MicroRNA在环境毒理学中的研究进展

MicroRNA在环境毒理学中的研究进展ResearchProgressofMicroRNAinEnvironmentalToxicology摘要MicroRNA（miRNA）是一类长度约为20-25个碱基的非编码单链RNA，通过与靶基因的3’非翻译区碱基配对结合引起mRNA的降解、抑制翻译进程，进而下调靶基因的表达，可参与调控机体生长、发育和代谢等多种生命活动。越来越多的环境毒理学研究表明，miRNA在环境有毒物质诱导的基因活动中起着重要的调控作用。通过综述miRNA与毒物的关系，以及miRNA作为生物标志物、治疗靶点和在环境监测中的应用前景，为miRNA更好地在环境毒理学中发挥作用提供一定的依据。关键词：miRNA环境毒理学环境毒物生物标志物环境监测ABSTRACTMicroRNA(miRNA)isakindofnon-codingsingle-strandedRNAwithalengthofabout20-25bases.Bypairingandbindingwiththe3’non-translationregionofthetargetgene,itcancausethedegradationofthemRNAandinhibitthetranslationprocess,soastodown-regulatetheexpressionofthetargetgene,whichcanparticipateintheregulationofgrowth,development,metabolismandotherlifeactivities.MoreandmoreenvironmentaltoxicologicalstudieshaveshownthatmiRNAsplayanimportantregulatoryroleingeneactivityinducedbyenvironmentaltoxicsubstances.BysummarizingtherelationshipbetweenmiRNAandtoxicants,andtheapplicationprospectofmiRNAasabiomarker,therapeutictargetandinenvironmentalmonitoring,acertainbasisisprovidedformiRNAtoplayabetterroleinenvironmentaltoxicology.Keywords：miRNA;environmentaltoxicology;environmentaltoxicants;biomarker;environmentalmonitoring目录第一章引言 第一章引言随着人们对环境有害物质深入的研究，越来越多的证据表明，环境毒物对人、们的健康有不良影响，并可能会增加患病的风险。近年来，流行病学证据显示，大部分的癌症是由暴露于化学物质所引起的。例如，接触砷可能与膀胱癌有关ADDINEN.CITEADDINEN.CITE.DATA[1]，暴露于双酚A可能与乳腺癌有关ADDINEN.CITEADDINEN.CITE.DATA[2]，金属与包括癌症在内的许多健康问题有关ADDINEN.CITEADDINEN.CITE.DATA[3]。除癌症之外，许多环境毒物也会对人体造成多种多样的损害。例如，镉与各种癌症和心血管疾病有关ADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2012</Year><RecNum>213</RecNum><DisplayText><styleface="boldsuperscript">[4]</style></DisplayText><record><rec-number>213</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585398101">213</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,B.</author><author>Li,Y.</author><author>Shao,C.</author><author>Tan,Y.</author><author>Cai,L.</author></authors></contributors><auth-address>DepartmentofPathophysiology,ProstateDiseasesPreventionandTreatmentResearchCenter,NormanBethuneCollegeofMedicine,JilinUniversity,Changchun,China.</auth-address><titles><title>Cadmiumanditsepigeneticeffects</title><secondary-title>CurrMedChem</secondary-title><alt-title>Currentmedicinalchemistry</alt-title></titles><periodical><full-title>CurrMedChem</full-title><abbr-1>Currentmedicinalchemistry</abbr-1></periodical><alt-periodical><full-title>CurrMedChem</full-title><abbr-1>Currentmedicinalchemistry</abbr-1></alt-periodical><pages>2611-20</pages><volume>19</volume><number>16</number><edition>2012/04/05</edition><keywords><keyword>Animals</keyword><keyword>Cadmium/*toxicity</keyword><keyword>Carcinogens/*toxicity</keyword><keyword>DNAMethylation</keyword><keyword>*Epigenesis,Genetic</keyword><keyword>GeneExpression/drugeffects</keyword><keyword>Humans</keyword><keyword>Metallothionein/metabolism</keyword></keywords><dates><year>2012</year></dates><isbn>0929-8673</isbn><accession-num>22471978</accession-num><urls></urls><electronic-resource-num>10.2174/092986712800492913</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[4]。