资源预览内容
第1页 / 共73页
第2页 / 共73页
第3页 / 共73页
第4页 / 共73页
第5页 / 共73页
第6页 / 共73页
第7页 / 共73页
第8页 / 共73页
第9页 / 共73页
第10页 / 共73页
亲,该文档总共73页,到这儿已超出免费预览范围,如果喜欢就下载吧!
资源描述
INTRACELLULARRECEPTORS Theintracellular nuclear receptorsuperfamilySteroidhormones thyroidhormones retinoidsandvitaminD Regulationoftranscriptionactivity RegulatorymechanismsvaryHeterodimericreceptors exclusivelynuclear withoutligand represstranscriptionbybindingtotheircognatesitesinDNAHomodimericreceptors mostlycytoplasmic withoutligands hormonebindingleadstonucleartranslocationofreceptorsWithoutligand aggregationofreceptorwithinhibitorproteins egHsp90 SteroidhormonesareoftenrequiredtodimerizewithapartnertoactivategenetranscriptionReceptorsforvitaminD retinoicacidandthyroidhormonebindtoresponsiveelementsasheterodimersSecondcomponentoftheheterodimerisRXRmonomer i e RXR RAR RXR VDR Specificitiesofsomereceptors Intracellularsignalmoleculessmall lipid solublemoleculessuchassteroidhormones retinoids thyroidhormones VitaminD madefromcholesterol Thesemoleculesdiffusethroughplasmaandnuclearmembranesandinteractdirectlywiththetranscriptionfactorstheycontrol 6 LipophilicHormones CirculationinthebloodboundtotransportproteinsDissociationfromcarrierattargetcellsActioninthecell Passthroughthecellmembraneandbindtoanintracellularreceptor eitherinthecytoplasmorthenucleus Hormone receptorcomplexbindstohormoneresponseelementsinDNA Regulategeneexpression 7 SteroidHormones STEROIDHORMONES sexsteroids estrogen progesterone testosterone corticosteroids glucocorticoidsandmineralcorticoids OTHERHORMONESThyroidhormone vitaminD3 andretinoicacidhavedifferentstructureandfunctionbutsharethesamemechanismofactionwiththeothersteroids BIOSYNTHESISOFSTEROIDS Endocrinedisruption InterferenceofxenobioticswithnormalfunctionofhormonalsystemPossibleconsequences Disruptionofhomeostasis reproduction development and orbehavior andotherhormone controlledprocesses Shiftinsexratio defectivesexualdevelopmentLowfecundity fertilityHypo immunity carcinogenesisMalformations Toxicantsinteractwithhormonalsystematdifferentlevels Transport Metabolization Interactionwithreceptors Stimulation Suppression biosynthesisandreleaseofhormones bindingtoplasmatictransportproteins bindingtonuclearhormonalreceptor HR activationofHR dissociationofassociatedheatshockproteins formationofhomodimers bindingoftheactivatedreceptorcomplextospecificDNAmotifs HREs chromatinrearrangementandtranscriptionofestrogen induciblegenes effectsatthecellular tissue organ organism and orpopulationlevel e g modulationofCYP11Aand orCYP19activities e g down regulationofreceptorlevels e g modulationofothernuclearreceptors PPAR RXR RXR TR STEROIDOGENESIS Mechanismsofsteroidhormonessignallingdisruption Nonphysiologicalactivationofhormonereceptor HR BindingtoHRwithoutactivationDecreaseofHRcellularlevelsDisruptionofthe master hormones FSH LH Changesinhormonemetabolism Endocrinedisruptersintheenvironment EDCs PersistentOrganicCompounds POPsandtheirmetabolites steroidhormonesandtheirderivativesfromcontraceptionpillsalkylphenolsorganometallics butyltins pharmaceuticalsPesticides numberofunknowns ESTROGENRECEPTOR ERthemoststudiedtargetofEDCs Estrogens playakeyroleinfemalehormoneregulationandsignallingareresponsibleformetabolic behaviouralandmorphologicchangesoccurringduringstagesofreproductionareinvolvedinthegrowth developmentandhomeostasisofanumberoftissuescontroltheboneformation regulationofhomeostasis cardiovascularsystemandbehaviourregulateproduction transportandconcentrationoftesticularliquidandanabolicactivityofandrogensinmalesSynthesisinovariesDISRUPTION investigatedinaquaticbiota laboratoryorganisms seenotesonEDCs ESTROGENRECEPTORS ER ER subtype ER inbreast ovary brain liver boneandcardiovascularsystem adrenals testisandurogenitaltract ER inkidneys prostateandgastrointestinaltract ER infish Naturalproductsgenisteinnaringenincoumestrolzearalenone EnvironmentalpollutantDDTkeponePCBs OH PCBsPAHsanddioxins IndustrialchemicalsBisphenolANonionicsurfactantsPthalateestersendosulfan PharmaceuticalsEthinylestradiolDiethylstilbestrolgestodenenorgestrel DEHP Environmentalestrogens xenoestrogens exoestrogens adiversegroupofsubstancesthatdonotnecessarilysharestructuralsimilaritytotheprototypicalestrogen 17 estradiol MayactasAGONISTSand orANTAGONISTS Exoestrogens RelativePotenciestobindtoERa REPs Toxicityassessmentnumberofinvivoandinvitromethods Jano ek J Hilscherov K Bl ha L andHoloubek I 2006 Environmentalxenobioticsandnuclearreceptors Interactions effectsandinvitroassessment ToxicologyinVitro20 18 37 Invitroassays INTERACTION BINDING tothereceptorcompetitiveligandbindingassayEffectunknown Activation suppression noeffect Testingtheeffectatcellularlevel interferencewithreceptorbiologicalactivity cellproliferationassayendogenousproteinexpression orenzymeactivity assayreportergeneassay InvitroER mediatedeffectsluciferasereporterassay ER mediatedeffectsluciferasereporterassay 96microwellplatecultivationoftransgeniccelllinesER breastcarcinomaMVLNcellsSIMILARDESIGNFOROTHERRECEPTORS discussedbelow AhR H4IIE luccells AR MDAcells RAR RXR P19cells Celllysis extractionofinducedluciferase Exposure 6 24h standards samples L
网站客服QQ:2055934822
金锄头文库版权所有
经营许可证:蜀ICP备13022795号 | 川公网安备 51140202000112号