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（NDDS）在我们的孩子中以惊人的速度变得越来越普遍。研究表明，NDD可能是由于无意的早期暴露于环境毒素和污染物，特别是在室内丰富的污染物。我们将研究其中一个这样的神经发育角色一组持续的环境污染物，多溴二苯基醚（PBDES）。这个家庭在全球多种家用产品中使用了有机热的火焰 - 信念，PBDE-47是在我们的环境中最丰富。我们的中心假设是长期暴露于PBDE-47及其代谢产物通过精心策划的表观遗传机制来破坏神经发育神经发育基因转录。该提案将通过三个特定目标检验我们的中心假设。 1。我们将确定长期暴露于环境相关浓度的PBDE-47是否改变了皮质神经发育。测试该电位的实验将在大鼠和人类神经元祖细胞中进行细胞（RNPC和HNPC）在体内和大鼠体内区分。在这里，区分NPC将长期存在暴露于环境相关剂量的PBDE-47及其代谢物和神经元成熟随后在功能和功能上评估了电生物学。 2。我们将确定全球机制由于长期暴露于PBDE47而导致的基因放松调节。全基因组测定法（RNA-Seq，Chip-Seq和Cap- SEQ将用于检验我们的假设。 3。我们将确定长期暴露于PBDE-47及其代谢物改变了BAF（哺乳动物SWI/SNF）染色质重塑复合物，从而染色质神经发育过程中的允许性和基因转录。在这里，我们将测试慢性的影响 PBDE暴露于BAF复合物的功能，BAF复合物是一种染色质复合物复合物，非常相关神经发育相关的基因转录。我们将主要关注关键的BAF复杂组件， BAF170（SMARCC2）。 BAF170是候选自闭症基因，在我们对PBDE的初步筛选中是“打击” 受影响的基因。我们将使用RNAi和基于CRISPR的技术来了解BAF170在神经发育基因表达，特别是在受到PBDE-47暴露挑战时。带了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以及如何持续的环境污染物可能会通过干扰这些机制来调节NDD风险。