Research progress on roles and mechanisms of DNA hydroxymethylation in health effects induced by arsenic exposure
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摘要:
砷是一种天然类金属化学元素，是世界卫生组织公布的引起重大公共关注的10种危害环境与健康的化学品之一，可以通过呼吸、食物、饮水、皮肤等途径进入人体，长期接触砷会导致多器官癌症和多系统功能受损。表观遗传学机制在砷健康效应中发挥重要作用，研究表明，砷的致癌性可能是由表观遗传变化引起的。之前的研究主要集中在砷对DNA甲基化修饰的影响。近年来，研究表明DNA主动去甲基化的中间产物——5-羟甲基胞嘧啶（5-hmC），可作为一种敏感的表观遗传标记，在砷暴露与健康效应之间发挥至关重要的“桥梁”作用。本文基于DNA羟甲基化在砷暴露所致健康效应中作用的最新研究进展，简述了砷暴露的健康效应与DNA羟甲基化的关系，总结了DNA羟甲基化在砷暴露所致健康效应中的可能作用机制，为防治砷暴露所致健康效应提供科学依据。
Abstract:Arsenic, a naturally occurring metal-like chemical element, is one of the 10 chemicals of major public concerns listed by the World Health Organization as harmful to the environment and human health. It can enter the human body through breathing, intaking food, drinking water, skin exposure, and other ways, and long-term exposure to arsenic can cause cancer of multiple organs and impaired function of multiple systems. Epigenetic mechanisms play an important role in arsenic-induced health effects, and research suggested that the carcinogenicity of arsenic may be associated with epigenetic changes. Previous studies focused on the effects of arsenic on DNA methylation modification. In recent years, research showed that 5-hydroxymethylcytosine (5-hmC), an intermediate of active demethylation of DNA, can act as a sensitive epigenetic mark and play a crucial role as a "bridge" between arsenic exposure and health effects. Based on the latest research progress on the role of DNA hydroxymethylation in the health effects associated with arsenic exposure, this article briefly described the relationship between the health effects of arsenic exposure and DNA hydroxymethylation, summarized the possible mechanisms of DNA hydroxymethylation in the health effects associated with arsenic exposure, and provided a scientific basis for preventing and treating the health effects associated with arsenic exposure.
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Keywords:
- 5-hydroxymethylcytosine /
- epigenetics /
- arsenic /
- health effect /
- mechanism of action
