Nuclear-receptors(核受体))

INTRACELLULARRECEPTORS Theintracellular nuclear receptorsuperfamilySteroidhormones thyroidhormones retinoidsandvitaminD Intracellularreceptor HYDROPHOBIC Non polarmoleculesGasesSteroids 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 carcinogenesisMalations Toxicantsinteractwithhormonalsystematdifferentlevels Transport Metabolization Interactionwithreceptors Stimulation Suppression biosynthesisandreleaseofhormones bindingtoplasmatictransportproteins bindingtonuclearhormonalreceptor HR activationofHR dissociationofassociatedheatshockproteins ationofhomodimers 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 playakeyroleinfemalehormoneregulationandsignallingareresponsibleetabolic behaviouralandmorphologicchangesoccurringduringstagesofreproductionareinvolvedinthegrowth developmentandhomeostasisofanumberoftissuescontroltheboneation 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 Toxicityassessmentnumberofinvivoandinvitros 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 Celllysi