Estrogenic endocrine disruptors Molecular mechanisms of action原版完整詳細(xì)

ContentslistsavailableatScienceDirectEnvironmentInternationaljournalhomepage:/locate/envintEnvironmentInternational83(2015)11–40ContentslistsavailableatScienceDirectEnvironmentInternationaljournalhomepage:/locate/envintReviewErecnornedsutr:MlurehnssoftonRyoitiKiyamaa,?,YukoWada-KiyamabaBiomedicalResearchInstitute,NationalInstituteofAdvancedIndustrialScienceandTechnology(AIST),1-1-1Higashi,Tsukuba,Ibaraki305-8566,JapanbDepartmentofPhysiology,NipponMedicalSchool,Bunkyo-ku,Tokyo113-8602,Japanarticle infoArticlehistory:eevd6Dcmer214eevdinrvsdfrm26ay05Accepted27May2015Availableonline11June2015Keywords:EstrogenactionMolecularmechanismTechonologySgaloiiyphay

abstractAcmeesvesmayfmehn40ergncceiasiligetoeiceornedsuosispoiedeetonesadtecmlxndpfndiatfergnai.Frt,ergnchmasaecerzdbysrcueaselashiralcin,uaeadefcs.Scn,etoeicsgaigiseaiedbythemolecularmechanismbasedonthereceptors,signalingpathways,crosstalk/bypassingandautocrine/paracrine/homeostaticnetworksinvolvedinthesignaling.Third,evaluationofestrogenactionisdiscussedbyfuignheehlisadrclsoftesasfrassigergncy.Uesaighemluarmhnmsofetoenainisirnttoaesheatnfeoiedrposadilbeuedfrikmanagementbasedonpathway-basedtoxicitytesting.?2015ElsevierLtd.Allrightsreserved.Contentsnrcin 2srgncceils 2Srcuebsdceoiainofereicceias 3hnlcetgns 3Nnpelcergns 3hmalaisfrerenain 8ucinbsdceoiainfetoeicceias 8Foodsupplements 18eties 8hraooialetoes 2lties 222oelrmhimsofergncsgaig 2Receptors 24Ncereeos 4Membranereceptors 25Othermembranereceptors 25elfnisadsgaigahas 525acoeeis 6Cellgrowthandproliferation 26Differentiation/development 26In?ammation 26Signalingnetworks 26Crosstalk/bypassing 27uornpaieinlng 7Hmsaiceoks 7*Correspondingauthor.E-mailaddress:kiyama.r@aist.go.jp(R.Kiyama).2015ElsevierLtd.Allrightsreserved.PAGE14PAGE14R.Kiyama,Y.Wada-Kiyama/EnvironmentInternational83(2015)11–40R.Kiyama,Y.Wada-Kiyama/EnvironmentInternational83(2015)11–R.Kiyama,Y.Wada-Kiyama/EnvironmentInternational83(2015)11–40PAGE13vlainofergnain 7sasfrdeigerenain 8Ligand-bindingassay 28Reporter-geneassay 28Yeasttwo-hybridassay 29Tasiinasy 9Proteinassay 29Cellassay 29Animaltest 30Signalingpathwayanalysis 30Pathway-basedrisk30ocuinadftrepopcs 1cnlgets 1References 31Estrogenisafemalehormonethatplaysaroleinmenstrualandestrousreproductivecycles.Theroleofestrogenisthuscomplexincludesinvolvementinthephysiologyofreproductiveorgansandsynthesis,behavior(e.g.,lordosisbehavior)anddiseases(e.g.,cancerandneurodegenerative/cardiovasculardiseases)(DerooandKorach,2006;GilliesandMcArthur,2010).Whilethreemajorestrogens,estrone,estradiolandestriol,areknown,thereareanumberofestro-genicchemicalsofnaturalandindustrialorigins,asmostlycharacter-izedbycomparingthemwiththemajorestrogens.Furthermore,estrogenicchemicalsarethosethatarenotonlydirectlyresponsibleforactivatingorinhibitingestrogenaction,butalsothoseindirectlymuangtsain;h,avryfcmcshudbecnrdtonradisato.Etgncceiasaehscndedasatpefmotntcecsaigasanedcnedsutr,hchisndasnegnsanthtnfshtepun,-lease,transport,metabolism,binding,actionoreliminationofnatural

