基于羊水代谢组学策略评价妊娠禁忌中药的安全性
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摘要
妊娠期用药的安全性是当前亟需解决的问题,羊水作为一种生物体液,能同时反映胎儿和母体的健康状况,被用作临床条件下有力的诊断学工具。该文总结了近年来羊水代谢组学在胎儿预测中的相关研究,并以课题组前期研究为例,讨论了羊水代谢组学应用于妊娠期中药安全性评价的优势与可行性。我们认为羊水代谢组学作为一种创新工具,具有更高的敏感性和相关性,在中药的毒性筛查及机制研究方面有广泛的应用前景。
Medication in pregnancy is inevitable,and the public urgently needs accurate toxicological data to evaluate the safety of traditional Chinese medicine.Amniotic fluid can reflect the health status of the fetus as well as the mother at the same time.The change of amniotic fluid metabolism pattern is related to the pathogenesis during pregnancy.In this paper,the related researches on amniotic fluid metabolomics in fetal prediction were summarized and we took an our previous study as an example to discuss the advantages and feasibility of amniotic fluid metabolomics in the safety evaluation of Chinese medicine during pregnancy.We believe that the metabolomics of amniotic fluid,as an innovative tool with higher sensitivity and relevance,will have broad application prospects in toxicity screening and mechanism research of Chinese medicine.
Medication in pregnancy is inevitable,and the public urgently needs accurate toxicological data to evaluate the safety of traditional Chinese medicine.Amniotic fluid can reflect the health status of the fetus as well as the mother at the same time.The change of amniotic fluid metabolism pattern is related to the pathogenesis during pregnancy.In this paper,the related researches on amniotic fluid metabolomics in fetal prediction were summarized and we took an our previous study as an example to discuss the advantages and feasibility of amniotic fluid metabolomics in the safety evaluation of Chinese medicine during pregnancy.We believe that the metabolomics of amniotic fluid,as an innovative tool with higher sensitivity and relevance,will have broad application prospects in toxicity screening and mechanism research of Chinese medicine.
引文
[1]WANG CC,LI L,TANG LY,et al.Safety evaluation of commonly used Chinese herbal medicines during pregnancy in mice[J].Hum Reprod,2012,27(8):2448-2456.
[2]ANGELL M,KASSIRER JP.Alternative medicine-the risks of untested and unregulated remedies[J].N Engl J Med,1998,339(12):839-41.
[3]BUJAK R,STRUCK-LEWICKA W,MARKUSZEWSKI MJ,et al.Metabolomics for laboratory diagnostics[J].J Pharm Biomed Anal,2015,113:108-120.
[4]DU LN,XIE T,XU JY,et al.A metabolomics approach to studying the effects of Jinxin oral liquid on RSV-infected mice using UPLC/LTQ-Orbitrap mass spectrometry[J].J Ethnopharmacol,2015,174:25-36.
[5]WISHART DS.Emerging applications of metabolomics in drug discovery and precision medicine[J].Nat Rev Drug Discov,2016,15(7):473-484.
[6]SHI J,CAO B,WANG XW,et al.Metabolomics and its application to the evaluation of the efficacy and toxicity of traditional Chinese herb medicines[J].J Chromatogr B Analyt Technol Biomed Life Sci,2016,1026:204-216.
[7]PALMAS F,FATTUONI C,NOTO A,et al.The choice of amniotic fluid in metabolomics for the monitoring of fetus health[J].Expert Rev Mol Diagn,2016,16(4):473-486.
[8]FENG JH,YAN YE,LIANG G,et al.Maternal and fetal metabonomic alterations in prenatal nicotine exposure-induced rat intrauterine growth retardation[J].Mol Cell Endocrinol,2014,394(1/2):59-69.
[9]XIE HH,XU JY,XIE T,et al.Effects of Pinellia ternata(Thunb.)Berit.on the metabolomic profiles of placenta and amniotic fluid in pregnant rats[J].J Ethnopharmacol,2016,183:38-45.
[10]游云,黄芳华,韩玲.《中华人民共和国药典》收录孕妇禁用和慎用中药材生殖毒性研究进展[J].中国药理学与毒理学杂志,2018,32(5):364-370.
[11]TANG LY,LI L,BORCHERT A,et al.Molecular studies of the congenital malformation induced by Largehead Atractylodes Rhizome,the most commonly used Chinese medicine for threatened miscarriage[J].Mol Hum Reprod,2012,18(12):585-592.
