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.
Neurodevelopmental disorders are complex disorders with multiple causes (genetic and environmental) whose rates are rapidly rising and current evidence suggests that early life exposure to common household environmental pollutants such as PBDEs (flame retardant) may be a contributing factor. This study is designed to test if PBDE-47 ? the most common PBDE in our environment ? and their metabolic products contribute to neurodevelopmental disorders by interfering with epigenetic mechanisms that drive normal neurodevelopmental gene transcription. This work will contribute new insights regarding potential health impact mechanisms of early-life PBDEs exposure, and may help identify mitigating factors in the future.