暴露于空气污染物与多种心肺疾病有关等ADDINEN.CITE<EndNote><Cite><Author>Jardim</Author><Year>2011</Year><RecNum>182</RecNum><DisplayText><styleface="boldsuperscript">[5]</style></DisplayText><record><rec-number>182</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585398009">182</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Jardim,M.J.</author></authors></contributors><auth-address>NationalHealthandEnvironmentalEffectsResearchLaboratory,UnitedStatesEnvironmentalProtectionAgency,ChapelHill,NC,USA.melaniejardim@</auth-address><titles><title>microRNAs:implicationsforairpollutionresearch</title><secondary-title>MutatRes</secondary-title><alt-title>Mutationresearch</alt-title></titles><periodical><full-title>MutatRes</full-title><abbr-1>Mutationresearch</abbr-1></periodical><alt-periodical><full-title>MutatRes</full-title><abbr-1>Mutationresearch</abbr-1></alt-periodical><pages>38-45</pages><volume>717</volume><number>1-2</number><edition>2011/04/26</edition><keywords><keyword>AirPollutants/*toxicity</keyword><keyword>AirPollution/*adverseeffects</keyword><keyword>Animals</keyword><keyword>Epigenesis,Genetic/drugeffects</keyword><keyword>GeneExpressionRegulation/drugeffects</keyword><keyword>Humans</keyword><keyword>MicroRNAs/genetics/*metabolism</keyword><keyword>Research</keyword></keywords><dates><year>2011</year><pub-dates><date>Dec1</date></pub-dates></dates><isbn>0027-5107(Print) 0027-5107</isbn><accession-num>21515291</accession-num><urls></urls><electronic-resource-num>10.1016/j.mrfmmm.2011.03.014</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[5]。MiRNA是由20-25个核苷酸组成的，通过影响转录和翻译过程来控制基因表达的单链核糖核酸分子，可调控多种生理过程，如生长和发育、造血过程、脂肪代谢等ADDINEN.CITEADDINEN.CITE.DATA[6]。miRNA可调控体内的多种生物学过程以及包括癌症在内的很多疾病的发病过程ADDINEN.CITEADDINEN.CITE.DATA[7]。最近的研究表明，miRNA的表达受到某些环境化学物质的影响,包括有机污染物、金属、香烟烟雾等ADDINEN.CITEADDINEN.CITE.DATA[8]。大量研究结果表明，miRNA在毒理基因组学、疾病病因学和毒物效应中起着重要的作用ADDINEN.CITE<EndNote><Cite><Author>Yu</Author><Year>2015</Year><RecNum>277</RecNum><DisplayText><styleface="boldsuperscript">[9]</style></DisplayText><record><rec-number>277</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585474830">277</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yu,H.W.</author><author>Cho,W.C.</author></authors></contributors><auth-address>DepartmentofHealthTechnologyandInformatics,TheHongKongPolytechnicUniversity,Kowloon,HongKong.</auth-address><titles><title>TheroleofmicroRNAsintoxicology</title><secondary-title>ArchToxicol</secondary-title><alt-title>Archivesoftoxicology</alt-title></titles><periodical><full-title>ArchToxicol</full-title><abbr-1>Archivesoftoxicology</abbr-1></periodical><alt-periodical><full-title>ArchToxicol</full-title><abbr-1>Archivesoftoxicology</abbr-1></alt-periodical><pages>319-25</pages><volume>89</volume><number>3</number><edition>2015/01/15</edition><keywords><keyword>Animals</keyword><keyword>Dose-ResponseRelationship,Drug</keyword><keyword>EnvironmentalExposure/*analysis</keyword><keyword>EnvironmentalPollutants/*toxicity</keyword><keyword>GeneExpression/*drugeffects</keyword><keyword>Humans</keyword><keyword>MicroRNAs/*genetics</keyword><keyword>TimeFactors</keyword><keyword>*Toxicogenetics/methods/trends</keyword></keywords><dates><year>2015</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0340-5761</isbn><accession-num>25586887</accession-num><urls></urls><electronic-resource-num>10.1007/s00204-014-1440-2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[9]。因此，研究环境毒物导致miRNA水平的变化对于了解毒物的毒作用机制非常重要，可通过基因组学方法以及生物信息学与传统毒物学工具的结合来识别毒物靶标ADDINEN.CITE<EndNote><Cite><Author>Zarbl</Author><Year>2007</Year><RecNum>217</RecNum><DisplayText><styleface="boldsuperscript">[10]</style></DisplayText><record><rec-number>217</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585398114">217</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zarbl,H.</author></authors></contributors><auth-address>RobertWoodJohnsonMedicalSchool,UniversityofMedicineandDentistryofNewJersey,RutgersUniversity,Piscataway,NJ08854,USA.zarbl@</auth-address><titles><title>Toxicogenomicanalysesofgeneticsusceptibilitytomammaryglandcarcinogenesisinrodents:implicationsforhumanbreastcancer</title><secondary-title>BreastDis</secondary-title><alt-title>Breastdisease</alt-title></titles><periodical><full-title>BreastDis</full-title><abbr-1>Breastdisease</abbr-1></periodical><alt-periodical><full-title>BreastDis</full-title><abbr-1>Breastdisease</abbr-1></alt-periodical><pages>87-105</pages><volume>28</volume><edition>2007/12/07</edition><keywords><keyword>Animals</keyword><keyword>Animals,InbredStrains</keyword><keyword>Animals,OutbredStrains</keyword><keyword>BreastNeoplasms/genetics</keyword><keyword>Female</keyword><keyword>*GeneticPredispositiontoDisease</keyword><keyword>Humans</keyword><keyword>MammaryNeoplasms,Experimental/*genetics</keyword><keyword>Rats</keyword><keyword>*Toxicogenetics</keyword></keywords><dates><year>2007</year></dates><isbn>0888-6008(Print) 0888-6008</isbn><accession-num>18057546</accession-num><urls></urls><electronic-resource-num>10.3233/bd-2007-28109</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[10]。另外，miRNA调节的表观遗传学分析可能为临床管理提供帮助，可作为生物标志物用于疾病的诊断和治疗ADDINEN.CITEADDINEN.CITE.DATA[11]。此外，miRNA在环境监测中也可以发挥一定的作用，实验结果显示的miRNA表达的变化可以作为毒物对环境污染程度的指标，同时也可以评估污染物对人体的损害作用ADDINEN.CITE<EndNote><Cite><Author>黄涵年</Author><Year>2013</Year><RecNum>276</RecNum><DisplayText><styleface="boldsuperscript">[12]</style></DisplayText><record><rec-number>276</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585472928">276</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">黄涵年</style></author><author><styleface="normal"font="default"charset="134"size="100%">郭江峰</style></author></authors></contributors><auth-address><styleface="normal"font="default"charset="134"size="100%">浙江理工大学生物工程研究所</style><styleface="normal"font="default"size="100%">;</style></auth-address><titles><title><styleface="normal"font="default"size="100%">MicroRNA</style><styleface="normal"font="default"charset="134"size="100%">在环境毒理学中的研究进展</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">生命科学</style></secondary-title></titles><periodical><full-title>生命科学</full-title></periodical><pages>1115-1120</pages><volume>25</volume><number>11</number><keywords><keyword>microRNA</keyword><keyword>环境毒理学</keyword><keyword>环境化学物质</keyword><keyword>毒性</keyword><keyword>生物标记物</keyword></keywords><dates><year>2013</year></dates><isbn>1004-0374</isbn><call-num>31-1600/Q</call-num><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[12]。

第二章miRNA的生物发生和功能机制2.1miRNA的生物发生MiRNA是一类由内源基因编码的非编码单链RNA分子，其长度约为20-25nt，由DNA转录而来。首先，在细胞核内RNA聚合酶II或III将miRNA相关基因转录为长达几千nt的初级miRNA（pri-miRNA）。然后，微处理复合物Drosha-DGCR8将pri-miRNA裂解成为具有发卡结构的前体miRNA（pre-miRNA）。下一步Exportin-5-Ran-GTP复合物会将pre-miRNA转运到细胞质中，RNaseDicer酶与双链RNA结合蛋白TRBP作用，将pre-miRNA分解，但此时的miRNA依然是双链结构。最后，miRNA进入AGO2并形成RISC（RNA诱导沉默复合体），它的双链中的一条被保存在RISC复合物中，另一条链则排出复合物外并迅速降解。在这个过程中，有多种机制调控miRNA不同阶段的生物发生ADDINEN.CITEADDINEN.CITE.DATA[8]。图1miRNA的生物合成过程ADDINEN.CITE<EndNote><Cite><Author>Hironori</Author><Year>2019</Year><RecNum>402</RecNum><DisplayText><styleface="boldsuperscript">[13]</style></DisplayText><record><rec-number>402</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1587299585">402</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>MatsuyamaHironori</author><author>SuzukiHiroshiI</author></authors></contributors><auth-address>FujiiMemorialResearchInstitute,OtsukaPharmaceuticalCo.,Ltd.,1-11-1Karasaki,Otsu-shi,Shiga520-0106,Japan.;;DavidH.KochInstituteforIntegrativeCancerResearch,MassachusettsInstituteofTechnology,Cambridge,MA02139,USA.</auth-address><titles><title>SystemsandSyntheticmicroRNABiology:FromBiogenesistoDiseasePathogenesis</title><secondary-title>Internationaljournalofmolecularsciences</secondary-title></titles><periodical><full-title>IntJMolSci</full-title><abbr-1>Internationaljournalofmolecularsciences</abbr-1></periodical><volume>21</volume><number>1</number><keywords><keyword>Argonaute</keyword><keyword>Drosha</keyword><keyword>RNAi</keyword><keyword>Biogenesis</keyword><keyword>Diseasepathogenesis</keyword><keyword>MicroRNA</keyword><keyword>Super-enhancer</keyword><keyword>Syntheticbiology</keyword></keywords><dates><year>2019</year></dates><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[13]2.2miRNA的功能机制miRNA的作用方式主要有三种：（1）翻译抑制，miRNA与靶mRNA3’UTR的6-7个碱基互补结合，从而在翻译水平上抑制靶基因表达ADDINEN.CITEADDINEN.CITE.DATA[14,15]；（2）mRNA的降解，如果miRNA与靶位点完全互补（或者几乎完全互补），那么这些miRNA的结合往往会使其稳定性下降，从而引起靶mRNA的降解ADDINEN.CITEADDINEN.CITE.DATA[16]，通过这种机制作用的miRNA的结合位点通常都在mRNA的编码区或开放阅读框中；（3）转录调控，最近研究发现表明，miRNA可影响靶基因的转录，该过程主要是通过对基因启动子的CpG岛甲基化作用而完成的ADDINEN.CITE<EndNote><Cite><Author>Khraiwesh</Author><Year>2010</Year><RecNum>237</RecNum><DisplayText><styleface="boldsuperscript">[17]</style></DisplayText><record><rec-number>237</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585399802">237</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Khraiwesh,B.