andtheof(Kavlocketal.,ungrsachrcaaztnfernccmcl,eudttteanmerfceiashebnetdtoet-genic.Theybyaofassaysandedbydifferentcriteriatojudgethattheyareestrogenic.Furthermore,tirmcaimsfainsemtobeqtecmlct.Asefiedto?ndacomprehensivelistofestrogenicchemicalsinliteratures,weexaminedpotentiallyestrogenicchemicalsonebyoneto?ndwhyhyeetdtoetnc.EstrogenicTemchnimofesrgnicsinlngattecluarlvlissu-inFig.1(seealsoandZhu,2014;Kiyamaetal.,2014).secnlntkscnectiednonauaradx-alarts.Teeicpha,hchnlsactnfpathway,whichrapidlytransducessignalsmediatedbymembrane-boundestrogenreceptors(ERs)and/IntracellularNetwork ExtracellularNetworkGenomicPathway Non-genomicPathway Autocrine/ParacrineSignalingEstrogenEstrogenEstrogenHormone/GF/CytokineMembraneEROtherReceptorCrosstalkBypassingiilig Proteins ProteinSignaling-pathwayAnalysis(S)YeastTwo-hybridAssay(Y)EstrogenPolIICo-regulatorNuclearERTranscriptionProteinFunctionERETargetGeneProteinAssay(P)CellAssay(C)TranscriptionAssay(T)Ligand-bindingAssay(L)AnimalTest(A)Reporter-geneAssay(R)Fg..Sglngphy,coakndaornprci/oesaicsgaignwrsofetgncceias.orotherreceptorsthroughcrosstalkand/orbypassing,belongtotheformer,whilethepathwaysofautocrineand/orparacrinesignaling,

inassaysystems,whichwerereportedforthechemicalssummarizedbelow.whichinvolveotherhormones,growthfactorsandcytokines,belong tothelatter.Thegenomicpathway,ortheclassicalpathway,isinitiatedbythebindingofchemicals(orligands)withthenuclearERs,ERαandERβ,andtheligand-boundERsactastranscriptionfactorstoup-regulateordown-regulatethetranscriptionoftargetgenesorsgnsnvees,ntasitonmcnycningNApolymeraseIIandco-regulatorsoftranscription,suchasRIP-140,p300/CBPandSRC-1(Parker,1998;MoggsandOrphanides,2001).Onheohrhn,sennstohemmrneorcpamcee-torsandstimulatessignalingproteinsthroughthenon-genomicpath-way,whichoccursrapidly,sometimesjustminutesafterstimulation,andinvolvesanumberofsignalingpathways.Thistypeofsignalingstartsbythebindingofligandstomembrane/cytoplasmicERs,andseveralERs,includingG-protein-coupledestrogenreceptor1(GPER),havebeenidenti?ed.However,severalnewreceptorsandvariantsofknownreceptorswereidenti?ed,suchasER-XandER-α36(seecn,nanghecmyfncsnn.n-typesfatcneadraaiesnln,adtsclsindfettissuesorlocationsarealsoinvolvedintheextracellularnetworks(seeSection3).Oneofthereasonswhyanumberofnewsignalingpathwayswereidenti?edrecentlyistheavailabilityofavarietyofnewtechnologiesoectsonchis.;hyradtenvlcaa-escsfceias,schspacadmacfcstcedyulators(SERMs)detectedbycellassayandnewestrogen-responsivegenesdetectedbyDNAmicroarrayassay(seeSection4).Thus,estro-genicchemicalsincludechemicalsortheirmetabolitesthathavenotnytncfcsbtasoaerncoe,adtytadcelularofchemicalsTounderstandtheactionofestrogenicchemicalsatthemolecularlevel,especiallyatthecellsignalinglevel,wecategorizedestrogenicchemicalsbasedonseveralcharacteristics.First,theestrogenicchemicalscategorizedbystructurearesummarizedinTable1.Anumberofestrogenicchemicalsarephenolics,andphenolicestrogensincludesimplephenols,phenolicacids/phenolicalde-hydes,acetophenones,tyrosinederivatives,phenylaceticacids,hydroxycinnamicacids,phenylpropenes,coumarins/isocoumarins/chromones,naphthoquinones,bisphenols,benzophenones,stil-benes/stilbenoids,anthraquinones,chalcones/chalconoids,?a-vones/?avonoids,lignans/neolignans,diarylheptanoids,?avolansandhydroxylatedpolycyclicaromatichydrocarbons(PAHs).Onthetrhn,cmclstutahnlcngcnasoswsgncatvt,wihncueanlns,croae,idls,mtlosrgn,per?uorinatedcompounds,phthalates,PAHsandterpenes/terpenoidshesrncratsgncaiycnbetcedya-ousmethods(seeSection4),theyhavelimitationsintheirsensitivity(e.g.,concentration-dependentactivity),distinguishingagonists/antagonistsandspeci?city(e.g.,cell/tissuetypesandsignalingpath-ways).Thus,thesameestrogenicchemicalscanshowcontradictoryresults(listedinTables1and2),suchasdifferencesinestrogenicandanti-estrogenic,agonisticandantagonistic,andligand/pathway-dependentand-independentresponses,differencesinincreaseddcadeeepeinrnyacait,aslasifrnes

