多环芳烃暴露致女性生殖毒性及其分子机制
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摘要
多环芳烃(PAHs)是广泛存在的持久性环境毒物,其典型代表苯并[a]芘(BaP)是人类致癌物质,可通过胎盘屏障,最终代谢形成7,8-二氢二羟基-9,10-环氧化苯并[a]芘(BPDE)及其DNA加合物,直接影响女性生殖健康。本文从人群、动物、细胞和分子层次上阐述了PAHs对女性生殖健康的毒害作用和机制。在人群层次上,孕妇暴露于PAHs会导致流产、早产、胚胎停止发育等不良妊娠结局,并影响胎儿的正常生长发育。在动物水平上,BaP不仅会影响雌鼠的生殖健康,也会导致幼鼠生长发育不良。在细胞层次上,BaP或BPDE会抑制滋养层细胞的侵袭、迁移和增殖能力,促进滋养层细胞的凋亡、死亡。表观遗传学因素,例如DNA甲基化、miRNA、lncRNA,会直接参与导致细胞功能障碍的分子过程。目前该研究领域尚处于初级阶段,需要多学科合作,深入研究,为保障女性生殖健康提供科学依据和预防途径。
Polycyclic aromatic hydrocarbons(PAHs) are widespread persistent environmental toxicants. Their typical representative benzo[a]pyrene(BaP), a human carcinogen, can pass through the placental barrier and be finally metabolized into benzo[a]pyrene-7, 8-dihydrodiol-9, 10-epoxide(BPDE) and its DNA adducts, directly affecting female reproductive health. This article reviewed the toxic effects and mechanisms of PAHs on female reproductive health at various levels such as populations, animals, cells, and molecules. At population level, exposure to PAHs in pregnant women could lead to adverse pregnancy outcomes such as abortion, premature delivery, and embryo undevelopment, and also affect the normal growth and development of fetuses. At animal level, BaP could not only affect the reproductive health of female rats, but also cause adverse developmental outcomes in young rats. At cel ular level, BaP or BPDE could inhibit the invasion, migration, and proliferation of human trophoblastic cells, and promote the apoptosis and death of trophoblastic cells. Epigenetic factors, such as DNA methylation, miRNA, and lncRNA, are directly involved in the BaP exposure relevant molecular processes leading to cell dysfunction. At present, this research field is still in its primary stage, and requires multidisciplinary cooperation and in-depth studies, aiming to provide a scientific basis and preventive approach for female reproductive health protection.
Polycyclic aromatic hydrocarbons(PAHs) are widespread persistent environmental toxicants. Their typical representative benzo[a]pyrene(BaP), a human carcinogen, can pass through the placental barrier and be finally metabolized into benzo[a]pyrene-7, 8-dihydrodiol-9, 10-epoxide(BPDE) and its DNA adducts, directly affecting female reproductive health. This article reviewed the toxic effects and mechanisms of PAHs on female reproductive health at various levels such as populations, animals, cells, and molecules. At population level, exposure to PAHs in pregnant women could lead to adverse pregnancy outcomes such as abortion, premature delivery, and embryo undevelopment, and also affect the normal growth and development of fetuses. At animal level, BaP could not only affect the reproductive health of female rats, but also cause adverse developmental outcomes in young rats. At cel ular level, BaP or BPDE could inhibit the invasion, migration, and proliferation of human trophoblastic cells, and promote the apoptosis and death of trophoblastic cells. Epigenetic factors, such as DNA methylation, miRNA, and lncRNA, are directly involved in the BaP exposure relevant molecular processes leading to cell dysfunction. At present, this research field is still in its primary stage, and requires multidisciplinary cooperation and in-depth studies, aiming to provide a scientific basis and preventive approach for female reproductive health protection.
引文
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[24]KHLOOD E B,MIYOSHI H,IWATA H,et al.Effects of concurrent exposure to 3-methylcholanthrene and vitamin A on fetal development in rats[J].Jpn J Vet Res,1999,47(1-2):13-23.
[25]RODRIGUEZ J W,KOHAN M J,KING L C,et al.Detection of DNA adducts in developing CD4+CD8+thymocytes and splenocytes following in utero exposure to benzo[a]pyrene[J].Immunopharmacol Immunotoxicol,2002,24(3):365-381.
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[28]BARR D B,BISHOP A,NEEDHAM L L.Concentrations of xenobiotic chemicals in the maternal-fetal unit[J].Reprod Toxicol,2007,23(3):260-266.