[12]SORENSEN D,SACKETT A,URBAN DJ,et al.A new mammalian model system for thalidomide teratogenesis:Monodelphis domestica[J].Reprod Toxicol,2017,70:126-132.
[13]VARGESSON N.Thalidomide-induced teratogenesis:History and mechanisms[J].Birth Defects Res C Embryo Today,2015,105(2):140-156.
[14]HAN JY,YAN Y,LIANG AH,et al.Thought and method of reproductive toxicity research in traditional Chinese medicine[J].Acta Pharm Sin,2014,49(11):1498-1503.
[15]LIANG B,LI L,TANG LY,et al.Safety of Chinese herbal medicines during pregnancy[J].J Appl Toxicol,2015,35(5):447-458.
[16]MADSEN R,LUNDSTEDT T,TRYGG J.Chemometrics in metabolomics:a review in human disease diagnosis[J].Anal Chim Acta,2010,659(1/2):23-33.
[17]NICHOLSON JK,LINDON JC.Systems biology:Metabonomics[J].Nature,2008,455(7216):1054-1056.
[18]GIL AM,DUARTE D.Biofluid metabolomics in preterm birth research[J].Reprod Sci,2018,25(7):967-977.
[19]DUNN WB,BROADHURST D,BEGLEY P,et al.Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry[J].Nat Protoc,2011,6(7):1060-1083.
[20]NICHOLSON JK,CONNELLY J,LINDON JC,et al.Metabonomics:aplatform for studying drug toxicity and gene function[J].Nat Rev Drug Discov,2002,1(2):153-161.
[21]WANT EJ,WILSON ID,GIKA H,et al.Global metabolic profiling procedures for urine using UPLC-MS[J].Nat Protoc,2010,5(6):1005-1018.
[22]COURANT F,ANTIGNAC JP,MONTEAU F,et al.Metabolomics as a potential new approach for investigating human reproductive disorders[J].J Proteome Res,2013,12(6):2914-2920.
[23]AMORINI AM,GIORLANDINO C,LONGO S,et al.Metabolic profile of amniotic fluid as a biochemical tool to screen for inborn errors of metabolism and fetal anomalies[J].Mol Cell Biochem,2012,359(1/2):205-216.
[24]VIRGILIOU C,SAMPSONIDIS I,GIKA HG,et al.Development and validation of a HILIC-MS/MS multitargeted method for metabolomics applications[J].Electrophoresis,2015,36(18):2215-2225.
[25]FANOS V,ATZORI L,MAKARENKO K,et al.Metabolomics application in maternal-fetal medicine[J].Biomed Res Int,2013,2013:720514.
[26]PERSSON M,WINKVIST A,MOGREN I.Lifestyle and health status in a sample of Swedish women four years after pregnancy:a comparison of women with a history of normal pregnancy and women with a history of gestational diabetes mellitus[J].BMC Pregnancy Childbirth,2015,15:57.
[27]ORCZYK-PAWILOWICZ M,JAWIEN E,DEJA S,et al.Metabolomics of human amniotic fluid and maternal plasma during normal pregnancy[J].PLoS ONE,2016,11(4):e0152740.
[28]O'NEILL K,ALEXANDER J,AZUMA R,et al.Gestational diabetes alters the metabolomic profile in 2nd trimester amniotic fluid in a sex-specific manner[J].Int J Mol Sci,2018,19(9):2696.
[29]IADAROLA P,FUMAGALLI M,BARDONI AM,et al.Recent applications of CE-and HPLC-MS in the analysis of human fluids[J].Electrophoresis,2016,37(1):212-230.
[30]HUANG J,MO J,ZHAO G,et al.Application of the amniotic fluid metabolome to the study of fetal malformations,using down syndrome as a specific model[J].Mol Med Rep,2017,16(5):7405-7415.
[31]VIRGILIOU C,GIKA HG,WITTING M,et al.Amniotic fluid and maternal serum metabolic signatures in the second trimester associated with preterm delivery[J].J Proteome Res,2017,16(2):898-910.
[32]BARALDI E,GIORDANO G,STOCCHERO M,et al.Untargeted metabolomic analysis of amniotic fluid in the prediction of preterm delivery and bronchopulmonary dysplasia[J].PLoS ONE,2016,11(10):e0164211.