Thelistofchemicalsshowingcontradictoryresultsinestrogenicity.Phlorizin(Wangetal.,2010),quercetin/naringenin(Marinoetal.,2012),naringin(Guoetal.,2011),epigallocatechin3-gallate(Kuruto-Niwaetal.,2000),glabridin(Tamiretal.,2000),enterodiol/enterolactone(Fengetal.,2008),3-methylcholanthrene(Swedenborgetal.,2008),abieticacid/botulin/β-sitosterolMlaeneta.,19,mhxclreareetl,20),bfnhi/emhin(Branderetal.,2012),raloxifene(Leeetal.,2011),tamoxifen(Jiangetal.,1995;Obreroetal.,2002),PCBs(Zhangetal.,2014a)andBDE47(Karpetaetal.,2014).Biphasicactivity,whereestrogenicactivitywasobservedatlowcnetainsadat-srecatiyathhcnetain,hsenetdrhttesWn,20).Etatn,alnn,smaesDAsnhssnMF7clsat150,btihbtsitathhrcnnan.nocneshnoealceRa-tivatorthroughitsinteractionwithER(Penttinenetal.,2007).SERMs(agonistorantagonist)effectsondifferentorcells,theeffectsarebasedonthemodula-tionofreceptorfunctionsbydifferentialinteractionsbetweentheandbeofhormone-responsivecancerandosteoporosis(Maximovetal.,2013).aretoatasinthecaseofraloxifene(Leeetal.,2011)andtamoxifen(Jiangetal.,1995;Obreroetal.,2002),whereER-dependentand-independentmodula-ofPhenolicPhenolicestrogensarecategorizedbythenumberofskeletalcarbons(Table1;VermerrisandNicholson,2008).Whilephenolitselfisnotestrogenic,simplemodi?cations,suchaschlorination(pentachlorophenol),nitration(nitrophenol)andalkylationofphenolicacidandphenolicaldehyde,suchasgallicacid,parabens,ezeds,sncaidadeccd,swtnc.ecomplexphenolicsandtheirderivatives,includingphenylethanoids(acteosideandmartynoside),tyrosinederivatives(thyroidhormone),phenylaceticacid,naphthoquinones,bisphenols,benzophenonesandphenylpropanoids,alsoshowestrogenicity.Phenylpropanoidsareagroupofchemicalssynthesizedbyplantsfromphenylalanine,andincludehydroxycinnamicacids(caffeicacidandferulicacid),phenylpropenes(anetholeandeugenol),coumarinsandrelatedchemicals(auraptene,bergapten,daphnetin,esculetin,icariinandanthocyanidines,iso?avones,iso?avanes,iso?avenes,coumestans,toisbyteprseceofhdrxyatdpenlcrigs(,9-enz]atracneandA;Table2)orbytheofaprnrnna.estrogensAnumberofnon-phenolicshavebeenidenti?edasestrogenic,he,sn,pne/trenisTble).Anlnsarearmaicamnsandusdasprecursorstopolyurethane,syntheticdyesandother.efsnredl,anilineswereexpectedtoshowestrogenicity(Hamblenetal.,2003).seapfsdf,nd-drogenatomsinpolyhedralforms,andhaveadvantagesfordesigningnewERagonists/antagonistsandSERMsduetotheiruniquethree-andofatoaSomeindolesshowestrogenicitywithouthavingaphenolichydroxylTable1Ergncceiasctgrzdbysrcue.Estrogenicchemical Signalingpathway ReferencePhenolicbSimplephenol(C6)(C6–C4–C6–C12) ER TollefsenandNilsen,2008(L)3,4-Dichlorophenol,4-tert-octylphenol,pentachlorophenol(agonist)

ER Lietal.,2010b(R)4-Nitrophenol(estrogenic) ER Lietal.,2006(A)4-Nitrophenol,3-methyl-4-nitrophenol,4-Nitro-3-phenylphenol(estrogenic)

ER Tanedaetal.,2004(R)p-n-Nonylphenol,p-n-octylphenol ER/NF-κB/NO/in?ammation Yoshitakeetal.,2008Phenolicacid/phenolicaldehyde(C6–C1)Octylgallate ERα/PI3K/Akt/Alzheimer'sdisease Zhangetal.,2013(S)Parabens(methyl-,ethyl-,propyl-,isopropyl-,butyl-,isobutylparabens)