[29]MAKRI A,GOVEIA M,BALBUS J,et al.Children's susceptibility to chemicals:a review by developmental stage[J].J Toxicol Environ Health B Crit Rev,2004,7(6):417-435.
[30]WANG R,WANG W,AO L,et al.Benzo[a]pyrene-7,8-diol-9,10-epoxide suppresses the migration and invasion of human extravillous trophoblast HTR-8/SVneo cells by downregulating MMP2 through inhibition of FAK/SRC/PI3K/AKTpathway[J].Toxicology,2017,386:72-83.
[31]ZHANG L,CONNOR E E,CHEGINI N,et al.Modulation by benzo[a]pyrene of epidermal growth factor receptors,cell proliferation,and secretion of human chorionic gonadotropin in human placental cell lines[J].Biochem Pharmacol,1995,50(8):1171-1180.
[32]GENBACEV O,MCMASTER M T,LAZIC J,et al.Concordant in situ and in vitro data show that maternal cigarette smoking negatively regulates placental cytotrophoblast passage through the cell cycle[J].Reprod Toxicol,2000,14(6):495-506.
[33]DRUKTEINIS J S,MEDRANO T,ABLORDEPPEY E A,et al.Benzo[a]pyrene,but not 2,3,7,8-TCDD,induces G2/Mcell cycle arrest,p21CIP1 and p53 phosphorylation in human choriocarcinoma JEG-3 cells:a distinct signaling pathway[J].Placenta,2005,26(S1):S87-S95.
[34]XIE Y,ABDALLAH M E,AWONUGA A O,et al.Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells[J].Mol Reprod Dev,2010,77(6):533-539.
[35]FADIEL A,EPPERSON B,SHAW M I,et al.Bioinformatic analysis of benzo-α-pyrene-induced damage to the human placental insulin-like growth factor-1 gene[J].Reprod Sci,2013,20(8):917-928.
[36]连立芬.山奈酚抑制BaP致HTR8-SVneo细胞氧化损伤的研究[D].石家庄:河北医科大学,2014.
[37]WANG W,WANG R,ZHANG Q,et al.Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide induces human trophoblast Swan 71 cell dysfunctions due to cell apoptosis through disorder of mitochondrial fission/fusion[J].Environ Pollut,2018,233:820-832.
[38]DONG Q,HOU H,WU J,et al.The Nrf2-ARE pathway is associated with Schisandrin b attenuating benzo(a)pyreneInduced HTR cells damages in vitro[J].Environ Toxicol,2016,31(11):1439-1449.
[39]PERERA F,HERBSTMAN J.Prenatal environmental exposures,epigenetics,and disease[J].Reprod Toxicol,2011,31(3):363-373.
[40]RAZIN A,RIGGS AD.DNA methylation and gene function[J].Science,1980,210(4470):604-610.
[41]HU Y,BLAIR J D,YUEN RKC,et al.Genome-wide DNAmethylation identifies trophoblast invasion-related genes:claudin-4 and Fucosyltransferase IV control mobility via altering matrix metalloproteinase activity[J].Mol Hum Reprod,2015,21(5):452-465.
[42]LAN X,FU L J,HU Z Y,et al.Methylated oligonucleotide(MON)-induced promoter hypermethylation is associated with repression of CDH1 expression and contributes to the migration and invasion of human trophoblast cell lines[J].Reprod Fertil Dev,2017,29(8):1509-1520.
[43]PENG W,CHEN Y,LUO X,et al.DNA methylation-associated repression of MEST/PEG1 expression contributes to the invasion of extravillous trophoblast cells[J].Placenta,2016,46:92-101.
[44]ZHANG G,HUANG H,LIU D,et al.N6-methyladenine DNAmodification in Drosophila[J].Cell,2015,161(4):893-906.
[45]LIU J,ZHU Y,LUO G Z,et al.Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig[J].Nat Commun,2016,7:13052.
[46]GAO X,LI H,WEI J X.MiR-4421 regulates the progression of preeclampsia by regulating CYP11B2[J].Eur Rev Med Pharmacol Sci,2018,22(6):1533-1540.
[47]LIU M,WANG Y,LU H,et al.miR-518b enhances human Trophoblast cell Proliferation Through Targeting Rap1b and activating Ras-MaPK signal[J].Front Endocrinol,2018,9:100.
