PCB Epigenomic Brain & Behavior Lasting Effects Study (PEBBLES)

PCB表观基因组大脑

• 批准号: 10183250
• 负责人: Janine M LaSalle
• 金额: $ 47.3万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183250
• 关键词: ATAC-seq; Adolescence; Adult; Affect; Age; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Bioinformatics; Biological Markers; Birth; Blood specimen; Brain; Cells; Child; Chromatin; Cognitive; Cohort Studies; Complement; Complex; Confounding Factors (Epidemiology); DNA; DNA Methylation; DNA analysis; DNA methylation profiling; Data; Data Analyses; Development; Diagnosis; Disease model; Dose; Embryo; Enhancers; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epigenetic Process; Event; Experimental Models; Exposure to; Family history of; Female; Freezing; General Population; Genes; Genetic; Genetic Markers; Genetic Models; Genetic Risk; Genetic Screening; Genome; Genotype; Gestational Age; Goals; Heterogeneity; Human; Language Delays; Learning; Maps; Marble; Measurement; Measures; Methylation; Molecular; Molecular Genetics; Molecular Profiling; Monitor; Mothers; Mus; Neurodevelopmental Disorder; Neurologic; Outcome; Outcome Measure; Pathway interactions; Perinatal Exposure; Phenotype; Placenta; Plasma; Polychlorinated Biphenyls; Population; Populations at Risk; Pregnancy; Risk; Risk Marker; Rodent; Rodent Model; Sample Size; Sampling; Scientist; Serum; Severities; Siblings; Source; Specificity; Statistical Data Interpretation; Technology; Testing; Time; Tissues; United States; Urine; autism spectrum disorder; base; behavioral outcome; bisulfite sequencing; blastocyst; brain behavior; brain tissue; capsule; cell free fetal DNA; cell type; cohort; epigenetic marker; epigenome; epigenomics; fetal; genome wide methylation; genomic data; health plan; high risk; improved outcome; in utero; male; methylation biomarker; methylation pattern; methylome; mouse model; neurodevelopment; neurotoxic; persistent organic pollutants; phenotypic data; predictive marker; pregnant; prenatal exposure; prospective; recruit; transcriptome; transcriptome sequencing; trophoblast; whole genome

Placental tissue is normally discarded at birth, but is essentially a molecular time capsule for gene by environmental interactions and dysregulated molecular and cellular pathways that can be revealed at the level of the epigenome. Identifying epigenetic biomarkers at birth that reflect in utero exposures or predict adverse neurodevelopmental outcomes is an important goal that has been limited by prior technologies or lack of relevant tissue availability. Our team of currently collaborating interdisciplinary scientists within the Children’s Center for Environmental Health plans to use existing placental samples from a prospective high-risk cohort study (MARBLES) to identify epigenetic biomarkers at birth for in utero exposure to polychlorinated biphenyls (PCB) and neurodevelopmental outcomes by age three. Using unbiased whole genome bisulfite sequencing (WGBS), we have previously demonstrated that placental tissues retain the distinctive DNA methylation patterns of the preimplantation embryo and so can capture the molecular state in very early development, a feature that is conserved across mammalian species, including mouse. The new hypothesis to be tested in this proposal is that perinatal exposures to PCB adversely impact neurodevelopment and leave a lasting molecular signature over genes relevant to neurodevelopment that can be detected in placenta. The proposed PCB Epigenomic Brain & Behavior Lasting Effects Study (PEBBLES) will combine the analysis of human placental samples from the high-risk MARBLES cohort with the analysis of placenta and brain tissues and sorted cell types derived from a mouse model of perinatal exposure to the same mixture of PCB congeners detected in MARBLES mothers. This study will leverage existing neurological and behavioral analyses and samples to examine the relationship between PCB-induced perturbations of DNA methylation marks with adverse neurotoxic outcomes. Epigenomic analyses of placenta and brain as well as sorted cellular subtypes from each of these tissues will include WGBS for methylome, RNA-seq for transcriptome, and ATAC-seq for chromatin accessibility. Bioinformatic and statistical analyses will integrate the genomic data sets with behavioral and molecular outcome measures and determine whether similar epigenetic marks are observed in placenta that could be used to predict long-lasting adverse brain and behavioral outcomes in humans. !

胎盘组织通常在出生时被丢弃，但本质上是一个分子时间胶囊 通过环境相互作用以及分子和细胞途径失调的基因 可以在表观基因组的水平上揭示。识别出生时表观遗传生物标志物 反映子宫内暴露或预测不良神经发育结果是重要的 受先前技术或缺乏相关组织可用性受到限制的目标。我们的 目前合作的儿童中心跨学科科学家的团队 环境健康计划使用潜在高风险的现有占地样品 队列研究（大理石）以鉴定出生时出生时的表观遗传生物标志物 到三岁的多氯联苯（PCB）和神经发育结果。使用 无偏见的整个基因组Bisulfite测序（WGB），我们以前已经证明了 胎盘组织保留了植入前的独特DNA甲基化模式 胚胎，因此可以在非常早期发育中捕获分子状态，这一特征是 包括小鼠在内的哺乳动物物种中保守。将在 该建议是，对PCB的围产期暴露会对神经发育产生不利影响和 在与神经发育相关的基因上留下持久的分子签名 在plapeta中检测到。拟议的PCB表观基因组脑和行为持久效果 研究（鹅卵石）将结合对高风险的人类位置样品的分析 大理石队列，分析了plapeta和脑组织以及分类的细胞类型 源自围产期暴露于同一混合物的小鼠模型 在大理石母亲中发现。这项研究将利用现有的神经系统和 行为分析和样本以检查PCB诱导的关系 具有不良神经毒性结果的DNA甲基化标记的扰动。表观基因组 分析胎盘和大脑以及从每种分类的细胞亚型分析 组织将包括用于甲基组的WGB，转录组的RNA-Seq和Atac-Seq的WGB 染色质可及性。生物信息学和统计分析将整合基因组数据 采用行为和分子结局指标的设置，并确定是否相似 在Pleceta中观察到表观遗传标记，可用于预测持久的对手 人类的大脑和行为结果。 呢