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秀丽隐杆线虫(Caenorhabditis elegans,简称线虫)是一种独立生存的非寄生性土壤线虫。作为经典模式生物之一,线虫与其他模式生物相比具有独特的优势:(1)通体透明,其细胞和器官发育可通过体视显微镜观察;(2)体积小,且基因组序列完整,拥有83%的人类同源基因[1];(3)发育周期较短,20℃的培养条件下,从虫卵发育到成虫仅需3 d。基于以上优势,线虫已成为多个研究领域,如阿尔茨海默症、帕金森病、肥胖症及衰老等研究领域的模式生物。用于疾病研究的线虫模型已建立成熟,通过对突变体线虫各项指标进行检测,即可完成对相关药物的筛选,这是一种高通量的药物筛选方式。
此外,线虫在电离辐射研究领域同样应用广泛。电离辐射可以通过改变基因从而对受照者及其后代的健康产生影响。电离辐射可诱导生殖细胞凋亡、细胞周期阻滞和DNA损伤。1985年,Hartman[2]发现了多种线虫突变体,其中2个是辐射敏感性突变体rad-1和rad-2。线虫拥有敏感的神经系统,能够及时响应外界刺激,在响应DNA损伤方面与人类有相似之处,并已有大量辐射敏感性突变体可供使用[3]。线虫可耐受>1 kGy的γ射线[4],故适用于电离辐射研究。且线虫寿命较短,可以在很短的时间内观察其受到电离辐射后的生物学效应,如寿命和产卵率的变化、畸形的发生和行为学的改变。
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线虫的生殖系统DNA损伤可诱导细胞周期阻滞和凋亡,这2种反应在空间上是独立的。电离辐射诱导的生殖细胞凋亡不同于体细胞凋亡。细胞核是辐射损伤的敏感部位,DNA是辐射损伤的关键靶点。电离辐射可诱导线虫的生殖细胞发生多种反应,包括细胞凋亡、细胞周期阻滞以及DNA双链断裂修复,从而维持基因组的完整性等。雌雄同体线虫有2条生殖腺,呈U型,并在子宫近端连接在一起,且其在空间上可分为3个区域:有丝分裂区、过渡区、减数分裂区。最远端的生殖细胞以有丝分裂的方式增殖,并作为干细胞群;当通过过渡区时,生殖细胞停止分裂,进入减数分裂前期[19]。在减数分裂后期生殖细胞对辐射诱导的凋亡较敏感[20]。线虫暴露于电离辐射会导致其生殖腺远端细胞周期进程暂时停滞,有丝分裂的生殖细胞数量减少[21]。在成虫中,电离辐射诱导的生殖细胞凋亡仅发生在粗线期,且呈剂量依赖性,在凋亡形态上与生理性凋亡没有区别。凋亡细胞数量在线虫接受辐照后2~3 h显著增加,且可持续增加至辐照后24~36 h[20]。早前的研究结果表明,给予线虫急性电离辐射(>60 Gy)才能检测出生殖细胞凋亡[22]。而近几年研究者发现,给予L1~L4期线虫低至2.9 Gy的辐照便可有效增加凋亡细胞数量[7]。线虫的DNA修复能力在胚胎发育的早期非常强,幼虫的体细胞比生殖细胞对DNA损伤的耐受性更强[23]。神经酰胺重新合成途径和DNA损伤响应途径在辐射诱导的生殖细胞凋亡中可能具有协同作用[24]。最新的研究结果显示,神经酰胺可能通过调节DNA损伤检查点hus-1和细胞凋亡调控基因egl-1来介导辐射诱导的生殖细胞凋亡[25]。
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辐射引起的旁观者效应已在生物体内得到证实,有研究者建立了一个自上而下布局的线虫共培养实验系统,其中顶部和底部线虫之间的交流以空气为传播介质,利用辐射适应性反应可评估顶部线虫的辐射反应,结果表明,对底部线虫进行γ射线辐照可降低顶部线虫的胚胎致死率,顶部线虫通过头部感觉神经元感知挥发性信号,刺激处于有丝分裂期的生殖细胞的DNA损伤修复,从而增强DNA损伤修复能力[26]。
由细胞促凋亡基因(caspase同源物,ced-3)和凋亡蛋白酶激活因子1(apaf-1同源物,ced-4)调控的核心凋亡途径是电离辐射诱导的生理性细胞凋亡以及胚胎发育期间的生理性体细胞凋亡的主要途径[27]。ced-4活性受到ced-9的抑制[28]。egl-1和ced-13可从ced-4/ced-9异四聚体中解离出ced-4,ced-4可作为DNA损伤引起细胞凋亡的诱导剂[29]。当野生型线虫暴露于电离辐射后,efl-1和ced-13基因的转录水平上调,其方式依赖于p53同源基因cep-1的积累[30](图1)。通过对不同基因缺陷突变体进行遗传筛选,已发现3种在辐射诱导的细胞凋亡方面有缺陷的突变体:hus-1、mrt-2和rad-5,它们均可消除DNA损伤引起的细胞周期阻滞和凋亡,而不影响生殖细胞的发育或生理性死亡[31]。有研究结果表明,电离辐射通过激活神经酰胺合成途径,以DNA损伤依赖的方式诱导细胞凋亡[32]。同时,电离辐射诱导的DNA损伤可以激活DNA损伤检查点hus-1,进而激活p53同源物基因cep-1和细胞凋亡调控基因egl-1,从而诱导细胞凋亡。
