基于循环血miRNAs评估空间铁离子辐射暴露的新方法
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摘要
目的寻找具有作为空间铁离子辐射生物标志物潜力的循环血microRNAs(miRNAs)分子,并探索基于这些分子的辐射暴露风险评估新方法。方法利用重离子加速器产生的高能铁离子束对小鼠进行全身照射,通过定制miRNA PCR array芯片检测了13种辐射相关的循环血miRNAs表达水平,筛选出4种miRNAs作为候选标志物进行验证。利用实时定量PCR技术检测了候选miRNAs在铁离子束照射下的剂量效应和时间效应关系。此外,利用多元线性回归的方法建立了结合4种辐射敏感miRNAs预测辐射暴露程度的数学模型,并通过受试者工作特征曲线对模型准确性进行了评估。结果铁离子束照射后,循环血中miR-21a、miR-200b表达水平上调,miR-574、miR-342表达水平下调,且具有较强的剂量效应关系,在6～72h内,其表达差异能稳定维持。结合4种候选miRNAs建立的多元线性回归方程在预测不同程度的辐射暴露方面具有很好的特异性和敏感性。结论循环血辐射敏感miRNAs具有作为空间铁离子辐射生物标志物的潜力,而基于这些循环血miRNAs的多元线性回归模型可应用于评估空间辐射暴露风险。
Objective To identify serum miRNAs which may serve as potential biomarkers for iron ion radiation in space and then explore a new method based on these miRNAs for the assessment of radiation exposure risks.Methods Kunming mice were total-body exposed to high energy iron ions generated by heavy ions accelerator.Expression levels of 13 serum miRNAs in relation with radiation were detected by custom miRNA PCR array,and four miRNAs were selected for following validation.Candidate miRNAs were validated for their dose-dependent and time-dependent effect after exposure to iron ion radiation.Moreover,a mathematical model based on these miRNAs was built by multiple linear regression and was verified by receiver operating characteristic curves.Results The expression levels of miR-21 a,miR-200 bincreased and miR-342,miR-574 decreased with a significant dose-dependent after exposure to iron ion irradiation.Its differential expression kept in a stable threshold value within6～72 h.A multiple linear regression model combining four candidate miRNAs showed remarkable specificity and sensitivity in predicting the exposure degree.Conclusion The radiosensitive circulating miRNAs have the potential of being used as biomarkers for iron ion radiation in space.Multiple linear regression model based on these circulating miRNAs are capable of assessing the exposure risks of space radiation.
Objective To identify serum miRNAs which may serve as potential biomarkers for iron ion radiation in space and then explore a new method based on these miRNAs for the assessment of radiation exposure risks.Methods Kunming mice were total-body exposed to high energy iron ions generated by heavy ions accelerator.Expression levels of 13 serum miRNAs in relation with radiation were detected by custom miRNA PCR array,and four miRNAs were selected for following validation.Candidate miRNAs were validated for their dose-dependent and time-dependent effect after exposure to iron ion radiation.Moreover,a mathematical model based on these miRNAs was built by multiple linear regression and was verified by receiver operating characteristic curves.Results The expression levels of miR-21 a,miR-200 bincreased and miR-342,miR-574 decreased with a significant dose-dependent after exposure to iron ion irradiation.Its differential expression kept in a stable threshold value within6～72 h.A multiple linear regression model combining four candidate miRNAs showed remarkable specificity and sensitivity in predicting the exposure degree.Conclusion The radiosensitive circulating miRNAs have the potential of being used as biomarkers for iron ion radiation in space.Multiple linear regression model based on these circulating miRNAs are capable of assessing the exposure risks of space radiation.
引文
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[3]Caffrey JA,Hamby DM.A review of instruments and methods for dosimetry in space[J].Advances in Space Research,2011,47(4):563-574.
[4]George K,Durante M,Wu H,et al.Chromosome aberrations in the blood lymphocytes of astronauts after space flight[J].Radiat Res,2001,156(6):731-738.
[5]Goans RE,Holloway EC,Berger ME,et al.Early dose assessment following severe radiation accidents[J].Health Phys,1997,72(4):513-538.
[6]Hu S,Smirnova OA,Cucinotta FA.A biomathematical model of lymphopoiesis following severe radiation accidents--potential use for dose assessment[J].Health Phys,2012,102(4):425-436.
[7]Bartel DP.MicroRNAs:Genomics,biogenesis,mechanism,and function[J].Cell,2004,116(2):281-297.
[8]Blondal T,Nielsen SJ,Baker A,et al.Assessing sample and miRNA profile quality in serum and plasma or other biofluids[J].Methods,2013,59(1):S1-S6.
[9]Bertoia ML,Bertrand KA,Sawyer SJ,et al.Reproducibility of circulating microRNAs in stored plasma samples[J].PloS One,2015,10(8):e0136665
[10]Balzano F,Deiana M,Dei Giudici S,et al.miRNA stability in Frozen plasma samples[J].Molecules,2015,20(10):19030-19040.
[11]Cortez MA,Bueso-Ramos C,Ferdin J,et al.MicroRNAs in body fluids-the mix of hormones and biomarkers[J].Nat Rev Clin Oncol,2011,8(8):467-477.
[12]潘益凯,李程飞,高原,等.模拟失重48h后血管内皮细胞长链非编码RNA的差异表达分析[J].航天医学与医学工程,2019,32(1):80-83.Pan YK,Li CF,Gao Y,et al.Differential expression analysis of long non-coding RNAs in human vascular endothelial cells after 48hsimulated weightlessness[J].Space Medicine&Medical Engineering,2019,32(1):80-83.
[13]Armand-Labit V,Meyer N,Casanova A,et al.Identification of a circulating microrna profile as a biomarker of metastatic cutaneous melanoma[J].Acta Derm-Venereol,2016,96(1):29-34.
[14]Avigad S,Verly IRN,Lebel A,et al.miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia[J].Gene Chromosome Canc,2016,55(4):328-339.
[15]Do Canto LM,Marian C,Willey S,et al.MicroRNA analysis of breast ductal fluid in breast cancer patients[J].Int J Oncol,2016,48(5):2071-2078.
[16]Jacob NK,Cooley JV,Yee TN,et al.Identification of sensitive serum microRNA Biomarkers for radiation biodosimetry[J].PloS One,2013,8(2):e57603.
[17]危文俊,华君瑞,林素兰,等.循环血miR-21在空间辐射监测中的应用潜力[J].载人航天,2016,22(6):714-719.Wei WJ,Hua JR,Lin SL,et al.Study on potential of circulating miR-21as a dosimeter for space radiation[J].Manned Spaceflight,2016,22(6):714-719.
[18]Templin T,Amundson SA,Brenner DJ,et al.Whole mouse blood microRNA as biomarkers for exposure to gamma-rays and Fe-56ions[J].Int J Radiat Biol,2011,87(7):653-662.
[19]Cui WC,Ma JF,Wang YL,et al.Plasma miRNA as biomarkers for assessment of total-body radiation exposure dosimetry[J].PloS One,2011,6(8):e22988
[20]Friedman RC,Farh KK,Burge CB,et al.Most mammalian mRNAs are conserved targets of microRNAs[J].Genome Res,2009,19(1):92-105.
[21]Jain A,Das S.Synteny and comparative analysis of miR-NA retention,conservation,and structure across Brassicaceae reveals lineage-and sub-genome-specific changes[J].Funct Integr Genomic,2016,16(3):253-268.