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砷是自然界普遍存在的一种有毒类金属和一类致癌物，对人类及动植物都具有很强的毒性作用[1]。火山喷发、岩石侵蚀等自然现象和开采、燃烧矿物等人类活动都会向环境释放大量砷[2]。砷可分为无机砷和有机砷，饮用被高浓度无机砷污染的地下水是砷暴露的主要途径[3]。砷污染现象在全世界范围内普遍存在，全球近70个国家地下水砷浓度（质量浓度）超过了世界卫生组织的饮用水标准限定值（10 μg·L−1），约有2.2亿人的饮用水受到砷污染[4]，仅孟加拉国就有近43000人因慢性砷暴露死亡[5]。我国是地方性砷中毒危害最严重的国家之一，涉及内蒙古、山西、新疆等10余个省[6]，国内地方性砷中毒类型主要为饮水型砷中毒、燃煤型砷中毒和职业砷中毒[7]。目前砷的毒理机制尚不明确，有研究认为，表观遗传修饰在砷损害人体健康中发挥重要作用 [8]。
表观遗传修饰是指参与基因表达的DNA在序列不变的情况下，其表达功能发生了可遗传、稳定的改变[9]，常见的表观遗传修饰有DNA甲基化、组蛋白修饰、染色质重塑和非编码RNA[10]。砷是明确的表观遗传毒物，之前的研究主要集中于砷对DNA甲基化修饰的影响。近年来，有研究表明DNA羟甲基化能够响应多种环境因素的改变，本文综述砷对DNA羟甲基化修饰影响。
1. DNA羟甲基化
1.1 5-羟甲基胞嘧啶（5-hydroxymethylcytosine, 5-hmC）的生成及发现
5-hmC，也称为“第六碱基”，是一种新的表观遗传标记[11]，是指在10-11易位（ten-eleven translocation, TET）蛋白催化作用下，5-甲基胞嘧啶（5-methylcytosine, 5-mC）第五位碳原子上的甲基被氧化成羟基[12]，此外，研究表明，TET蛋白可以进一步将5-hmC氧化为5-甲酰基胞嘧啶（5-formylcytosine, 5fC）和5-羧基胞嘧啶（5-carboxylcytosine, 5caC）[13–14]。1952年，5-hmC首次发现于噬菌体中[15]，20年后，又被发现存在于哺乳动物基因组中[16]，直到2个研究小组独立证明5-hmC存在于小鼠浦肯野神经元和胚胎干细胞中[17–18]，人们对5-hmC的研究才有了突破性的进展。作为去甲基化的中间产物，5-hmC较为稳定，在指示某些环境暴露导致的健康效应时比甲基化更加敏感，在环境与疾病之间发挥重要的“桥梁”作用。
1.2 5-hmC在组织和器官中的分布及检测方法
不同研究关于5-hmC丰度和基因表达关系的观点并不十分一致，这可能是因为5-hmC的丰度受细胞类型和发育调控，而不是简单的基因活性激活或抑制[19]。5-hmC广泛分布于哺乳动物的组织中，其含量具有组织特异性，在神经元组织中的含量最高，从提取的DNA中检测到约0.3%~0.7%的5-hmC，来自肝脏、脾脏和内分泌腺（睾丸和垂体）的DNA的5-hmC含量最低，水平在0.03%~0.06%之间[20]。
目前有多种方法用于5-hmC的检测，主要从基因组总体、基因组特定区域、基因组单碱基3个层面检测5-hmC水平[21]，分为免疫组化、羟甲基化DNA免疫共沉淀测序[22]，以及TET辅助重亚硫酸盐测序（TET-assisted bisulfite sequencing, TAB-Seq）、氧化重亚硫酸盐测序（oxidative bisulfite sequencing, OxBS-Seq）[23]等方法。
2. 砷暴露影响DNA羟甲基化的分子机制
2.1 改变TET蛋白活性
TET蛋白是一类α-酮戊二酸（α-ketoglutaric acid, α-KG）和Fe2+依赖的双加氧酶[24]，包括TET1、TET2和TET3三种[25]。这3种TET蛋白的C末端都含有一个富含半胱氨酸和双链β螺旋结构的催化结构域(catalytic domain, CD)，可与Fe2+和α-KG结合，从而将5-mC氧化为5-hmC[26–27]。
砷可以改变TET活性，从而影响DNA羟甲基化。一方面，砷可下调TET蛋白活性，动物实验发现，砷可引起小鼠肝脏TET活性降低，导致肝脏单个基因过氧化物酶体增殖物激活受体（peroxisome proliferators-activated receptor α, PPARα）羟甲基化水平也降低[28]。Xiong等[29]研究发现砷可下调小鼠胚胎干细胞TET蛋白活性，改变DNA全基因组和印记基因羟甲基化模式。而另一方面，砷可上调TET基因表达，实验发现砷可抑制CCCTC结合因子（CCCTC-binding factor, CTCF）的结合能力，导致TET的表达水平增加，进而上调总5-hmC表达水平[30]。
2.2 引起线粒体损伤