[48]YANG M,CHEN Y,CHEN L,et al.miR-15b-AGO2 play a critical role in HTR8/SVneo invasion and in a model of angiogenesis defects related to inflammation[J].Placenta,2016,41:62-73.
[49]ZHAO J R,CHENG W W,WANG Y X,et al.Identification of microRNA signature in the progression of gestational trophoblastic disease[J].Cell Death Dis,2018,9(2):94.
[50]TIAN Z,WANG R,ZHANG X,et al.Benzo[a]pyrene-7,8-diol-9,10-epoxide suppresses the migration and invasion of human extravillous trophoblast Swan 71 cells due to the inhibited filopodia formation and down-regulated PI3K/AKT/CDC42/PAK1 pathway mediated by the increased miR-194-3p[J].Toxicol Sci,2018,166(1):25-38.
[51]YANG G,LU X,YUAN L.LncRNA:a link between RNA and cancer[J].Biochim Biophys Acta,2014,1839(11):1097-1109.
[52]XU J,XIA Y,ZHANG H,et al.Overexpression of long noncoding RNA H19 promotes invasion and autophagy via the PI3K/AKT/mTOR pathways in trophoblast cells[J].Biomed Pharmacother,2018,101:691-697.
[53]ZOU Y,LI Q,XU Y,et al.Promotion of trophoblast invasion by lncRNA MVIH through inducing Jun-B[J].J Cell Mol Med,2018,22(2):1214-1223.
[54]ZUCKERWISE L C,LU L,MEN Y,et al.161:H19 lncRNAalters trophoblast cell migration and invasion through TGF-βsignaling in placentas with fetal growth restriction[J].Am JObstet Gynecol,2016,214(1):S103-S104.
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[2]LALA P K,NANDI P.Mechanisms of trophoblast migration,endometrial angiogenesis in preeclampsia:the role of decorin[J].Cell Adh Migr,2016,10(1-2):111-125.
[3]KADYROV M,SCHMITZ C,BLACK S,et al.Pre-eclampsia and maternal anaemia display reduced apoptosis and opposite invasive phenotypes of extravillous trophoblast[J].Placenta,2003,24(5):540-548.
[4]BALL E,BULMER J N,AYIS S,et al.Late sporadic miscarriage is associated with abnormalities in spiral artery transformation and trophoblast invasion[J].J Pathol,2006,208(4):535-542.
[5]ANDRIJONO A,HEFFEN W L.Study of apoptosis induction of hydatidiform mole trophoblastic cell by the administration of retinoic acid[J].Indones J Obstet Gynecol,2008,32(2):99-104.
[6]LASH G E,OTUN H A,INNES B A,et al.Regulation of extravillous trophoblast invasion by uterine natural killer cells is dependent on gestational age[J].Hum Reprod,2010,25(5):1137-1145.
[7]WORMLEY D D,RAMESH A,HOOD D B.Environmental contaminant-mixture effects on CNS development,plasticity,and behavior[J].Toxicol Appl Pharmacol,2004,197(1):49-65.
[8]LEE B M,SHIM G A.Dietary exposure estimation of benzo[a]pyrene and cancer risk assessment[J].J Toxicol Environ Health A,2007,70(15-16):1391-1394.
[9]SLAGA T J,BRACKEN W J,GLEASON G,et al.Marked differences in the skin tumor-initiating activities of the optical enantiomers of the diastereomeric benzo(a)pyrene 7,8-diol-9,10-epoxides[J].Cancer Res,1979,39(1):67-71.
[10]LING H,SAYER J M,PLOSKY B S,et al.Crystal structure of a benzo[a]pyrene diol epoxide adduct in a ternary complex with a DNA polymerase[J].Proc Natl Acad Sci USA,2004,101(8):2265-2269.
[11]CHEPELEV N L,MOFFAT I D,BOWERS W J,et al.Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment[J].Mutat Res Rev Mutat Res,2015,764:64-89.
[12]RAMESH A,INYANG F,HOOD D B,et al.Metabolism,bioavailability,and toxicokinetics of Benzo(α)pyrene in F-344 rats following oral administration[J].Exp Toxicol Pathol,2001,53(4):275-290.
[13]KELMAN B J,SPRINGER D L.Movements of benzo[a]pyrene across the hemochorial placenta of the guinea pig[J].Proc Soc Exp Biol Med,1982,169(1):58-62.