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电离辐射可通过2种方式引起生物体的毒性效应:一是直接将能量沉积在生物分子上,二是通过产生自由基造成间接损害。间接损害通过一系列物理和化学事件进行,从而导致自由基的产生。水的解离会产生剂量依赖性的ROS,电离辐射会造成线虫体内ROS水平上升。随着照射总剂量的增加,线虫体内的ROS水平逐步升高,并主要集中在肠道两端[33]。ROS的积累(线粒体呼吸链系统)和消除(抗氧化系统)之间的平衡决定了线虫的衰老速度和寿命。自由基衰老学说认为,线粒体中大分子氧化损伤的积累是衰老的原因之一。在较高强度的紫外线辐照下,线粒体DNA损伤水平显著升高,线虫的寿命缩短;然而,在中等剂量的紫外线辐照下,尽管线粒体DNA损伤水平也显著升高,但线虫的寿命并没有缩短[34]。
线虫细胞内的ROS平衡可通过胰岛素(Ins)/胰岛素样生长因子1(IGF-1)信号通路调节。该通路分泌的胰岛素样肽与胰岛素受体样基因daf-2受体结合,可激活daf-2信号通路。活化的daf-2信号抑制daf-16的核转位和活性[35](图1)。在该通路中,转录因子daf-16的突变会抑制age-1和daf-2突变体的长寿表型[36]。同时,胰岛素(Ins)/胰岛素样生长因子1(IGF-1)信号通路受损可促进线粒体L-脯氨酸分解代谢,进而诱导瞬时的ROS水平升高,延长线虫寿命[37](图1)。在应激条件下,线虫中控制抗氧化和线粒体呼吸链系统的daf-16的许多下游靶点被连续激活[38]。ROS还可以通过激活或抑制其他细胞内途径影响线虫的寿命[39]。暴露于低剂量应激源(如X射线、热应激或高氧)的线虫会产生一种刺激效应,从而延长其寿命。
线粒体是ROS的主要来源,线粒体功能障碍通常与ROS的增加有关。ROS是电离辐射诱导生殖细胞凋亡的核心因素。自由基清除剂二甲基亚砜(DMSO)可抑制电离辐射诱导的生殖细胞凋亡。DNA损伤诱导的ROS能上调碱性神经酰胺酶2(ACER2)的表达,使神经酰胺衍生物之一的细胞鞘磷脂水平升高,从而导致细胞凋亡[40](图1)。最新的研究结果表明,通过RNA抑制敲除人神经酰胺合成酶1同源基因lagr-1可以抑制电离辐射诱导的ROS积累[25]。外源性C16-神经酰胺能促进线虫体内ROS的积累,但不能拮抗体积浓度为5‰的二甲基亚砜(DMSO)对电离辐射诱导的生殖细胞凋亡的抑制作用。以上研究结果表明,神经酰胺可通过增加ROS的积累来介导电离辐射诱导的生殖细胞凋亡[25]。在幼虫的发育过程中,长期的电离辐射会显著提高线虫体内ROS水平,同时诱导抗氧化防御激活,该防御激活对接受慢性γ射线照射后的线虫维持体内氧化还原稳态至关重要[33]。常作为辐射损伤模型的线虫突变体总结于表1。
突变体 功能 参考文献 rad-1 辐射敏感基因,在DNA损伤反应和细胞存活信号中起关键作用 [41] rad-2 辐射敏感基因,参与辐射损伤的修复过程 [42] cep-1 p53家族唯一同源基因,通过激活egl-1和ced-13的转录来调节DNA损伤诱导的生殖细胞凋亡 [43] daf-16 编码转录调控因子中叉头(forkhoad)家族/肝细胞核心因子3的成员,叉头转基因子(FoxO1)的同源基因,是daf-2的作
用目标,突变能够抑制daf-2、age-1突变的全部表型[44] daf-2 胰岛素受体样基因,在线虫内调控长寿和滞育 [45] age-1 是线虫中第一个长寿突变体,在20℃的培养条件下,平均寿命延长40%,最长寿命平均增加60%,雌雄同体自交能力
降低75%[46] egl-1 细胞凋亡调控基因,与哺乳动物BH3-only蛋白类似,通过拮抗核心B淋巴细胞瘤2基因家族的抗凋亡成员来触发凋亡 [47] ced-9 能够抑制线虫正常发育过程中几乎所有细胞凋亡,ced-9可调控ced-3和ced-4基因的活性 [28] 注:DNA为脱氧核糖核酸;ced为细胞促凋亡基因;daf为胰岛素受体样基因;egl-1为细胞凋亡调控基因 表 1 常作为辐射损伤模型的线虫突变体
Table 1. Mutants of Caenorhabditis elegans commonly used as models in ionizing radiation damage research
以秀丽隐杆线虫为模型的电离辐射损伤研究进展
Research progress in ionizing radiation damage using Caenorhabditis elegans as a model