</author><author>Arif,M.A.</author><author>Seumel,G.I.</author><author>Ossowski,S.</author><author>Weigel,D.</author><author>Reski,R.</author><author>Frank,W.</author></authors></contributors><auth-address>PlantBiotechnology,FacultyofBiology,UniversityofFreiburg,Schaenzlestrasse1,79104Freiburg,Germany.</auth-address><titles><title>TranscriptionalcontrolofgeneexpressionbymicroRNAs</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>111-22</pages><volume>140</volume><number>1</number><edition>2010/01/21</edition><keywords><keyword>BaseSequence</keyword><keyword>Bryopsida/*genetics/*metabolism</keyword><keyword>DNAMethylation</keyword><keyword>*GeneExpressionRegulation</keyword><keyword>MicroRNAs/genetics/*metabolism</keyword><keyword>MolecularSequenceData</keyword><keyword>PlantProteins/metabolism</keyword><keyword>RNA,Plant/genetics/*metabolism</keyword><keyword>RNA,SmallInterfering</keyword><keyword>Transcription,Genetic</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan8</date></pub-dates></dates><isbn>0092-8674</isbn><accession-num>20085706</accession-num><urls></urls><electronic-resource-num>10.1016/j.cell.2009.12.023</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[17]。

第三章miRNA与有毒物质的关系环境污染物包括化学污染物、物理污染物和生物污染物，其中化学污染物对生物和环境的影响最大。越来越多的环境毒理学研究结果表明，环境污染物的暴露可引起体内miRNA表达水平的变化，从而介导体内相关的生物学过程的调控。图2环境污染物的分类3.1化学因素暴露于某些环境化学物质和职业性毒物可成为包括癌症在内的疾病的危险因素之一。越来越多的证据表明，miRNA参与了外源性化学物质的代谢和活动ADDINEN.CITEADDINEN.CITE.DATA[11]。毒理基因组学的最新发现为基因和化学物质在转录组水平上的相互作用提供了有价值的见解ADDINEN.CITEADDINEN.CITE.DATA[18]。3.1.1有机污染物全氟辛酸（PFOA）是全氟化合物中的一种有机酸，主要用作表面活性剂、乳化剂，是一种致癌物质ADDINEN.CITEADDINEN.CITE.DATA[19]。Wang等人分析了氟化工厂的工人和附近居民中PFOA的浓度与循环miRNA的关系，发现随着血清PFOA浓度的升高，血清中miR-26b和miR-199−3p的水平显著升高，并发现miR-26b和miR-199−3p和PFOA水平之间具有显著相关性ADDINEN.CITEADDINEN.CITE.DATA[20]。MiR-26b通过抑制c-myc通路抑制食管鳞癌细胞增殖，miR-199a-3p通过靶向YAP1抑制细胞增殖和诱导凋亡，抑制人肝癌Jagged1-Notch信号通路ADDINEN.CITEADDINEN.CITE.DATA[21,22]。他们的另一个研究发现，暴露于高浓度PFOA后，循环miRNA的表达谱发生了改变，其中肝脏中miR-28-5p、miR-34a-5p、miR-199a-3p和miR-200c-3p在小鼠暴露PFOA后水平显著增高，在给予20mg/kg/dPFOA的小鼠中，miR-122-5p水平显著增加了391.8倍ADDINEN.CITE<EndNote><Cite><Author>Yan</Author><Year>2014</Year><RecNum>283</RecNum><DisplayText><styleface="boldsuperscript">[23]</style></DisplayText><record><rec-number>283</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585734662">283</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>ShengminYan</author><author>JiansheWang</author><author>WeiZhang</author><author>JiayinDai</author></authors></contributors><auth-address>KeyLaboratoryofAnimalEcologyandConservationBiology,InstituteofZoology,ChineseAcademyofSciences,Beijing100101,PRChina</auth-address><titles><title>CirculatingmicroRNAprofilesalteredinmiceafter28dexposuretoperfluorooctanoicacid</title><secondary-title>ToxicologyLetters</secondary-title></titles><periodical><full-title>ToxicolLett</full-title><abbr-1>Toxicologyletters</abbr-1></periodical><volume>224</volume><number>1</number><keywords><keyword>CirculatingmiRNAs</keyword><keyword>Biomarker</keyword><keyword>Perfluorononanoicacid</keyword><keyword>Hepatotoxicity</keyword></keywords><dates><year>2014</year></dates><isbn>0378-4274</isbn><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[23]。