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作者简介:

曹晨(1988—),男,江苏连云港人,教授,博士生导师,研究方向为生物信息与医学信息;

顾宁(1964—),男,江苏南京人,中国科学院院士,研究方向为纳米医学材料,通信作者,guning@seu.edu.cn。

中图分类号:R594.8

文献标识码:A

文章编号:1671-0479(2022)04-318-007

DOI:10.7655/NYDXBSS20220401

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目录contents

    摘要

    现代通信技术的快速发展与广泛应用,使得人们日常生活中使用电子设备越来越多,进而引发对电磁辐射是否损害健康更加密切的关注。一方面,已有许多研究表明,电磁辐射暴露影响人类或其他生物的健康,如电磁辐射暴露已被发现与多种疾病的高发生率相关,射频电磁场也被列为2B类致癌物;另一方面,电磁辐射可以作为一些疾病的治疗手段,如癌症的放射治疗、热磁疗等。文章通过整理多组学分析的研究成果,从细胞生物信息学、基因组学、转录组学、蛋白质组学、代谢组学、微生物组学等六个方面分别总结了电磁辐射对不同组学的影响及其生物学机制。 这些研究结果可以帮助人们更好地认识电磁辐射,并对日常生活中电磁辐射可能造成的危害进行预防。

    Abstract

    Due to the rapid development of modern communications technology,people are utilizing portable electronic devices more frequently in their daily lives,which has led to concerns about whether electromagnetic radiation(EMF)can be harmful to health. Many studies have demonstrated that exposure to EMF can influence an organism’s or a person’s health. For instance,EMF exposure has been identified as a Group 2B carcinogen and has been associated with a high incidence of numerous disorders. On the other hand, EMF exposure can also be used as a treatment for some diseases,such as radiation therapy and thermomagnetic therapy for cancer. By compiling research findings based on multi ⁃ omics big data analysis,this review summarizes the effects of EMF on human health in various omics environments and their biological mechanisms from six aspects respectively: cellular bioinformatics,genomics,transcriptomics,proteomics,metabolomics, and microbiomics. These discoveries can assist individuals to reduce the risks of EMF in their daily lives and have better understanding of the impacts of EMF on human health.

    关键词

    电磁辐射健康多组学

  • 电磁辐射是一种复合电磁波,可以通过相互垂直的电场和磁场来传递能量。按照频率从低到高分类,主要包括无线电波、微波、红外线、可见光、紫外线、X射线和伽马射线等等。虽然电磁辐射最早于19世纪被发现,但其在生命诞生以前就广泛存在于自然界中。雷电、宇宙射线、太阳热辐射、地球热辐射、静电辐射等均可以产生电磁辐射[1]

  • 人们可能暴露其中的电磁场(electromagnetic field,EMF)主要包括两个频段:一个是极低频段 (extremely low frequency,ELF),频率小于300赫兹,如大众熟知的电力供应中使用的50赫兹和60赫兹,以及电力线和电气/电子设备产生的电磁场的频率;另一个是射频段(radio frequency,RF),频率在10兆赫到300吉赫,包括微波,当前无线通信设备在这个频段运行,主要是移动电话使用的900兆赫和1 800兆赫。现代社会人们更多地暴露于人造来源的电磁场,主要包括四类:一是人工的无线发射设备,包括手机、无线路由器、电信基站、无线电台、计算机屏幕和许多其他日常生活中广泛使用的电子设备;二是电力工频强电系统发出的无源辐射,包括超高压输电线、变电所和磁悬浮轨道交通等;三是电子仪器、医疗仪器、激光照相设备等工业医疗设备产生的电磁辐射;四是电脑、冰箱、空调、微波炉、电磁炉、家用理疗仪等家用电器产生的电磁辐射。随着科技的发展进步,越来越多的高科技电子产品改变了人们的生活方式,在带来快捷和便利的同时也让人们无时无刻不暴露在电磁辐射之中。电磁辐射究竟会对人类健康造成什么影响,影响的大小及安全范围等,是目前研究中主要关心的问题。本文整理了多组学分析的研究成果,总结电磁辐射对不同组学的影响及其生物学机制。这些研究结果可以帮助人们更好地认识电磁辐射,并对日常生活中电磁辐射可能造成的危害进行预防。

