Exposuretodivalentcadmiumions(Cd2+)isaknowncancerriskfactor,butthemolecularmechanismsresponsIBLefortheinappropriateinductionofcellularproliferationbycadmiumarestillbeingfiguredout.Onecellularmodelusedtostudythisprocessismacrophagesgrowninculture.Inculturedmacrophages,cadmiumactsbothatthecellsurfaceandinthecytoplasmtoinduceproliferation.Atthecellsurface,cadmiuminteractswithapertussis-sensitivecellsurfacereceptor,probablyaGi-coupledGPCR,tostimulateproliferation.CadmiumcanentercellsthroughcalciumionchannelsandonceincellsaffectscalciumreleasebytheER.Inadditiontochangesinintracellularcalcium,theproliferativeeffectsofcadmiumaremediatedbytheRas/Mapkinasepathway,andalsoNF-kB.InhibitionofphospholipaseC,mapkinases,orNF-kBwithavarietyofpharmacologicalinhibitorsallblockedtheactivationofcellularproliferationbycadmium.ProteinkinaseCisalsoactivatedbycadmium,upstreamoftheMapkinasepathway.Changesintranscriptioninducedbycadmiumincludeinductionofimmediateearlygeneslikefos,jun,andmyc.Inadditiontoinducingcellularproliferation,cadmiumalsoisslightlygenotoxicduetoinhibitionofDNArepair,activatesstressgenes,andinhibitstheimmunesystem.Theimmuno-modulatoryeffectsobservedwithcadmiumtreatmentmayalsoinvolvementtranscriptionaldisregulation,includingtheexpressionofcytokinessuchasIL-4,IL-10,andTNF-alpha.Althoughmacrophageshavebeenusedformanystudies,othercelltypesarealsothetargetofcadmium’stoxicity.

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