[33]CHAFER-PERICAS C,STEFANOVIC V,SANCHEZ-ILLA-NA A,et al.Mass spectrometric detection of biomarkers for early assessment of intraamniotic fluid infection[J].Data Brief,2015,5:1026-1030.
[34]MADDIPATI KR,ROMERO R,CHAIWORAPONGSA T,et al.Clinical chorioamnionitis at term:the amniotic fluid fatty acyl lipidome[J].J Lipid Res,2016,57(10):1906-1916.
[35]MADDIPATI KR,ROMERO R,CHAIWORAPONGSA T,et al.Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals up-regulation of leukotriene B4[J].FASEB J,2016,30(10):3296-3307.
[36]BROWN AG,TULINA NM,BARILA GO,et al.Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid,fetal and neonatal brain in the mouse[J].PLoSONE,2017,12(10):e0186656.
[37]KIM SK,ROMERO R,SAVASAN ZA,et al.Endoglin in amniotic fluid as a risk factor for the subsequent development of bronchopulmonary dysplasia[J].Am J Reprod Immunol,2013,69(2):105-123.
[38]GERVASI MT,ROMERO R,BRACALENTE G,et al.Midtrimester amniotic fluid concentrations of interleukin-6and interferon-gamma-inducible protein-10:evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early(<32weeks)and late(>32weeks)preterm delivery[J].J Perinat Med,2012,40(4):329-343.
[39]REVELLO R,ALCAIDE MJ,DUDZIK D,et al.Differential amniotic fluid cytokine profile in women with chorioamnionitis with and without funisitis[J].J Matern Fetal Neonatal Med,2016,29(13):2161-2165.
[40]FATTUONI C,PALMAS F,NOTO A,et al.Primary HC-MV infection in pregnancy from classic data towards metabolomics:An exploratory analysis[J].Clin Chim Acta,2016,460:23-32.
[41]FISCHER ST,LI LN,LI S,et al.Low-level maternal exposure to nicotine associates with significant metabolic perturbations in second-trimester amniotic fluid[J].Environ Int,2017,107:227-234.
[42]HUANG PC,TSAI CH,LIANG WY,et al.Early phthalates exposure in pregnant women is associated with alteration of thyroid hormones[J].PLoS ONE,2016,11(7):e0159398.
[43]LOUGHHEAD AM,FISHER AD,NEWPORT DJ,et al.Antidepressants in amniotic fluid:Another route of fetal exposure[J].Am J Psychiatry,2006,163(1):145-147.
[44]DI VENERE M,VIGLIO S,CAGNONE M,et al.Advances in the analysis of"less-conventional"human body fluids:An overview of the CE-and HPLC-MS applications in the years2015-2017[J].Electrophoresis,2018,39(1):160-178.
[45]ANTUNES NDE J,CAVALLI RC,MARQUES MP,et al.Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients[J].Br J Clin Pharmacol,2015,79(4):605-616.
[46]BURRAI L,NIEDDU M,CARTA A,et al.Validated LC-MS-MS method for multiresidual analysis of 13illicit phenethylamines in amniotic fluid[J].J Anal Toxicol,2016,40(3):194-200.
[47]SHAN JJ,XIE T,XU J,et al.Metabolomics of the amniotic fluid:Is it a feasible approach to evaluate the safety of Chinese medicine during pregnancy?[J].J Appl Toxicol,2019,39(1):163-171.
[2]ANGELL M,KASSIRER JP.Alternative medicine-the risks of untested and unregulated remedies[J].N Engl J Med,1998,339(12):839-41.
[3]BUJAK R,STRUCK-LEWICKA W,MARKUSZEWSKI MJ,et al.Metabolomics for laboratory diagnostics[J].J Pharm Biomed Anal,2015,113:108-120.
[4]DU LN,XIE T,XU JY,et al.A metabolomics approach to studying the effects of Jinxin oral liquid on RSV-infected mice using UPLC/LTQ-Orbitrap mass spectrometry[J].J Ethnopharmacol,2015,174:25-36.
[5]WISHART DS.Emerging applications of metabolomics in drug discovery and precision medicine[J].Nat Rev Drug Discov,2016,15(7):473-484.
[6]SHI J,CAO B,WANG XW,et al.Metabolomics and its application to the evaluation of the efficacy and toxicity of traditional Chinese herb medicines[J].J Chromatogr B Analyt Technol Biomed Life Sci,2016,1026:204-216.