  • 一、 电磁辐射的危害

  • (一) 风险与警示

  • 在过去的几十年里,关于各类电磁场的生物效应和对人体健康危害的科学知识不断积累增加,研究发现电磁辐射暴露与退行性神经疾病、恶性肿瘤、生殖功能异常等多种疾病的发生率增高密切相关,并成为新的致病危险因素[1]。世卫组织/国际癌症研究机构(International Agency for Research on Cancer,IARC)于2011年5月将射频电磁场列为可能导致人类罹患癌症的物质(2B类),同时IARC网站列出的314种2B类致癌物中也包含极低频电磁场[2-3]

  • 除了地球的自然电磁场外,随着电子和通信领域新技术的不断发展,许多人造电磁场纷纷出现,如自20世纪开始出现的供电电网设施,就是人造极低频电磁场的重要来源[4]。在此之后,无线电广播技术和通信技术高速发展所产生的多种新型电子设备,使得电磁场的数量大大增加。例如在过去的几十年中,移动电话市场在全球范围内呈现惊人的增长。截至2022年2月,我国共有移动电话用户数165 060.5万户,市场规模居世界第一[5]。除此之外,无线网络技术的发展,如无线局域网(WLAN)热点,包括Wi⁃Fi网络,也会产生海量的射频电磁场[6]。研究表明,在不同国家的城市地区,包括射频电磁场在内的多源电磁辐射量均处于高水平[7],这使得人们越来越多地暴露在电磁辐射中。此外,在军事领域,发达军事强国以电磁辐射为杀伤因素的新型高科技武器不断出现,这些武器的使用将对人们的健康及生命安全造成巨大威胁。

  • 总而言之,电磁辐射的危害正逐渐成为严重影响人民健康和社会发展的突出问题。因此,深入研究电磁辐射损伤效应,阐明损伤机制,提出危害防治措施,是促进社会、经济、环境平衡协调发展和涉及国防安全的国家重大需求。

  • (二) 流行病学研究

  • 目前已有许多流行病学研究表明,电磁辐射与多种疾病的患病风险高度相关。例如,一项研究结果发现,当儿童暴露在磁感应强度高于0.3 μT的极低频电磁场中时,罹患白血病风险将增加1.4~1.7倍[8]。英国研究人员对29 081名儿童(包括9 700例白血病和6 605例脑瘤)进行病例对照研究,结果表明居住在高压线附近的儿童,白血病及脑肿瘤发病率显著增高[9]。在瑞典1997—2003年和2007—2009年的一项联合案例研究中发现,使用便携式手机会增加患神经胶质瘤的风险[10]。2017年一项Meta分析结果也显示,长期使用手机(超过10年)与胶质瘤风险呈显著正相关,其中低级别胶质瘤发生概率将增加2.22倍[11]。这些研究表明,电磁辐射暴露可能伴随着多种疾病患病风险。

  • 除了与癌症患病风险之间存在相关性之外,电磁辐射还与非肿瘤疾病发病率相关。早在1995年,芬兰的一项研究就表明中高度的极低频电磁场与散发性阿尔茨海默症之间存在关联[12]。随后在美国、丹麦、瑞典等地的类似研究也发现了这种联系[13-15]。近年来,多项研究提出极低频电磁场暴露可以通过激活钙信号和过氧亚硝酸盐/氧化应激/炎症等多种生物通路,改变细胞内钙离子的浓度进而引起早发性阿尔兹海默症[16]

  • (三) 电磁辐射的作用机制研究

  • 已经有相当多的研究表明,电磁辐射与多种生物效应和致病机制相关。例如电磁辐射可以影响细胞增殖分化,有研究发现低频电磁场和高频电磁场均可促进神经干细胞的体外增殖,同时低频电磁场还可以促进神经干细胞分化为神经元[17]。除此之外,电磁场还可以诱导骨髓干细胞分化为神经元,以及促进间充质干细胞的增殖和分化[18-19]

  • 电磁辐射可以通过非热机制影响细胞自噬。有研究发现暴露在1 800兆赫电磁场中的小鼠胚胎细胞内活性氧(reactive oxygen species,ROS)水平显著增加,促进了细胞凋亡[20]。同时,这种影响还受细胞类型、细胞微环境、剂量、时间等因素影响[21]

  • 电磁场还可以影响细胞的信号转导。有研究发现,利用异氟醚可以保护大脑皮层神经元免受电磁场暴露的损伤,减轻炎症反应和细胞凋亡,改善电磁脉冲(electromagnetic pulse,EMP)诱导的认知障碍[22]。另外有研究发现,暴露于1 760兆赫的射频电磁场会诱导细胞内产生ROS,刺激基质金属蛋白酶(matrix metalloproteinases,MMPs)家族蛋白产生并激活ERK1/2通路和FoxO3a通路,最终导致皮肤老化[23]。与之相近的最新研究表明,射频电磁场还可能通过激活Akt/mTOR/p53通路的方式引起细胞衰老[24]