另有研究结果也显示，PFOA暴露会使小鼠肝脏中miR-34a水平显著增加ADDINEN.CITEADDINEN.CITE.DATA[24]。这些实验结果都证明了miRNA参与了PFOA对机体的毒性作用。多氯联苯（PCB）是一种致癌物质，容易储存于脂肪组织，神经系统、生殖功能以及免疫功能都会造成损害。Krauskopf等人的研究表明PCB暴露与miRNA水平变化有关，这些miRNA及其靶基因与癌症相关ADDINEN.CITEADDINEN.CITE.DATA[25]。Wahlang等人将人内皮细胞暴露于PCB，miR-21、miR-31、miR-126、miR-221和miR-222的水平显著提高。mir-21在心脏损伤中被表达水平增高，而miR-126和miR-31具有调节炎症的作用ADDINEN.CITEADDINEN.CITE.DATA[26]。Zhu等人的研究结果表明，在P19细胞向心肌细胞分化的过程中，miRNA可调节PCB对机体的毒性作用，在此过程中，有14个miRNA上调，如mmu-miR-99a、mmu-miR-214*和mmu-miR-345-5p，31个miRNA下调，如mmu-miR-29a、mmu-miR-302c和mmu-miR-302bADDINEN.CITEADDINEN.CITE.DATA[27]。二恶英属于一类卤代芳烃，以其致癌特性而著称ADDINEN.CITEADDINEN.CITE.DATA[28,29]。Ribeiro等人发现，用四氯二苯并-p-二恶英（TCDD）处理人睾丸支持细胞后，78个miRNA表达发生改变ADDINEN.CITEADDINEN.CITE.DATA[30]。Elyakim等发现二恶英可上调在HepG2细胞中的miR-191。体外抑制miR-191可降低细胞增殖和诱导凋亡，并可显著减少肝癌原位移植小鼠模型中的肿瘤ADDINEN.CITEADDINEN.CITE.DATA[31]。许多实验结果显示多环芳烃（PAHs）可导致人类癌症。Jiang等发现miR-106a在人支气管上皮细胞经苯并（a）芘（BaP）治疗后过表达，并与细胞的恶性转化有关ADDINEN.CITEADDINEN.CITE.DATA[32]。当暴露于BaP时，miR-34c水平的升高与p53磷酸化水平一致。miR-34c的过表达可抑制BaP诱导的G1期向S期转化，并抑制cyclinD的上调，而上调miR-34c可阻止BaP诱导的恶性转化ADDINEN.CITEADDINEN.CITE.DATA[33]。双酚A（BPA）是一种典型的内分泌干扰物，会对肝脏和乳房造成基因毒性损伤ADDINEN.CITEADDINEN.CITE.DATA[2]。马等人的研究结果表明，用1和100μmol/L的BPA处理小鼠睾丸间质细胞（TM3），会引起miR-203-3p的表达升高，此miRNA在1000μmol/L的BPA处理时表达水平下降，并推测miR-203-3p表达的变化与TM3的损伤有关ADDINEN.CITEADDINEN.CITE.DATA[34]。Rodosthenous等人发现，将颗粒细胞暴露于20000ng/mL的BPA后，胞内和胞外的miR-27b-3p表达水平都下降，这与BPA对颗粒细胞的毒性作用有关ADDINEN.CITEADDINEN.CITE.DATA[35]。图3有机污染物与miRNA的关系3.1.2香烟烟雾烟草烟雾（CS）是世界上最普遍的致癌物之一，会引起不同的遗传、表观遗传以及miRNA表达的变化ADDINEN.CITEADDINEN.CITE.DATA[36]。miRNAs是与吸烟相关的肺部疾病的潜在生物标志物ADDINEN.CITE<EndNote><Cite><Author>Banerjee</Author><Year>2012</Year><RecNum>165</RecNum><DisplayText><styleface="boldsuperscript">[37]</style></DisplayText><record><rec-number>165</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585397949">165</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Banerjee,A.</author><author>Luettich,K.</author></authors></contributors><auth-address>BritishAmericanTobacco,GroupResearch&Development,Southampton,HampshireSO158TL,UK.anisha_banerjee@</auth-address><titles><title>MicroRNAsaspotentialbiomarkersofsmoking-relateddiseases</title><secondary-title>BiomarkMed</secondary-title><alt-title>Biomarkersinmedicine</alt-title></titles><periodical><full-title>BiomarkMed</full-title><abbr-1>Biomarkersinmedicine</abbr-1></periodical><alt-periodical><full-title>BiomarkMed</full-title><abbr-1>Biomarkersinmedicine</abbr-1></alt-periodical><pages>671-84</pages><volume>6</volume><number>5</number><edition>2012/10/19</edition><keywords><keyword>Animals</keyword><keyword>Disease/*genetics</keyword><keyword>GeneticMarkers/genetics</keyword><keyword>Humans</keyword><keyword>Inflammation/genetics</keyword><keyword>MicroRNAs/*genetics</keyword><keyword>Smoking/*genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1752-0363</isbn><accession-num>23075247</accession-num><urls></urls><electronic-resource-num>10.2217/bmm.12.50</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[37]。