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Epigenetic disruptions of PBDEs during neurodevelopment

神经发育过程中 PBDE 的表观遗传破坏

基本信息

批准号：
10163056
负责人：
Ramendra N Saha
金额：
$ 34.83万
依托单位：
UNIVERSITY OF CALIFORNIA, MERCED
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163056
关键词：
Acute American Animals Attention Attention deficit hyperactivity disorder Automobile Driving Behavioral Biological Assay Brain CRISPR/Cas technology Calcium Candidate Disease Gene Cells ChIP-seq Child Chromatin Chromatin Remodeling Factor Chronic Complex DNA DNA Methylation DNA Polymerase II Data Development Disease Dose Electrophysiology (science)Environment Environmental Pollutants Epigenetic Process Exposure to Family Flame Retardants Future Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Global Change Health Histones Household Household Products Human Image Impairment In Vitro Injections Intellectual functioning disability Intervention Laboratories Learning Life Measures Metabolic Microelectrodes Molecular Biology Neurodevelopmental Disorder Neurons Nuclear Pore Complex Oncogene Deregulation Outcome Outcome Study Perinatal Physiological Process RNA Interference RNA Polymerase II Rattus Reporter Research Risk Role SMARCC2 gene Slice Societies Specificity Testing Time Toxic Environmental Substances Toxic effect Transcriptional Regulation Work autism spectrum disorder base brain cell chromatin remodeling cognitive function design disability disorder risk early life exposure experimental study gene repression genome-wide high risk in utero in vitro Assay in vivo indexing insight molecular array nanomolar nerve stem cell neurodevelopment novel overexpression permissiveness pollutant polybrominated diphenyl ether precursor cell promoter screening transcriptome sequencing

项目摘要

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.

项目摘要神经发育障碍（NDD）正在以惊人的速度在我们的儿童中变得越来越普遍。研究表明，NDDs可能是由于无意中早期生活暴露于环境毒素，污染物，特别是那些在室内丰富。我们将研究神经发育的作用，这样的一个多溴联苯醚（PBDEs）是一组持久性环境污染物。有机卤代阻燃剂用于全世界的几种家用产品，其中PBDE-47是我们的中心假设是，长期接触PBDE-107及其代谢物通过失调表观遗传机制破坏神经发育，神经发育基因转录。这一建议将通过三个具体目标来检验我们的中心假设。我们将确定长期暴露于环境相关浓度的PBDE-47是否会改变大脑皮层测试这种可能性的实验将在大鼠和人类神经元祖细胞中进行。细胞（rNPC和hNPC）在体外和大鼠体内分化。暴露于环境相关剂量的PBDE-1047及其代谢物和神经元成熟将随后评估电生理和功能。2.我们将确定全球机制全基因组检测（RNA-PCR、ChIP-PCR和CAP-PCR） 3.我们将确定长期接触PBDE-147及其代谢物改变BAF（哺乳动物SWI/SNF）染色质重塑复合物，从而改变染色质在这里，我们将测试长期的放纵和基因转录的影响。多溴联苯醚暴露对BAF复合物功能的影响，BAF复合物是一种染色质重塑复合物，神经发育相关的基因转录。我们将主要集中在一个关键的BAF复合体组成部分， BAF 170（SMARCC 2）：BAF 170是一个自闭症候选基因，在我们的PBDE-binding初步筛选中是一个“命中” 我们将使用基于RNAi和CRISPR-PCR的技术来了解BAF 170在神经发育基因表达，特别是当受到PBDE-147暴露的挑战时。这项研究将为驱动神经发育的表观遗传机制提供更深入的见解，持久性环境污染物可能通过干扰这些机制来调节NDD风险。