  • 电磁场还会通过增加氮中间体和ROS水平的方式间接引发DNA链断裂[25-26]。有研究发现,暴露于电磁辐射后,人成纤维细胞染色体畸变和微核数量显著增加[27]。后续研究还发现,反复电磁场暴露将导致宫颈癌细胞和正常肺成纤维细胞中的DNA双链断裂[28]

  • 以上研究表明,电磁场可以通过多种方式影响细胞的生理活动,进而导致人体健康失衡。因此,基于多组学分析技术,进一步探究电磁辐射对人体的影响机制,是未来研究的一个发展方向。

  • 二、 电磁辐射的多组学研究

  • (一) 细胞生物信息学

  • 宇宙辐射顾名思义是来自太空的辐射,一般分为银河宇宙射线和太阳宇宙射线。对于普通人群来说,宇宙辐射就像经常能够接触到的其他低水平辐射一样,不会造成伤害。但对于特殊职业人群,例如机组人员,频繁的高海拔和高纬度飞行可能会受到来自太空的高水平辐射,产生潜在的健康风险,因此有专门的国际航空运输协会控制机组人员的飞行时间。而对于宇航员来说,在空间站中的生活会接受到更高的辐射剂量,进而影响健康水平。

  • 目前有研究使用了NASA GeneLab数据库[29] 中59名宇航员的多组学数据,全面分析太空飞行对人体健康影响的生物学机制[30]。结果发现,太空飞行会引起线粒体功能障碍,进而导致人体不同组织中与线粒体功能相关的代谢物发生不同程度的变化,其中肝脏组织中的基因表达水平和蛋白质表达水平变化最为明显,这是因为肝脏对于维持体内成分平衡起关键枢纽作用。这一研究通过对转录组学数据、蛋白质组学数据和代谢组学数据进行全面分析,揭示了太空辐射可能造成的健康风险,阐明了以线粒体功能失调为中心的一系列生物学机制。

  • 除此之外,还有研究发现太空飞行后宇航员的端粒长度往往比太空飞行前短,而在太空飞行期间端粒延长且伴随着持续性的DNA损伤、线粒体应激、氧化应激、炎症反应和染色体畸变等现象[31-32]。端粒是真核生物染色体末端的DNA重复序列,负责保持染色体的完整性和控制细胞分裂周期。端粒长度是一种遗传性状,会随着正常衰老而减少,一旦端粒消耗殆尽,细胞将会立即启动凋亡机制。因此端粒常被认为与细胞衰老有关系[33]。通过对宇航员飞行前后的端粒长度进行分析,解释了端粒长度变化的分子机制,但太空飞行对人体长期健康的影响还待进一步研究。

  • 一方面,研究宇宙辐射引发细胞损伤的分子机制,可以帮助推进使用高能粒子加速器治疗癌症的方案,使用与太空辐射类似的带电粒子束摧毁深层肿瘤的同时,最大限度地减少对周围组织的损伤。另一方面,研究太空辐射引发细胞损伤的分子机制,还可以帮助改进太空辐射防护措施,进一步降低太空飞行引起的健康风险。

  • (二) 基因组学

  • 1986年切尔诺贝利核电站发生的核反应堆破裂事故,导致周边地区的居民暴露于辐射中,使得当地居民甲状腺乳头状癌(papillary thyroid cancer, PTC)的发病率显著升高。有研究通过全基因组测序技术分析了这些癌症患者的基因变异,发现无论是辐射暴露组还是对照组,其多种调控细胞生长的基因都发生了变异,但两组的基因变异类型存在明显差异。小时候暴露在辐射下的人群的关键基因更多地出现“融合变异”,这可能因为辐射带有能量,打断了DNA双链,当DNA双链重新修复时,将错误的片段连接进来,进而产生了变异。相反,对于那些没有暴露在辐射下的人群,他们更多出现的是点突变。而且研究人员也观察到,暴露于辐射中的儿童年龄越小,DNA双链断裂与辐射暴露之间的关联就越强。这也表明DNA双链断裂可能是暴露于辐射后最早出现的基因变异之一,这一研究结果对辐射诱导的癌症研究有着重要的启示作用[34]。与之类似,有研究通过基因组测序分析发现,强紫外线照射可以导致DNA双链断裂[35]。这些研究说明电磁场暴露一定程度上可以导致DNA双链断裂,进而在基因组水平上影响人体健康,因此通过全基因组测序等分析手段可以深入研究电磁场对人类基因组学的影响。