ERα/PR/pituitarycancer Voetal.,2011(S)Phenoxybenzaldehyde(estrogenic) ER McCarthyetal.,2006(R)Syringicacid,ellagicacid ER/NO/endothelialcells Simoncinietal.,2011Acetophenone(C6–C2)2,2-Dimethoxy-2-phenyl-acetophenone(estrogenic) ER Wadaetal.,2004Phenylethane/phenylethanoid(C6–C2)Acteoside,martynoside(estrogenic) ER Papoutsietal.,2006Tyrosinederivative(C6–C2)Thyroidhormone TR/Integrinreceptor/ERα/proliferation(crosstalk)

Mengetal.,2011(S)Phenylaceticacid(C6–C2)Phenylacetate(anti-estrogenic) ER/CDKN1A/breastcancer Liuetal.,2007Hydroxycinnamicacid(C6–C3)Caffeicacidphenethylester ERβ Jungetal.,2010(A,C,L,P,R)Caffeicacidphenethylester(SERM) ERα,ERβ/ERK/Akt/apoptosis Tolbaetal.,2013(S)Ferulicacid(estrogenic) HER2/ERα/ERK/Akt/CyclinD1/proliferation Changetal.,2006(S)Rhodoeosein(p-coumaricacid)(estrogenic) ERβ Brennanetal.,2013Phenylpropene(C6–C3)Anethole(estrogenic),eugenol(anti-estrogenic) ER Howesetal.,2002(C)Eugenol(antagonist) ER Anitaetal.,2012Coumarin/isocoumarin/chromone(C6–C3)Aryl-coumarindimer(estrogenic) ER Nishimuraetal.,2000(C,L)Auraptene(anti-estrogenic) ER deMedinaetal.,2010(L,R,T)Bergapten(anti-estrogenic) TGF-β/SMAD4/ERα/proliferation Pannoetal.,2012(S)Daphnetin,esculetin(anti-estrogenic) ER/proliferation Jiménez-Orozcoetal.,(A,C,P,T)Icariin ER/ERK/JNK/osteoblasts Songetal.,2013(S)Icariin TGF-β/Smad/ERK/GPER/nephropathy Lietal.,2013a(S)Icariin,icaritin(estrogenic) GPER/EGFR/MAPK/proliferation Maetal.,2014(S)Isocoumarins(estrogenic) ERβ DeAngelisetal.,2005(L,R)SP500263(asyntheticSERM) ER/Osteoclastogenesis KungSutherlandetal.,2003(S)Umbelliferone ER Kirkiacharianetal.,2004Naphthoquinone(C6–C4)Alkannin(shikonin) ERα/Nrf2/NQO1/DNAdamage Yaoetal.,2010(S)Juglone ER/Pin1/ERK/LC-3/autophagy Namgoongetal.,2010(S)Juglone,lawsone,menadione,1,4-naphthaquinone,plumbagin(antagonist)

ER Thasnietal.,2013(C,L,T)Menadione(vitaminK3)(anti-estrogenic) ER Jungetal.,2004(L,R,Y)Menatetrenone(vitaminK2) ERα/vitaminK/leukemia Nishiguchietal.,1999(S)Plumbagin ERα(46kDa)/BRCA1/apoptosis Thasnietal.,2008(S)Plumbagin NF-κB/Bcl-2/apoptosis Ahmadetal.,2008Bisphenol(C6–C1–C6)BisphenolA GPER/ERK/c-Fos/transcription Dongetal.,2011(S)Bisphenols(A,B,F)(estrogenic) ER Hashimotoetal.,2001(C,L,Y)BisphenolA,4,4′-dihydroxybiphenyl,4-hydroxybiphenyl,tetrabromobisphenolA,tetrachlorobisphenolA(estrogenic)

ERα Olsenetal.,2003(C,L,P)ChlorinatedbisphenolAs(estrogenic) ER Huetal.,2002(L,Benzophenone(C6–C1–C6)2,4-Dihydroxybenzophenone,2,2′,4,4′-tetrahydroxybenzophenone(agonist/antagonist)Stilbene/stilbenoid(C6–C2–C6)