TET催化的氧化甲基化反应，需以氧气为底物, Fe2+、α-KG为辅因子[18]。线粒体是氧化磷酸化的重要场所，也是α-KG合成和代谢的重要细胞器。α-KG产生于线粒体三羧酸循环[31]，是异柠檬酸脱氢酶（isocitrate dehydrogenase, IDH）通过氧化脱羧反应将异柠檬酸转化生成的[32]。
孕期砷暴露可下调雌性子代肝脏中IDH1和IDH2的表达，导致α-KG含量、TET活性和5-hmC水平下降[28]。此外，砷会损害线粒体的形态和功能[33]。砷暴露可导致人胎盘滋养层细胞线粒体膜电位降低、线粒体活性氧（reactive oxygen species, ROS）生成量增加以及氧化磷酸化进程受到抑制[31]，高水平线粒体ROS直接攻击α-KG的主要代谢酶α-酮戊二酸脱氢酶[34]，导致α-KG累积增多，从而上调TET活性并影响全基因组羟甲基化模式。
2.3 改变锌指蛋白结构
锌指蛋白是一类含锌蛋白，通过结合Zn2+以稳定结构，可自我折叠形成“手指状”[35]，具有DNA的识别与结合、RNA的修饰与剪接、基因的转录激活与调控、蛋白质的折叠与组装以及脂质的结合等功能[36]。锌指蛋白和TET2在细胞分化过程中相互作用，并共同参与基因转录的调节。Hu等[37]表明，锌阳离子可以与TET2中的特定氨基酸残基形成配位键，增强TET2的稳定性，维持其结构完整性；此外，锌离子可以促进TET2的催化活性，从而影响5-hmC的表达水平。
砷会结合锌指蛋白影响DNA羟甲基化。研究发现三氧化二砷能够与锌指蛋白结合[38]，导致锌指蛋白构象发生变化，干扰TET酶的活性，进而影响DNA羟甲基化。Liu等[39]也发现，亚砷酸盐可以与TET蛋白的锌指结构域结合，损害细胞中TET酶的催化效率，大大削弱TET蛋白将5-mC氧化为5-hmC的作用，导致5-hmC水平的降低。
2.4 诱导氧化应激
氧化应激是指有机体在受到强烈的热刺激、机械刺激、化学刺激时，引起ROS产生过多，使体内抗氧化系统的防御和修复系统功能出现超负荷，导致脂质过氧化[40]。无机砷在机体内需经过2次氧化甲基化反应，最终生成一甲基砷酸和二甲基砷酸[41]。砷代谢需要消耗大量的谷胱甘肽，导致氧化系统和抗氧化系统失衡，引起氧化应激[42–44]。氧化应激可直接下调TET活性。Niu等[45]发现氧化应激阻断了Fe3+还原为Fe2+，从而影响TET蛋白活性，导致细胞中5-hmC减少。另外，高水平ROS可直接攻击α-KG的主要代谢酶α-酮戊二酸脱氢酶[34]，导致α-KG累积增多，从而上调TET活性并影响全基因组羟甲基化模式。
2.5 干扰碱基切除修复途径
碱基切除修复是细胞内DNA损伤修复的最主要途径之一[46]。是由DNA糖苷酶启动的一种修复机制，主要负责修复因氧化、脱氨或烷基化等造成的一类未明显影响DNA螺旋结构的碱基损伤。碱基切除修复途径在DNA甲基化中也发挥重要作用[47]。DNA糖苷酶可特异性识别并去除5-hmC的氧化产物5caC，启动碱基切除修复途径完成DNA脱甲基化[48]。碱基切除修复途径中的关键酶抑制剂会阻断小鼠受精卵中的DNA去甲基化[49–50]，导致5-hmC减少。
研究发现，砷可以抑制碱基切除修复途径[49]，干扰DNA羟甲基化。Ding等[51]发现，砷可下调碱基切除修复途径N-甲基嘌呤DNA糖基化酶（n-methylpurine DNA glycosylase, MPG）、X线修复交错互补基因1（X-ray repair cross complementing group 1, XRCC1）和多聚ADP核糖聚合酶1（poly ADP-ribose polymerase 1, PARP1）基因的组蛋白修饰和基因表达，从而干扰DNA羟甲基化。
3. 砷暴露的健康效应与DNA羟甲基化的关系
3.1 砷暴露导致的神经毒性与DNA羟甲基化的关系
砷暴露可导致神经毒性。流行病学研究发现，孟加拉国6岁儿童学龄前智力评分与饮水砷水平呈显著负相关[52]。动物实验发现，慢性砷暴露可诱导小鼠脑神经细胞DNA损伤[53]。Chattopadhyay等[54]发现砷可以诱导人胚脑细胞神经元退化，出现基质丢失、核固缩、空泡化等现象。
胚胎期是神经系统发育敏感期，也是DNA羟甲基化修饰的关键期。5-hmC在大脑中的含量最为丰富，在神经系统发育过程中发挥着非常重要的调控作用，可以调控多个基因如环状轴突导向受体1（roundabout guidance receptor 1, Robo1）、T-box脑基因1（t-box brain gene 1, Tbr1）、SRY-box转录因子5（sry-box transcription factor 5, Sox5）来促进神经分化[55]。同时，DNA羟甲基化修饰先后经历2次重编程（去除和重建）过程，极易受到环境毒物的干扰。母鼠孕期砷暴露可下调仔鼠胎脑5-hmC水平，诱发神经管畸形[56]。Lv等[57]发现，母鼠孕期饮水砷暴露可引起胎仔大脑中5-hmC含量降低，诱导子代成年期焦虑样行为，而TET的辅助因子维生素C可逆转砷诱导的TET活性降低和5-hmC减少，减轻了砷诱导的成年后代的焦虑样行为。此外，Du等[58]发现砷暴露可以降低大脑皮层和海马组织中5-hmC的水平，损害大鼠的认知能力。
