.1Gy, 0.3Gy, 1Gy, 3Gy and 9Gy. each containing about 250 fish eggs. Meanwhile, this study also made a similar scale of gamma ray radiation. The radiation dose of 0.1Gy to 27Gy was divided into 6 groups, which were 0.1Gy, 0.3Gy, 1Gy, 3Gy, 9Gy and 27Gy., respectively. The control group that did not receive radiation was set up in the two group of radiation groups, and the control group was the same as the radiation group. This study selected four observation time points for 250 days, 400 days, 500 days and 600 days after receiving radiation. In the control group, the survival rate, the level of development, the histomorphology, the mitochondrial function and the level of the transcriptional group were observed, and the correlation analysis of the experimental results was carried out, so as to try to discuss and explain the biological function and mechanism of the high-energy electric particle radiation.
Result
The survival rate of the remaining dose group was not significantly different from that of the control group at the 600 day after radiation, and there was no significant difference in the level of individual development between the radiation group and the control group. The first batch of specimens was observed at 250 days after radiation, and the high spoke was found in this study. In the dose group, the liver cell fatty changes, cavernous changes and balloon like changes in the liver were found in the liver. Previous studies showed that the fatty changes, cavernous changes and balloon like changes in the liver cells were highly related to the natural aging of the green cells. These changes appeared in the "elderly" green bodies (older than 24 months). Therefore, this study will be accepted. .4- hydroxyl 2 one nonylaldehyde (4-hydroxy-2-nonenal, 4-HNE) is a kind of lipid peroxidation product, and oxygen in the body. There was a high degree of correlation between the response of the chemical stress response. This study found that there was a large accumulation of 4-HNE in the liver of young adults receiving high energy radiation (1.8-5 times higher than that of the control group). The accumulation of 4-HNE in the liver of the liver after gamma radiation was only slightly higher, and there was no significant difference between the control group and the control group. The mitochondrial DNA would appear in the natural aging process. The study found that there was no significant difference between the mitochondrial DNA in the radiation group and the control group, but when the gene expression level was observed in the transcriptional group, the mRNA of the mitochondrial regulatory factor peroxisome proliferator activated receptor gamma co activating factor -1 alpha (PGC-1 alpha) decreased significantly in the high-energy particle radiation group and accepted the PGC-1 alpha modulation. The controlled estrogen receptor related protein alpha (ERR alpha) and the mRNA dependent on nicotinamide adenine dinucleotide deacetylase Sirtuin-3 (Sirt3) also decreased correspondingly. Cell cyclin dependent kinase inhibitor 1A (CDKN1A), prostaglandin E synthase (PTGES), superoxide dismutase 2 (SOD2) and catalase (CAT) were also changed. The change was not obvious in gamma radiation group.
conclusion
The results of this study support the assumption that high energy particle radiation from the related doses of space exploration tasks at the stage of development will cause long-term oxidative stress responses and related changes in the body, which eventually lead to a similar ageing of the body's liver in advance.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R85

【参考文献】