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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES028738-02
Application #
9767157
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Tyson, Frederick L
Project Start
2018-09-01
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Merced
Department
Biochemistry
Type
Earth Sciences/Resources
DUNS #
113645084
City
Merced
State
CA
Country
United States
Zip Code
95343