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摘要: 秀丽隐杆线虫(简称线虫)作为一种经典模式生物,已被广泛应用于辐射损伤研究领域。电离辐射在线虫体内造成的损伤与脊椎动物相似,主要体现在DNA损伤、活性氧水平上升、衰老加速和生殖系统受损等。以线虫作为电离辐射动物模型的研究已经在辐射损伤领域中取得很多突破。电离辐射引起的线虫衰老受多种因素影响,包括错误的蛋白表达、脂质代谢的改变等。电离辐射可诱导线虫生殖细胞凋亡、细胞周期阻滞和DNA损伤。以线虫作为电离辐射动物模型的研究对高等生物的辐射效应研究有重要意义。笔者简要综述了以线虫为模型的辐射损伤研究进展。Abstract: Caenorhabditis elegans (C.elegans for short) has been widely used in researches on ionizing radiation as a classic model organism. Similar to vertebrates, the injury induced by radiation mainly include DNA damage, increase of reactive oxygen species level, accelerated aging, and the injury in reproductive system. As a model of ionizing radiation, C.elegans have made many breakthroughs in the field of radiation damage. The accelerated aging induced by ionizing radiation is controlled by multiple factors, like the incorrect expression of proteins and altered lipid metabolism. Ionizing radiation induces apoptosis, cell cycle arrest, and DNA damage in germ cells. C.elegans, as a well-established model of ionizing radiation, has significant implications for the study of radiation effects in higher organisms. The research progress in ionizing radiation damage using C.elegans as a model is reviewed in this paper.
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Key words:
- Caenorhabditis elegans /
- Radiation, ionizing /
- Germ cells /
- Aging /
- Model organisms
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表 1 常作为辐射损伤模型的线虫突变体
Table 1. Mutants of Caenorhabditis elegans commonly used as models in ionizing radiation damage research
突变体 功能 参考文献 rad-1 辐射敏感基因,在DNA损伤反应和细胞存活信号中起关键作用 [41] rad-2 辐射敏感基因,参与辐射损伤的修复过程 [42] cep-1 p53家族唯一同源基因,通过激活egl-1和ced-13的转录来调节DNA损伤诱导的生殖细胞凋亡 [43] daf-16 编码转录调控因子中叉头(forkhoad)家族/肝细胞核心因子3的成员,叉头转基因子(FoxO1)的同源基因,是daf-2的作
用目标,突变能够抑制daf-2、age-1突变的全部表型[44] daf-2 胰岛素受体样基因,在线虫内调控长寿和滞育 [45] age-1 是线虫中第一个长寿突变体,在20℃的培养条件下,平均寿命延长40%,最长寿命平均增加60%,雌雄同体自交能力
降低75%[46] egl-1 细胞凋亡调控基因,与哺乳动物BH3-only蛋白类似,通过拮抗核心B淋巴细胞瘤2基因家族的抗凋亡成员来触发凋亡 [47] ced-9 能够抑制线虫正常发育过程中几乎所有细胞凋亡,ced-9可调控ced-3和ced-4基因的活性 [28] 注:DNA为脱氧核糖核酸;ced为细胞促凋亡基因;daf为胰岛素受体样基因;egl-1为细胞凋亡调控基因 -
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