Izzotti等人将大鼠暴露于烟草烟雾4周后，肺中126个miRNAs下调，这些miRNAs参与调控与应激反应、细胞增殖及凋亡有关的基因ADDINEN.CITE<EndNote><Cite><Author>Izzotti</Author><Year>2009</Year><RecNum>146</RecNum><DisplayText><styleface="boldsuperscript">[38]</style></DisplayText><record><rec-number>146</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="0">146</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Izzotti,A.</author><author>Calin,G.A.</author><author>Arrigo,P.</author><author>Steele,V.E.</author><author>Croce,C.M.</author><author>DeFlora,S.</author></authors></contributors><auth-address>DepartmentofHealthSciences,UniversityofGenoa,viaA.Pastore1,I-16132Genoa,Italy.</auth-address><titles><title>DownregulationofmicroRNAexpressioninthelungsofratsexposedtocigarettesmoke</title><secondary-title>Fasebj</secondary-title><alt-title>FASEBjournal:officialpublicationoftheFederationofAmericanSocietiesforExperimentalBiology</alt-title></titles><alt-periodical><full-title>FASEBjournal:officialpublicationoftheFederationofAmericanSocietiesforExperimentalBiology</full-title></alt-periodical><pages>806-12</pages><volume>23</volume><number>3</number><edition>2008/10/28</edition><keywords><keyword>Animals</keyword><keyword>Down-Regulation/*drugeffects</keyword><keyword>GeneExpressionProfiling</keyword><keyword>Humans</keyword><keyword>Lung/metabolism</keyword><keyword>LungInjury/etiology/*metabolism</keyword><keyword>MicroRNAs/*metabolism</keyword><keyword>MicroarrayAnalysis</keyword><keyword>Rats</keyword><keyword>Rats,Sprague-Dawley</keyword><keyword>*TobaccoSmokePollution/adverseeffects</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0892-6638(Print) 0892-6638</isbn><accession-num>18952709</accession-num><urls></urls><custom2>PMC2653990</custom2><electronic-resource-num>10.1096/fj.08-121384</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[38]。该研究组还研究了CS暴露对小鼠肺中miRNA表达的影响，发现与大鼠的结果相似，小鼠肺部的miRNA变化主要是下调的ADDINEN.CITE<EndNote><Cite><Author>Izzotti</Author><Year>2009</Year><RecNum>304</RecNum><DisplayText><styleface="boldsuperscript">[39]</style></DisplayText><record><rec-number>304</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585909164">304</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>AlbertoIzzotti</author><author>GeorgeA.Calin</author><author>VernonE.Steele</author><author>CarloM.Croce</author><author>SilvioDeFlora</author></authors></contributors><auth-address>DepartmentofHealthSciencesUniversityofGenoaGenoaItaly;;M.D.AndersonCancerCenterUniversityofTexasHoustonTexasUSA;;NationalCancerInstituteRockvilleMarylandUSA;;ComprehensiveCancerCenterOhioStateUniversityColumbusOhioUSA</auth-address><titles><title>RelationshipsofmicroRNAexpressioninmouselungwithageandexposuretocigarettesmokeandlight</title><secondary-title>TheFASEBJournal</secondary-title></titles><periodical><full-title>TheFASEBJournal</full-title></periodical><volume>23</volume><number>9</number><keywords><keyword>Lungcancer</keyword><keyword>Molecularmechanisms</keyword></keywords><dates><year>2009</year></dates><isbn>0892-6638</isbn><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[39]。