[14]RICE J M,WARD J M.Age dependence of susceptibility to carcinogenesis in the nervous system[J].Ann N Y Acad Sci,1982,381(1):274-289.
[15]ZENZES M T.Smoking and reproduction:gene damage to human gametes and embryos[J].Hum Reprod Update,2000,6(2):122-131.
[16]SOBINOFF A P,PYE V,NIXON B,et al.Jumping the gun:smoking constituent BaP causes premature primordial follicle activation and impairs oocyte fusibility through oxidative stress[J].Toxicol Appl Pharmacol,2012,260(1):70-80.
[17]WU J,HOU H,RITZ B,et al.Exposure to polycyclic aromatic hydrocarbons and missed abortion in early pregnancy in a Chinese population[J].Sci Total Environ,2010,408(11):2312-2318.
[18]SANYAL M K,MERCAN D,BELANGER K,et al.DNA adducts in human placenta exposed to ambient environment and passive cigarette smoke during pregnancy[J].Birth Defects Res A Clin Mol Teratol,2007,79(4):289-294.
[19]VASSILEV Z P,ROBSON M G,KLOTZ J B.Associations of polycyclic organic matter in outdoor air with decreased birth weight:a pilot cross-sectional analysis[J].J Toxicol Environ Health A,2001,64(8):595-605.
[20]DUARTE-SALLES T,MENDEZ M A,MELTZER H M,et al.Dietary benzo(a)pyrene intake during pregnancy and birth weight:associations modified by vitamin C intakes in the Norwegian Mother and Child Cohort Study(MoBa)[J].Environ Int,2013,60:217-223.
[21]WILHELM M,GHOSH J K,SU J,et al.Traffic-related air toxics and preterm birth:a population-based case-control study in Los Angeles County,California[J].Environ Health,2011,10:89.
[22]DETMAR J,RABAGLINO T,TANIUCHI Y,et al.Embryonic loss due to exposure to polycyclic aromatic hydrocarbons is mediated by Bax[J].Apoptosis,2006,11(8):1413-1425.
[23]ARCHIBONG AE,INYANG F,RAMESH A,et al.Alteration of pregnancy related hormones and fetal survival in F-344rats exposed by inhalation to benzo(a)pyrene[J].Reprod Toxicol,2002,16(6):801-808.
[24]KHLOOD E B,MIYOSHI H,IWATA H,et al.Effects of concurrent exposure to 3-methylcholanthrene and vitamin A on fetal development in rats[J].Jpn J Vet Res,1999,47(1-2):13-23.
[25]RODRIGUEZ J W,KOHAN M J,KING L C,et al.Detection of DNA adducts in developing CD4+CD8+thymocytes and splenocytes following in utero exposure to benzo[a]pyrene[J].Immunopharmacol Immunotoxicol,2002,24(3):365-381.
[26]YU Z,LOEHR C V,FISCHER K A,et al.In utero exposure of mice to dibenzo[a,l]pyrene produces lymphoma in the offspring:role of the aryl hydrocarbon receptor[J].Cancer Res,2006,66(2):755-762.
[27]段利.苯并[a]芘诱导新生幼鼠Glu和GABA神经递质释放及传导障碍的机制研究[D].重庆:重庆医科大学,2014.
[28]BARR D B,BISHOP A,NEEDHAM L L.Concentrations of xenobiotic chemicals in the maternal-fetal unit[J].Reprod Toxicol,2007,23(3):260-266.
[29]MAKRI A,GOVEIA M,BALBUS J,et al.Children's susceptibility to chemicals:a review by developmental stage[J].J Toxicol Environ Health B Crit Rev,2004,7(6):417-435.
[30]WANG R,WANG W,AO L,et al.Benzo[a]pyrene-7,8-diol-9,10-epoxide suppresses the migration and invasion of human extravillous trophoblast HTR-8/SVneo cells by downregulating MMP2 through inhibition of FAK/SRC/PI3K/AKTpathway[J].Toxicology,2017,386:72-83.
[31]ZHANG L,CONNOR E E,CHEGINI N,et al.Modulation by benzo[a]pyrene of epidermal growth factor receptors,cell proliferation,and secretion of human chorionic gonadotropin in human placental cell lines[J].Biochem Pharmacol,1995,50(8):1171-1180.