  • (三) 转录组学

  • 转录组学是研究单个细胞或一群细胞所能转录出的所有RNA的学科。转录组是基因组的主要产物,因此分析转录组可以反映基因组的功能,同时还可以揭示不同类别RNA的表达变化及其转录调控情况[36]。目前运用转录组学分析电磁辐射对人体健康影响的研究中,多使用RNA测序技术进行分析。

  • 有研究通过RNA测序技术分析发现,经X射线照射后人肺微血管内皮细胞(human lung microvascular endothelial cells,HLMVEC)中衰老相关基因的表达发生改变,同时其他显著差异表达基因富集在细胞周期、细胞凋亡、DNA损伤、炎症反应和内皮向间充质细胞转化(endothelial⁃to⁃mesenchymal transition,EMT) 等生物通路中。这些结果表明,X射线可能会导致细胞衰老、低水平的细胞凋亡、炎症增加和促进EMT,而对这些通路的进一步研究可以预防电磁辐射对正常组织的伤害[37]。有研究通过敲除p53基因进行转录组学分析,研究电磁辐射后p53基因的转录调控情况。结果发现,敲除p53基因后暴露于电磁辐射中会导致转录组的显著失调,也就是说,多个mRNA的表达水平会随着p53基因辐射暴露后的状态变化而显著改变。这说明p53基因在辐射暴露后的损伤反应中起重要作用[38]。除了研究基因表达改变情况和转录调控情况之外,转录组分析还可以研究表达水平对放射治疗效果的影响。例如,有研究通过转录组分析发现,特定基因的高表达可以影响患者对放射治疗的敏感性[39],这有助于进一步改善患者的预后情况。现有电磁辐射对转录组影响的研究绝大部分都是基于bulk转录组测序,bulk转录组测序中的样本混合会导致均质化从而掩盖单细胞异质性,单细胞转录组测序和空间转录组测序技术能在单细胞水平更精细地揭示电磁辐射对不同组织区域的影响,将是未来研究的发展方向。

  • (四) 蛋白质组学

  • 蛋白质组学是利用高通量和低通量技术研究生物体内存在的蛋白质种类的科学。相较于基因组学或转录组学,蛋白质组学可以更好地了解细胞内正在进行的功能过程。蛋白质是直接调节生理过程的分子,而并非所有基因表达的变化都必然反映在蛋白质组上,特别是无线通信设备所产生的射频电磁场具有的能量非常低,难以直接诱发基因突变,因此可以使用蛋白质组学方法研究射频电磁场对生物健康的影响[40]

  • 目前有许多研究观察到电磁暴露会在一定程度上影响人体的生殖相关蛋白,例如有研究表明,暴露于射频电磁场中会导致成人睾丸蛋白增加,这与致癌风险和生殖损伤有关。而男性往往会在靠近性腺的口袋里随身携带手机,在这种情况下,可能会使性腺暴露在过强的电磁场中,进而影响男性生殖健康[41]。除此之外,有研究发现经X射线辐射后,人类肝星状细胞的促纤维化标志物表达增加,导致辐射诱导的肝纤维化[42]。针对以上电磁场对健康的潜在危害,通过分析细胞系的蛋白质表达谱来制定放射治疗策略,可以最大限度地减少电磁辐射导致的生殖损伤或肝纤维化。

  • (五) 代谢组学

  • 代谢组学是对细胞、组织或生物体中的代谢物、小分子底物、代谢中间体和产物的系统研究,可以发现特定细胞过程中的代谢标志物。目前关于电磁场与人体健康的代谢组学研究较少,但仍有研究通过多变量统计分析健康群体与电磁场敏感(idiopathic environmental intolerance attributed to electromagnetic fields,IEI⁃EMF)群体之间的代谢谱差异。与健康群体比较,敏感群体的代谢组学特征是甘氨酸和焦谷氨酸水平较高,2⁃羟基异己酸盐、胆碱、谷氨酰胺和异亮氨酸水平较低。而这些代谢物主要涉及氧化应激防御、疼痛机制和肌肉代谢过程,因此,这些标志物的代谢水平可能揭示了纤维肌痛(fibromyalgia,FM)的发病机制,并可以作为识别疾病发生的特异性标志物[43]。除此之外,还有研究利用代谢组学研究磁热疗在抗肿瘤中的疗效,例如有研究发现,接受12小时的磁热疗后,动物肝酶水平会显著升高,而10天后则检测不到这一现象。这说明磁热疗会在12小时内显著改变肝脏的代谢模式,但10天后则恢复至原始水平。这个过程中涉及的代谢组学特征包括磷脂酰胆碱、牛磺酸、葡萄糖、乳酸和丙酮酸等在代谢组学层面上具有显著差异,因此认为磁热疗是一种可以安全治疗肝转移瘤的方法[44]

