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， 基因与环境的相互作用和失调的分子和细胞途径， 可以在表观基因组的水平上揭示出来。在出生时识别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一个重要的 这一目标受到现有技术或缺乏相关组织可用性的限制。我们 目前在儿童中心合作的跨学科科学家团队， 环境卫生计划使用现有的胎盘样本，从一个前瞻性的高风险 队列研究（MARBLES），以确定出生时子宫内暴露于 多氯联苯（PCB）和神经发育的结果。使用 无偏全基因组亚硫酸氢盐测序（WGBS），我们以前已经证明 胎盘组织保留了着床前的独特DNA甲基化模式， 胚胎，因此可以捕捉分子状态在非常早期的发展，这是一个特点， 在哺乳动物物种中是保守的，包括小鼠。新的假设将在 这一建议是，围产期暴露于多氯联苯对神经发育产生不利影响， 在与神经发育相关的基因上留下持久的分子标记， 在胎盘中检测到。拟议的PCB表观基因组大脑和行为持久效应 研究（PEBBLES）将结合联合收割机对来自高危人群的人胎盘样本的分析， MARBLES队列分析胎盘和脑组织以及分选的细胞类型 来自围产期接触相同多氯联苯同系物混合物的小鼠模型 在大理石母亲身上检测到。这项研究将利用现有的神经和 行为分析和样本，以检查多氯联苯引起的 DNA甲基化标记的扰动与不良神经毒性结果。表观 胎盘和大脑的分析以及来自这些中的每一个的分类的细胞亚型 组织将包括甲基化组的WGBS、转录组的RNA-seq和 染色质可及性生物信息学和统计分析将整合基因组数据 与行为和分子结果的措施，并确定是否类似 在胎盘中观察到表观遗传标记，可用于预测长期不良反应， 大脑和行为的结果。 !