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1、INTRACELLULARRECEPTORS Theintracellular nuclear receptorsuperfamilySteroidhormones thyroidhormones retinoidsandvitaminD Intracellularreceptor HYDROPHOBIC Non polarmoleculesGasesSteroids Regulationoftranscriptionactivity RegulatorymechanismsvaryHeterodimericreceptors exclusivelynuclear withoutligand
2、represstranscriptionbybindingtotheircognatesitesinDNAHomodimericreceptors mostlycytoplasmic withoutligands hormonebindingleadstonucleartranslocationofreceptorsWithoutligand aggregationofreceptorwithinhibitorproteins egHsp90 Steroidhormonesareoftenrequiredtodimerizewithapartnertoactivategenetranscrip
3、tionReceptorsforvitaminD retinoicacidandthyroidhormonebindtoresponsiveelementsasheterodimersSecondcomponentoftheheterodimerisRXRmonomer i e RXR RAR RXR VDR Specificitiesofsomereceptors Intracellularsignalmoleculessmall lipid solublemoleculessuchassteroidhormones retinoids thyroidhormones VitaminD ma
4、defromcholesterol Thesemoleculesdiffusethroughplasmaandnuclearmembranesandinteractdirectlywiththetranscriptionfactorstheycontrol 6 LipophilicHormones CirculationinthebloodboundtotransportproteinsDissociationfromcarrierattargetcellsActioninthecell Passthroughthecellmembraneandbindtoanintracellularrec
5、eptor eitherinthecytoplasmorthenucleus Hormone receptorcomplexbindstohormoneresponseelementsinDNA Regulategeneexpression 7 SteroidHormones STEROIDHORMONES sexsteroids estrogen progesterone testosterone corticosteroids glucocorticoidsandmineralcorticoids OTHERHORMONESThyroidhormone vitaminD3 andretin
6、oicacidhavedifferentstructureandfunctionbutsharethesamemechanismofactionwiththeothersteroids BIOSYNTHESISOFSTEROIDS Endocrinedisruption InterferenceofxenobioticswithnormalfunctionofhormonalsystemPossibleconsequences Disruptionofhomeostasis reproduction development and orbehavior andotherhormone cont
7、rolledprocesses Shiftinsexratio defectivesexualdevelopmentLowfecundity fertilityHypo immunity carcinogenesisMalformations Toxicantsinteractwithhormonalsystematdifferentlevels Transport Metabolization Interactionwithreceptors Stimulation Suppression biosynthesisandreleaseofhormones bindingtoplasmatic
8、transportproteins bindingtonuclearhormonalreceptor HR activationofHR dissociationofassociatedheatshockproteins formationofhomodimers bindingoftheactivatedreceptorcomplextospecificDNAmotifs HREs chromatinrearrangementandtranscriptionofestrogen induciblegenes effectsatthecellular tissue organ organism
9、 and orpopulationlevel e g modulationofCYP11Aand orCYP19activities e g down regulationofreceptorlevels e g modulationofothernuclearreceptors PPAR RXR RXR TR STEROIDOGENESIS Mechanismsofsteroidhormonessignallingdisruption Nonphysiologicalactivationofhormonereceptor HR BindingtoHRwithoutactivationDecr
10、easeofHRcellularlevelsDisruptionofthe master hormones FSH LH Changesinhormonemetabolism Endocrinedisruptersintheenvironment EDCs PersistentOrganicCompounds POPsandtheirmetabolites steroidhormonesandtheirderivativesfromcontraceptionpillsalkylphenolsorganometallics butyltins pharmaceuticalsPesticides
11、numberofunknowns ESTROGENRECEPTOR ERthemoststudiedtargetofEDCs Estrogens playakeyroleinfemalehormoneregulationandsignallingareresponsibleformetabolic behaviouralandmorphologicchangesoccurringduringstagesofreproductionareinvolvedinthegrowth developmentandhomeostasisofanumberoftissuescontrolthebonefor
12、mation regulationofhomeostasis cardiovascularsystemandbehaviourregulateproduction transportandconcentrationoftesticularliquidandanabolicactivityofandrogensinmalesSynthesisinovariesDISRUPTION investigatedinaquaticbiota laboratoryorganisms seenotesonEDCs ESTROGENRECEPTORS ER ER subtype ER inbreast ova
13、ry brain liver boneandcardiovascularsystem adrenals testisandurogenitaltract ER inkidneys prostateandgastrointestinaltract ER infish Naturalproductsgenisteinnaringenincoumestrolzearalenone EnvironmentalpollutantDDTkeponePCBs OH PCBsPAHsanddioxins IndustrialchemicalsBisphenolANonionicsurfactantsPthal
14、ateestersendosulfan PharmaceuticalsEthinylestradiolDiethylstilbestrolgestodenenorgestrel DEHP Environmentalestrogens xenoestrogens exoestrogens adiversegroupofsubstancesthatdonotnecessarilysharestructuralsimilaritytotheprototypicalestrogen 17 estradiol MayactasAGONISTSand orANTAGONISTS Exoestrogens
15、RelativePotenciestobindtoERa REPs Toxicityassessmentnumberofinvivoandinvitromethods Jano ek J Hilscherov K Bl ha L andHoloubek I 2006 Environmentalxenobioticsandnuclearreceptors Interactions effectsandinvitroassessment ToxicologyinVitro20 18 37 Invitroassays INTERACTION BINDING tothereceptorcompetit
16、iveligandbindingassayEffectunknown Activation suppression noeffect Testingtheeffectatcellularlevel interferencewithreceptorbiologicalactivity cellproliferationassayendogenousproteinexpression orenzymeactivity assayreportergeneassay InvitroER mediatedeffectsluciferasereporterassay ER mediatedeffectsluciferasereporterassay 96microwellplatecultivationoftransgeniccelllinesER breastcarcinomaMVLNcellsSIMILARDESIGNFOROTHERRECEPTORS discussedbelow AhR H4IIE luccells AR MDAcells RAR RXR P19cells Celllysi
