(from the parent R01) 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. Note: Supplemental support is requested for the bold section.
(from the parent R01) 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.