3.2 砷暴露导致的恶性肿瘤与DNA羟甲基化的关系
砷是明确的一类致癌物，慢性砷暴露会使人患肺癌、皮肤癌、膀胱癌等的风险明显增加[59–60]。过去研究认为，砷可引起多种癌基因和抑癌基因异常甲基化，导致基因突变、癌基因活化和抑癌基因失活[61]。由于之前羟甲基化检测技术不是很成熟，常用甲基化检测技术如重亚硫酸盐测序（bisulfite sequencing, BS-Seq）等进行羟甲基化检测，但是并不能很好地区分5-mC和5-hmC，而随着DNA羟甲基化多种检测技术的开发，如TAB-Seq、OxBS-Seq等，为DNA羟甲基化在砷暴露与肿瘤关系的研究中提供了更好的技术支持。
研究发现，基因组5-hmC和TET的改变与乳腺癌、前列腺癌、肝癌多种癌症患者的存活率密切相关[26，62–64]，与基因组5-mC相比，癌症状态下基因组5-hmC的下降幅度远大于正常组织[26，62]。Lian等[65]发现，黑色素瘤细胞中5-hmC的水平低于健康成熟黑色素细胞和良性痣，但5-mC的水平则不然。这些研究提示，DNA羟甲基化可能在砷暴露与恶性肿瘤发生中发挥重要作用，但DNA羟甲基化对砷与肿瘤的作用仍需进一步探索。
3.3 砷暴露导致的心血管疾病与DNA羟甲基化的关系
慢性砷暴露也与心血管疾病的发展有关[66]。低剂量砷暴露可增加缺血性心脏病和心血管病的死亡率[67]。流行病学研究发现，砷暴露可以导致心电图ST-T段改变和引起窦性心律失常[68]。动物实验表明，低剂量砷暴露可引起兔心血管内皮和心肌损伤[69]。
DNA羟甲基化修饰与心血管疾病的发生发展密切相关[70]。胡春晓等[71]研究发现老年心肌梗死患者外周血全基因组羟甲基化水平明显增加，与冠状动脉粥样硬化程度显著相关。Jiang等[72]研究发现，老年冠心病患者外周血单个核细胞羟甲基化水平明显升高，与冠状动脉粥样硬化程度呈正相关。课题组体外研究表明，砷可以通过ROS介导的三磷酸腺苷结合盒转运体A1（adenosine triphosphate binding cassette transporter A1, ABCA1）高甲基化抑制THP-1巨噬细胞的胆固醇流出[73]。砷引起的心血管疾病是否通过异常羟甲基化还有待进一步研究。
3.4 砷暴露导致的糖脂代谢与DNA羟甲基化的关系
砷暴露是糖代谢异常的潜在环境风险因素。动物实验表明砷可以干扰肝脏中的葡萄糖生成，增强肝组织的形态和功能损伤，抑制胰岛素刺激的葡萄糖摄取，从而导致高血糖、高胰岛素血症和低胰岛素敏感性[74]。流行病学研究表明饮水型砷暴露可增加糖尿病的患病风险[75]。砷暴露也可以引起脂代谢紊乱。动物实验发现，亚砷酸钠可引起雌性Albino大鼠总胆固醇（total cholesterol, TC）及甘油三酯水平明显升高[76]；流行病学调查发现，砷暴露导致儿童血清TC和低密度脂蛋白水平都明显升高[77]。
DNA羟甲基化修饰与糖脂代谢密切相关。Wu等[22]研究表明，持续的高血糖会破坏TET2的稳定，并使5-hmC的水平降低。流行病学研究表明，血糖控制不佳的2型糖尿病患者的外周血5-hmC水平高于健康人[78]。胚胎期生殖细胞发生阶段先后需经历2次重编程（去除和重建）过程，是DNA羟甲基化修饰的关键阶段，极易受到环境毒物的干扰[79–80]。母鼠孕期砷暴露会下调胎鼠和成年子代肝脏多个β-氧化基因羟甲基化修饰，诱导肝脏脂质积聚和糖代谢受损[28]。
3.5 砷暴露的其他系统损伤与DNA羟甲基化的关系
砷是一种雄性生殖毒物，可导致睾丸雄激素分泌减少、生殖细胞退化和精子数量减少[81]。流行病学报告显示，饮用水中砷含量超标会导致男性精子数量和精子存活率均下降[82–83]，动物实验也发现，慢性砷暴露可导致小鼠精子质量下降[84]。研究表明，环境毒物暴露与表观遗传修饰密切相关，职业性接触环境毒物与人类精液样本中长散布核元件-1（long interspersed nuclear element-1, LINE-1）羟甲基化呈正相关[85]，证明5-hmC可能作为一种新的表观遗传学修饰，用于环境毒物对男性精液质量影响的流行病学研究。
4. 总结
本文综述了砷暴露影响DNA羟甲基化修饰的研究进展。DNA羟甲基化模式的改变可被视为对许多环境因素的敏感反应指标。对5-hmC的深入研究可以提供更多关于其功能和机制的信息，这有助于阐明5-hmC相关疾病的形成和发展，可用在癌症早期筛查或作为标志性事件方面，并可能最终促进早期诊断和治疗。作为一种稳定的表观遗传标记，尽管已有研究将5-hmC变化与砷暴露与疾病的发生发展相关联，但DNA羟甲基化改变的分子机制尚不完全清楚，需要进一步研究。
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