Projectsummary Neurodevelopmentaldisorders(NDDs)arebecomingmoreprevalentamongourchildrenatanalarmingrate. StudiessuggestthatNDDsmaybecausedbyinadvertentearly-lifeexposuretoenvironmentaltoxinsand pollutants,especiallytheonesthatareabundantindoors.Wewillstudyneurodevelopmentalrolesofonesuch groupofpersistentenvironmentalpollutants,polybrominateddiphenylethers(PBDEs).Thisfamilyof organohalogenatedflame-retardantsisusedinseveralhouseholdproductsworldwide,withPBDE-47beingthe mostabundantinourenvironment.OurcentralhypothesisisthatchronicexposuretoPBDE-47andits metabolitesdisruptsneurodevelopmentbydysregulatingepigeneticmechanismsthatorchestrate neurodevelopmentalgenetranscription.Thisproposalwilltestourcentralhypothesisviathreespecificaims.1. WewilldetermineifchronicexposuretoenvironmentallyrelevantconcentrationsofPBDE-47alterscortical neurodevelopment.Experimentstotestthispossibilitywillbeconductedinratandhumanneuronalprogenitor cells(rNPCsandhNPCs)differentiatinginvitroandinratsinvivo.Here,differentiatingNPCswillbechronically exposedtoenvironmentallyrelevantdosesofPBDE-47anditsmetabolitesandneuronalmaturationwillbe subsequentlyassessedelectro-physiologicallyandfunctionally.2.Wewilldeterminemechanismsofglobal genederegulationduetochronicexposuretoPBDE47.Genome-wideassays(RNA-seq,ChIP-seq,andCAP- seq)willbeemployedtotestourhypothesis.3.WewilldetermineifchronicexposuretoPBDE-47andits metabolitesalterstheBAF(mammalianSWI/SNF)chromatinremodelingcomplexandtherebychromatin permissivenessandgenetranscriptionduringneurodevelopment.Here,wewilltesttheeffectsofchronic PBDEexposureonfunctionsoftheBAFcomplex,achromatin-remodelingcomplexthatishighlyrelevantfor neurodevelopment-relatedgenetranscription.WewillmainlyfocusonakeyBAFcomplexcomponent, BAF170(SMARCC2).BAF170isacandidateautismgeneandisa?hit?inourpreliminaryscreeningofPBDE- impactedgenes.WewilluseRNAiandCRISPR-basedtechnologytounderstandtheroleofBAF170in neurodevelopmentalgeneexpression,especiallywhenchallengedwithPBDE-47exposure.Takentogether, thisstudywillprovidedeeperinsightsintoepigeneticmechanismsdrivingneurodevelopmentandhow persistentenvironmentalpollutantsmaymodulateNDDrisksbyinterferingwiththesemechanisms.
NIH ExPorter
NIH ExPorter