  • (六) 微生物组学

  • 近年来,人们发现微生物对人体各类疾病以及免疫系统等都发挥着重要作用,而随着测序技术的发展,人们对微生物的研究也进入了组学时代,可以利用16S rRNA宏基因组测序技术加深对微生物组的研究。目前已有研究通过测序技术分析电磁辐射暴露对微生物组组成的影响,例如有研究使用UVA和UVB波段的紫外线照射受试者皮肤,发现受到辐射后皮肤微生物组的构成发生了变化,而变化的程度则因人而异,但存在的总体趋势为紫外线照射后蓝藻、梭杆菌和疣微菌会普遍增加,而乳酸杆菌会减少[45]。除了皮肤的微生物组之外,电磁场还会影响肠道微生物组。有研究通过16S rRNA测序分析发现,经高剂量的全身辐射暴露后,肠道微生物组的构成发生了变化,与腹泻相关的罗伊氏乳杆菌增加,而扁豆菌、疣微菌门和拟杆菌减少,从而导致腹泻症状[46]。类似研究发现,电磁场暴露不仅会导致抑郁样神经行为障碍,还会导致肠道微生物群失衡,而热习服(heat acclimation,HA)则可以减轻电磁辐射引起的抑郁特征[47]。还有研究表明,在高剂量电磁辐射中仍存活至正常寿命的部分小鼠,其胃肠道中存在着独特的微生物组,其中毛螺菌科和肠球菌科的细菌最为丰富。单关联分析发现毛螺菌与保护作用显著相关,而肠球菌则与促进造血、减轻胃肠道损失显著相关。这一结果揭示了新的辐射防护机制,并为减轻辐射治疗引起的不良反应提供了新的思路[48]

  • 目前还需要更多的研究来了解电磁场对人体微生物组的影响,通过测序技术可以快速高效地识别电磁辐射暴露的微生物组标志物,有助于开发有效的治疗干预措施以减轻辐射损伤;了解辐射损伤和辐射引起症状的病理生理学机制,有助于开发新药和制定预防措施,改善接受放疗的癌症患者的生活质量。

  • 三、 未来与展望

  • 科学技术的发展产生了大量的人造电磁场,使得人们越来越多地暴露在电磁辐射中,进而引发了对于电磁辐射对人体健康危害的广泛关注。另外,近年来测序技术的迅速发展产生了海量的多组学数据,研究人员使用高通量技术和分析手段可以更好地了解疾病的致病机制以及研发治疗手段。这些发展为使用多组学数据分析电磁辐射对人体健康的影响打下了基础。在高通量测序技术分析下,可以同时研究细胞、组织、人体中与环境因素关联的数千个基因。同时相较于低通量实验手段,高通量测序技术更为经济有效,可以对同一批样本进行不同组学层面测序,进而进行多组学综合分析。

  • 在过去很长一段时间里研究人员都在使用传统实验方法研究电磁辐射对人类健康的影响,不但效率较低,关于电磁辐射对生物影响的评估也不够全面。目前基于组学大数据的研究越来越受到关注,但大多数研究成果都来自欧洲机构[49],国内的研究尚较少,补齐国内短板任重道远。因此,基于多组学数据进一步研究电磁辐射对人体健康的影响,可作为未来国内电磁学与医学交叉领域研究的重点。虽然目前已经有很多研究工作探索电磁辐射对生物体的影响,但是人们日常生活中广泛接触到的电磁辐射如Wi⁃Fi网络、手机、计算机屏幕等对健康的影响尚需要更多的研究去探索及验证。

  • 另外,与低通量实验的可比性是使用高通量测序技术进行分析时存在的普遍问题。例如,两种实验方法是否得出一致结论,如何展示两者之间在多大程度上具有可比性,使用实验方法进行复现得到验证的比例是多少等等。针对这些问题,还亟需制定规范的分析流程和标准化实验方法以确保结论的可比性和研究的高质量性。

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    • [41] SEPEHRIMANESH M,KAZEMIPOUR N,SAEB M,et al.Proteomic analysis of continuous 900 ⁃ mhz radiofre⁃ quency electromagnetic field exposure in testicular tis⁃ sue:a rat model of human cell phone exposure[J].En⁃ viron Sci Pollut Res Int,2017,24(15):13666-13673

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