[7]PALMAS F,FATTUONI C,NOTO A,et al.The choice of amniotic fluid in metabolomics for the monitoring of fetus health[J].Expert Rev Mol Diagn,2016,16(4):473-486.
[8]FENG JH,YAN YE,LIANG G,et al.Maternal and fetal metabonomic alterations in prenatal nicotine exposure-induced rat intrauterine growth retardation[J].Mol Cell Endocrinol,2014,394(1/2):59-69.
[9]XIE HH,XU JY,XIE T,et al.Effects of Pinellia ternata(Thunb.)Berit.on the metabolomic profiles of placenta and amniotic fluid in pregnant rats[J].J Ethnopharmacol,2016,183:38-45.
[10]游云,黄芳华,韩玲.《中华人民共和国药典》收录孕妇禁用和慎用中药材生殖毒性研究进展[J].中国药理学与毒理学杂志,2018,32(5):364-370.
[11]TANG LY,LI L,BORCHERT A,et al.Molecular studies of the congenital malformation induced by Largehead Atractylodes Rhizome,the most commonly used Chinese medicine for threatened miscarriage[J].Mol Hum Reprod,2012,18(12):585-592.
[12]SORENSEN D,SACKETT A,URBAN DJ,et al.A new mammalian model system for thalidomide teratogenesis:Monodelphis domestica[J].Reprod Toxicol,2017,70:126-132.
[13]VARGESSON N.Thalidomide-induced teratogenesis:History and mechanisms[J].Birth Defects Res C Embryo Today,2015,105(2):140-156.
[14]HAN JY,YAN Y,LIANG AH,et al.Thought and method of reproductive toxicity research in traditional Chinese medicine[J].Acta Pharm Sin,2014,49(11):1498-1503.
[15]LIANG B,LI L,TANG LY,et al.Safety of Chinese herbal medicines during pregnancy[J].J Appl Toxicol,2015,35(5):447-458.
[16]MADSEN R,LUNDSTEDT T,TRYGG J.Chemometrics in metabolomics:a review in human disease diagnosis[J].Anal Chim Acta,2010,659(1/2):23-33.
[17]NICHOLSON JK,LINDON JC.Systems biology:Metabonomics[J].Nature,2008,455(7216):1054-1056.
[18]GIL AM,DUARTE D.Biofluid metabolomics in preterm birth research[J].Reprod Sci,2018,25(7):967-977.
[19]DUNN WB,BROADHURST D,BEGLEY P,et al.Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry[J].Nat Protoc,2011,6(7):1060-1083.
[20]NICHOLSON JK,CONNELLY J,LINDON JC,et al.Metabonomics:aplatform for studying drug toxicity and gene function[J].Nat Rev Drug Discov,2002,1(2):153-161.
[21]WANT EJ,WILSON ID,GIKA H,et al.Global metabolic profiling procedures for urine using UPLC-MS[J].Nat Protoc,2010,5(6):1005-1018.
[22]COURANT F,ANTIGNAC JP,MONTEAU F,et al.Metabolomics as a potential new approach for investigating human reproductive disorders[J].J Proteome Res,2013,12(6):2914-2920.
[23]AMORINI AM,GIORLANDINO C,LONGO S,et al.Metabolic profile of amniotic fluid as a biochemical tool to screen for inborn errors of metabolism and fetal anomalies[J].Mol Cell Biochem,2012,359(1/2):205-216.
[24]VIRGILIOU C,SAMPSONIDIS I,GIKA HG,et al.Development and validation of a HILIC-MS/MS multitargeted method for metabolomics applications[J].Electrophoresis,2015,36(18):2215-2225.
[25]FANOS V,ATZORI L,MAKARENKO K,et al.Metabolomics application in maternal-fetal medicine[J].Biomed Res Int,2013,2013:720514.
[26]PERSSON M,WINKVIST A,MOGREN I.Lifestyle and health status in a sample of Swedish women four years after pregnancy:a comparison of women with a history of normal pregnancy and women with a history of gestational diabetes mellitus[J].BMC Pregnancy Childbirth,2015,15:57.
[27]ORCZYK-PAWILOWICZ M,JAWIEN E,DEJA S,et al.Metabolomics of human amniotic fluid and maternal plasma during normal pregnancy[J].PLoS ONE,2016,11(4):e0152740.
[28]O'NEILL K,ALEXANDER J,AZUMA R,et al.Gestational diabetes alters the metabolomic profile in 2nd trimester amniotic fluid in a sex-specific manner[J].Int J Mol Sci,2018,19(9):2696.
