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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：
10413852
负责人：
Ramendra N Saha
金额：
$ 34.77万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413852
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.

项目总结：神经发育障碍(NDDS)正以惊人的速度在我们的孩子中变得越来越普遍。研究表明，NDDs可能是由于儿童早期无意中接触到环境中的有毒物质而引起的。污染物，特别是那些在室内空气中非常丰富的污染物。我们将继续研究它们在神经发育和发育中的作用。一组持久性环境污染物质，包括多溴联苯醚(PBDEs)。这是一组环境污染物家族成员。有机卤化有机阻燃剂被广泛用于世界各地的几种主要家用电子产品中，其中最常用的是二溴二苯醚-47。在我们的商业环境中，大多数人都有丰富的营养。我们的第二个中央银行假说是，长期的风险暴露与多溴联苯醚-47%和它的风险有关。代谢物可以通过调节协调的表观遗传代谢机制来扰乱神经发育。神经发育基因转录。这项新的提案将通过三个具体的目标来测试我们的中枢神经假说。我们还不会确定长期接触多溴联苯醚是否会改变大脑皮层的环境相关物质浓度。神经发育。为了测试这种可能性，我们还将在大鼠和人类神经干细胞上进行实验。细胞分化基因(rNPCs和hNPC)是指在体外分化的细胞和在体内分化的大鼠的细胞。在这里，我们将不会长期地研究细胞分化的问题。暴露在与环境相关的高剂量多溴联苯醚-47及其主要代谢物和神经细胞成熟过程中的人将无法存活。随后进行电生理评估和功能评估。2.我们将不确定全球气候变化的机制。由于对PBDE47的慢性暴露，基因调控被放松。全基因组检测(RNA-seq，芯片-seq，芯片) (SEQ)将继续被用来检验我们的假设。3.我们不会确定慢性药物暴露是否与多溴联苯醚-47%及其影响有关。代谢产物改变了BAF(哺乳动物的SWI/SNF)和染色质的结构，重塑了复杂的结构，从而改变了染色质。神经发育过程中的放任行为和基因转录改变。在这里，我们将进一步测试慢性精神分裂症的临床效果。 PBDE对BAF的核心功能进行了曝光，这是一个与公司高度相关的染色质重塑和综合功能。与神经发育相关的基因转录。我们将主要专注于生物滤池的一个关键组成部分--复杂的生物滤池。 BAF170基因(SMARCC2)。BAF170基因是自闭症基因的候选基因，在我们的PBDE初步筛查计划中，它是一个很受欢迎的基因。受影响的基因。我们将继续使用RNAi技术和基于CRISPR的基因技术来进一步了解BAF170基因在人类中的重要作用。神经发育相关基因的表达，尤其是在暴露于多溴联苯醚-47的情况下。这项研究还将为推动神经发育的表观遗传学机制以及如何实现这一目标提供更深入的见解。持续存在的环境污染物质可能会通过干预这些机制来调节NDD的风险。