[32]GENBACEV O,MCMASTER M T,LAZIC J,et al.Concordant in situ and in vitro data show that maternal cigarette smoking negatively regulates placental cytotrophoblast passage through the cell cycle[J].Reprod Toxicol,2000,14(6):495-506.
[33]DRUKTEINIS J S,MEDRANO T,ABLORDEPPEY E A,et al.Benzo[a]pyrene,but not 2,3,7,8-TCDD,induces G2/Mcell cycle arrest,p21CIP1 and p53 phosphorylation in human choriocarcinoma JEG-3 cells:a distinct signaling pathway[J].Placenta,2005,26(S1):S87-S95.
[34]XIE Y,ABDALLAH M E,AWONUGA A O,et al.Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells[J].Mol Reprod Dev,2010,77(6):533-539.
[35]FADIEL A,EPPERSON B,SHAW M I,et al.Bioinformatic analysis of benzo-α-pyrene-induced damage to the human placental insulin-like growth factor-1 gene[J].Reprod Sci,2013,20(8):917-928.
[36]连立芬.山奈酚抑制BaP致HTR8-SVneo细胞氧化损伤的研究[D].石家庄:河北医科大学,2014.
[37]WANG W,WANG R,ZHANG Q,et al.Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide induces human trophoblast Swan 71 cell dysfunctions due to cell apoptosis through disorder of mitochondrial fission/fusion[J].Environ Pollut,2018,233:820-832.
[38]DONG Q,HOU H,WU J,et al.The Nrf2-ARE pathway is associated with Schisandrin b attenuating benzo(a)pyreneInduced HTR cells damages in vitro[J].Environ Toxicol,2016,31(11):1439-1449.
[39]PERERA F,HERBSTMAN J.Prenatal environmental exposures,epigenetics,and disease[J].Reprod Toxicol,2011,31(3):363-373.
[40]RAZIN A,RIGGS AD.DNA methylation and gene function[J].Science,1980,210(4470):604-610.
[41]HU Y,BLAIR J D,YUEN RKC,et al.Genome-wide DNAmethylation identifies trophoblast invasion-related genes:claudin-4 and Fucosyltransferase IV control mobility via altering matrix metalloproteinase activity[J].Mol Hum Reprod,2015,21(5):452-465.
[42]LAN X,FU L J,HU Z Y,et al.Methylated oligonucleotide(MON)-induced promoter hypermethylation is associated with repression of CDH1 expression and contributes to the migration and invasion of human trophoblast cell lines[J].Reprod Fertil Dev,2017,29(8):1509-1520.
[43]PENG W,CHEN Y,LUO X,et al.DNA methylation-associated repression of MEST/PEG1 expression contributes to the invasion of extravillous trophoblast cells[J].Placenta,2016,46:92-101.
[44]ZHANG G,HUANG H,LIU D,et al.N6-methyladenine DNAmodification in Drosophila[J].Cell,2015,161(4):893-906.
[45]LIU J,ZHU Y,LUO G Z,et al.Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig[J].Nat Commun,2016,7:13052.
[46]GAO X,LI H,WEI J X.MiR-4421 regulates the progression of preeclampsia by regulating CYP11B2[J].Eur Rev Med Pharmacol Sci,2018,22(6):1533-1540.
[47]LIU M,WANG Y,LU H,et al.miR-518b enhances human Trophoblast cell Proliferation Through Targeting Rap1b and activating Ras-MaPK signal[J].Front Endocrinol,2018,9:100.
[48]YANG M,CHEN Y,CHEN L,et al.miR-15b-AGO2 play a critical role in HTR8/SVneo invasion and in a model of angiogenesis defects related to inflammation[J].Placenta,2016,41:62-73.
[49]ZHAO J R,CHENG W W,WANG Y X,et al.Identification of microRNA signature in the progression of gestational trophoblastic disease[J].Cell Death Dis,2018,9(2):94.
[50]TIAN Z,WANG R,ZHANG X,et al.Benzo[a]pyrene-7,8-diol-9,10-epoxide suppresses the migration and invasion of human extravillous trophoblast Swan 71 cells due to the inhibited filopodia formation and down-regulated PI3K/AKT/CDC42/PAK1 pathway mediated by the increased miR-194-3p[J].Toxicol Sci,2018,166(1):25-38.
[51]YANG G,LU X,YUAN L.LncRNA:a link between RNA and cancer[J].Biochim Biophys Acta,2014,1839(11):1097-1109.
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