ER Ohtaetal.,2012(A)Piceatannol(estrogenic/anti-estrogenic)ER/MAPK/ERK/Akt/PR/proliferationVoetal.,2010(S)Piceid,pterostilbene,resveratrolERβ/oxidativestressRobbandStuart,2014(S)Pinosylvin,isorhapontigenin,isorhapontin(estrogenic)ERMellanenetal.,1996(A,C)ResveratrolERα,ERβ/MAPK/atheroprotectionKlingeetal.,2005(S)ResveratrolER/NO/cGMP/differentiationSongetal.,2006(S)ResveratrolGPER/cAMP/PKC/KchannelsDongetal.,2013b(S)ResveratrolERα/SIRT1/cAMP/in?ammationNwachukwuetal.,2014(S)VitisinB(aresveratroltetramer)ER/PDGF/celladhesionOngetal.,2011(S)Anthraquinone(C6–C2–C6)Aloe-emodin,emodin(anti-estrogenic)ERα/proliferationHuangetal.,2013(S)Anthraquinone,benzanthrone(estrogenic)ERαMachalaetal.,2001(R)R.Kiyama,Y.Wada-Kiyama/EnvironmentInternational83(2015)11–40R.Kiyama,Y.Wada-Kiyama/EnvironmentInternational83(2015)11–40PAGE17Table1(continued)PAGE18R.Kiyama,Y.Wada-Kiyama/EnvironmentInternational83(2015)11PAGE18R.Kiyama,Y.Wada-Kiyama/EnvironmentInternational83(2015)11–40Table1(continued)Estrogenicchemical Signalingpathway ReferenceAnthraquinone(C6–C2–C6)2,6-Dihydroxyanthraquinone(estrogenic) ER Matsudaetal.,2001(C)Emodin ERα/PI3K/Akt/JNK/Alzheimer'sdisease Liuetal.,2010a(S)2-Hydroxyanthraquinone(estrogenic) ER Kuriharaetal.,2005(Y)Mitoxantrone(estrogenic) ERα Odaetal.,2013Chalcone/chalconoid(C6–C3–C6)Candidachalcone ER Hegazyetal.,2011(L)Chalcone(anti-estrogenic) ERα/MAPK/JNK/MCF-7cells Collins-Burowetal.,2012(S)2-Hydroxychalcone,4-hydroxychalcone,4′-hydroxychalcone(estrogenic)

ER Kohnoetal.,2005(R)Isoliquiritigenin(estrogenic/anti-estrogenic) ERα/cellgrowth Maggiolinietal.,2002(S)LicochalconeA(estrogenic) ER Ra?etal.,2000(C)Nothofagin,(isovitexin;a?avone)(estrogenic) ER Shimamuraetal.,2006(P)Phloretin(estrogenic) ER Iseetal.,2005(T)Phloretin Non-genomicER/LXR/fattyliver Hanetal.,2014(S)Phlorizin(estrogenic/anti-estrogenic) ER Wangetal.,2010(C,Flavone/?avonoid(C6–C3–C6)Anthoxanthin(?avoneand?avonol)Apigenin(anti-estrogenic) ERβ Maketal.,2006(C,R,T)Apigenin ER/TNF-α/NO/Akt/vasculardiseases Palmierietal.,2014(S)Apigenin,luteolin ER Innocentietal.,2007(R)Baicalein ER/NF-?B/NO/TNF-α/in?ammation Fanetal.,2013(S)Baicalein,daidzein ER/neuroprotection Choietal.,2013(S)Baicalein,quercetin(anti-estrogenic) ER/IRS-1/ROS/ERK/JNK/proliferation Linetal.,2007(S)Fisetin,galangin,luteolin(estrogenic) ER Resendeetal.,2013(C,R)Isorhamnetin,kaempferol,quercetin(estrogenic) ER OhandChung,2004(C,L,T)Kaempferide(anti-estrogenic) ER Collins-Burowetal.,2000(L)Kaempferol(estrogenic) ERα Guoetal.,2012(R,T)Luteolin(anti-estrogenic) ERα/IGF-1/PI3K/Akt/proliferation Wangetal.,2012(S)Myricetin(estrogenic) ERα etP,R,T)β-Naphtho?avone AhR/PI3K/Akt/MAPK/ERK/ERα/carcinogenesis Wangetal.,2014(S)Oroxylin-A ER/TNF-α/IL-1β/IL-6/NO/in?ammation Wangetal.,2013c(S)Quercetin ERβ/cyclinD1/caspase-3/apoptosis Bulzomietal.,2012b(S)Quercetin,naringenin(differentialeffects) ER Marinoetal.,2012(review)Quercetin,naringenin(anti-estrogenic) Non-genomicERα/ERK/proliferation Virgilietal.,2004(S)Wogonin ER/PARP/Bax/apoptosis Chungetal.,2008FlavanoneChrysin(estrogenic) ERα Berthieretal.,2007(C,T)Hesperetin TrkAreceptor/MAPK/PKA/PKC/ERα/neuroprotection HwangetHYPERLI