[29]IADAROLA P,FUMAGALLI M,BARDONI AM,et al.Recent applications of CE-and HPLC-MS in the analysis of human fluids[J].Electrophoresis,2016,37(1):212-230.
[30]HUANG J,MO J,ZHAO G,et al.Application of the amniotic fluid metabolome to the study of fetal malformations,using down syndrome as a specific model[J].Mol Med Rep,2017,16(5):7405-7415.
[31]VIRGILIOU C,GIKA HG,WITTING M,et al.Amniotic fluid and maternal serum metabolic signatures in the second trimester associated with preterm delivery[J].J Proteome Res,2017,16(2):898-910.
[32]BARALDI E,GIORDANO G,STOCCHERO M,et al.Untargeted metabolomic analysis of amniotic fluid in the prediction of preterm delivery and bronchopulmonary dysplasia[J].PLoS ONE,2016,11(10):e0164211.
[33]CHAFER-PERICAS C,STEFANOVIC V,SANCHEZ-ILLA-NA A,et al.Mass spectrometric detection of biomarkers for early assessment of intraamniotic fluid infection[J].Data Brief,2015,5:1026-1030.
[34]MADDIPATI KR,ROMERO R,CHAIWORAPONGSA T,et al.Clinical chorioamnionitis at term:the amniotic fluid fatty acyl lipidome[J].J Lipid Res,2016,57(10):1906-1916.
[35]MADDIPATI KR,ROMERO R,CHAIWORAPONGSA T,et al.Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals up-regulation of leukotriene B4[J].FASEB J,2016,30(10):3296-3307.
[36]BROWN AG,TULINA NM,BARILA GO,et al.Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid,fetal and neonatal brain in the mouse[J].PLoSONE,2017,12(10):e0186656.
[37]KIM SK,ROMERO R,SAVASAN ZA,et al.Endoglin in amniotic fluid as a risk factor for the subsequent development of bronchopulmonary dysplasia[J].Am J Reprod Immunol,2013,69(2):105-123.
[38]GERVASI MT,ROMERO R,BRACALENTE G,et al.Midtrimester amniotic fluid concentrations of interleukin-6and interferon-gamma-inducible protein-10:evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early(<32weeks)and late(>32weeks)preterm delivery[J].J Perinat Med,2012,40(4):329-343.
[39]REVELLO R,ALCAIDE MJ,DUDZIK D,et al.Differential amniotic fluid cytokine profile in women with chorioamnionitis with and without funisitis[J].J Matern Fetal Neonatal Med,2016,29(13):2161-2165.
[40]FATTUONI C,PALMAS F,NOTO A,et al.Primary HC-MV infection in pregnancy from classic data towards metabolomics:An exploratory analysis[J].Clin Chim Acta,2016,460:23-32.
[41]FISCHER ST,LI LN,LI S,et al.Low-level maternal exposure to nicotine associates with significant metabolic perturbations in second-trimester amniotic fluid[J].Environ Int,2017,107:227-234.
[42]HUANG PC,TSAI CH,LIANG WY,et al.Early phthalates exposure in pregnant women is associated with alteration of thyroid hormones[J].PLoS ONE,2016,11(7):e0159398.
[43]LOUGHHEAD AM,FISHER AD,NEWPORT DJ,et al.Antidepressants in amniotic fluid:Another route of fetal exposure[J].Am J Psychiatry,2006,163(1):145-147.
[44]DI VENERE M,VIGLIO S,CAGNONE M,et al.Advances in the analysis of"less-conventional"human body fluids:An overview of the CE-and HPLC-MS applications in the years2015-2017[J].Electrophoresis,2018,39(1):160-178.
[45]ANTUNES NDE J,CAVALLI RC,MARQUES MP,et al.Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients[J].Br J Clin Pharmacol,2015,79(4):605-616.
[46]BURRAI L,NIEDDU M,CARTA A,et al.Validated LC-MS-MS method for multiresidual analysis of 13illicit phenethylamines in amniotic fluid[J].J Anal Toxicol,2016,40(3):194-200.
[47]SHAN JJ,XIE T,XU J,et al.Metabolomics of the amniotic fluid:Is it a feasible approach to evaluate the safety of Chinese medicine during pregnancy?[J].J Appl Toxicol,2019,39(1):163-171.