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Your Environment. Your Health.

EPIGENETIC DISRUPTIONS OF PBDES DURING NEURODEVELOPMENT

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Principal Investigator: Saha, Ramendra N
Institute Receiving Award University Of California, Merced
Location Merced, CA
Grant Number R01ES028738
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2018 to 31 May 2023
DESCRIPTION (provided by applicant): Project summary  Neurodevelopmental disorders (NDDs) are becoming more prevalent among our children at an alarming rate.  Studies suggest that NDDs may be caused by inadvertent early-­life exposure to environmental toxins and  pollutants, especially the ones that are abundant indoors. We will study neurodevelopmental roles of one such  group of persistent environmental pollutants, polybrominated diphenyl ethers (PBDEs). This family of  organohalogenated flame-­retardants is used in several household products worldwide, with PBDE-­47 being the  most abundant in our environment. Our central hypothesis is that chronic exposure to PBDE-­47 and its  metabolites disrupts neurodevelopment by dysregulating epigenetic mechanisms that orchestrate  neurodevelopmental gene transcription. This proposal will test our central hypothesis via three specific aims. 1.  We will determine if chronic exposure to environmentally relevant concentrations of PBDE-­47 alters cortical  neurodevelopment. Experiments to test this possibility will be conducted in rat and human neuronal progenitor  cells (rNPCs and hNPCs) differentiating in vitro and in rats in vivo. Here, differentiating NPCs will be chronically  exposed to environmentally relevant doses of PBDE-­47 and its metabolites and neuronal maturation will be  subsequently assessed electro-­physiologically and functionally. 2. We will determine mechanisms of global  gene deregulation due to chronic exposure to PBDE47. Genome-­wide assays (RNA-­seq, ChIP-­seq, and CAP-­ seq) will be employed to test our hypothesis. 3. We will determine if chronic exposure to PBDE-­47 and its  metabolites alters the BAF (mammalian SWI/SNF) chromatin remodeling complex and thereby chromatin  permissiveness and gene transcription during neurodevelopment. Here, we will test the effects of chronic  PBDE exposure on functions of the BAF complex, a chromatin-­remodeling complex that is highly relevant for  neurodevelopment-­related gene transcription. We will mainly focus on a key BAF complex component,  BAF170 (SMARCC2). BAF170 is a candidate autism gene and is a ‘hit’ in our preliminary screening of PBDE-­ impacted genes. We will use RNAi and CRISPR-­based technology to understand the role of BAF170 in  neurodevelopmental gene expression, especially when challenged with PBDE-­47 exposure. Taken together,  this study will provide deeper insights into epigenetic mechanisms driving neurodevelopment and how  persistent environmental pollutants may modulate NDD risks by interfering with these mechanisms. 
Science Code(s)/Area of Science(s) Primary: 10 - Epigenetics
Publications See publications associated with this Grant.
Program Officer Frederick Tyson
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