此外，他们还发现，miRNA表达的失调与性别和年龄有关，并且具有时间和剂量依赖性ADDINEN.CITEADDINEN.CITE.DATA[40]。Zhong等人的研究证实，hsa-miR-664a-3p在慢性阻塞性肺疾病（COPD）患者中显著上调，其靶基因FHL1下调，且与一秒率（FEV1/FVC%）呈正相关，且hsa-miR-664a-3p和FHL1均可被香烟烟雾提取物调控。生物信息学分析和扩展验证结果提示，hsa-miR-664a-3p到FHL1的调控轴可能在吸烟诱导的COPD中起关键作用ADDINEN.CITEADDINEN.CITE.DATA[41]。Pace等人首次确定了吸烟诱导miR-21表达增加在气道炎症反应放大和肿瘤形成过程中具有关键作用ADDINEN.CITE<EndNote><Cite><Author>Pace</Author><Year>2019</Year><RecNum>303</RecNum><DisplayText><styleface="boldsuperscript">[42]</style></DisplayText><record><rec-number>303</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585821091">303</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>ElisabettaPace</author><author>SerenaDiVincenzo</author><author>EleonoraDiSalvo</author><author>SaraGenovese</author><author>PaolaDino</author><author>ClaudiaSangiorgi</author><author>MariaFerraro</author><author>SebastianoGangemi</author></authors></contributors><auth-address>InstituteofBiomedicineandMolecularImmunology“A.Monroy”(IBIM)NationalResearchCouncilofItaly(CNR)PalermoItaly;;InstituteofBiologicalResourcesandMarineBiotechnology(IRBIM),CNRofMessinaMessinaItaly;;InstituteofAppliedSciences&IntelligentSystems“EduardoCaianiello”(ISASI)‐CNRofMessinaMessinaItaly;;InstituteforMarineandCoastalEnvironment(IAMC‐CNR)NationalResearchCouncilofItaly(CNR)MessinaItaly;;DepartmentofClinicalandExperimentalMedicineSchoolandDivisionofAllergyandClinicalImmunology,UniversityofMessinaMessinaItaly</auth-address><titles><title>MiR‐21upregulationincreasesIL‐8expressionandtumorigenesisprograminairwayepithelialcellsexposedtocigarettesmoke</title><secondary-title>JournalofCellularPhysiology</secondary-title></titles><periodical><full-title>JournalofCellularPhysiology</full-title></periodical><volume>234</volume><number>12</number><keywords><keyword>Bronchialepithelialcells</keyword><keyword>Cigarettesmoke</keyword><keyword>MiRNA</keyword><keyword>Oxidativestress</keyword></keywords><dates><year>2019</year></dates><isbn>0021-9541</isbn><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[42]。3.1.3空气污染物许多流行病学研究表明，暴露于与交通有关的空气污染（TRAP）会导致miR-145-5p和miR-193b-3p的血浆水平下降ADDINEN.CITEADDINEN.CITE.DATA[8]。一项关于柴油尾气暴露的交叉研究结果显示miR-21在暴露后显著下调ADDINEN.CITE<EndNote><Cite><Author>Masatsugu</Author><Year>2013</Year><RecNum>311</RecNum><DisplayText><styleface="boldsuperscript">[43]</style></DisplayText><record><rec-number>311</rec-number><foreign-keys><keyapp="EN"db-id="z05etdzp6sfepue0ztk5daze2axw29ar9ftp"timestamp="1585990668">311</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>YamamotoMasatsugu</author><author>SinghAmrit</author><author>SavaFrancesco</author><