Epigenomic Brain & Behavior Lasting Effects Study (PEBBLES) Admin Supplement

表观基因组脑

• 批准号: 9916517
• 负责人: Janine M LaSalle
• 金额: $ 15.7万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916517
• 关键词: ATAC-seq; Administrative Supplement; Adverse effects; Affect; Age; Air; Attention deficit hyperactivity disorder; Behavior; Behavioral; Bioinformatics; Biological Markers; Birth; Blood; Brain; Cells; Child; Child Health; Chromatin; Cognitive; Cohort Studies; Complex; Conceptions; DNA; DNA Methylation; DNA analysis; Data; Development; Diagnosis; Diet; Embryo; Enhancers; Environment; Environmental Exposure; Environmental Health; Environmental Pollution; Environmental Risk Factor; Epigenetic Process; Etiology; Event; Experimental Animal Model; Experimental Models; Exposure to; Folic Acid; Food Supply; Freezing; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Gestational Age; Goals; Grant; Heterogeneity; Human; Industrialization; Language Delays; Link; Maps; Measurement; Measures; Methylation; Microglia; Molecular; Molecular Profiling; Mothers; Mus; Neural Tube Defects; Neurodevelopmental Disorder; Neurons; Nutritional; Outcome; Outcome Measure; Parents; Pathway interactions; Perinatal; Perinatal Exposure; Placenta; Polychlorinated Biphenyls; Population; Predisposition; Pregnancy; Process; Production; Prospective Studies; Risk; Role; Sample Size; Sampling; Schools; Scientist; Serum; Severities; Source; Specificity; Statistical Data Interpretation; Technology; Testing; Time; Tissues; Toxic Environmental Substances; Toxicant exposure; United States; Vitamins; Work; autism spectrum disorder; autistic; base; behavioral outcome; bisulfite sequencing; blastocyst; brain behavior; brain tissue; capsule; cell type; cohort; dietary supplements; disorder risk; epigenetic marker; epigenetic regulation; epigenome; epigenomics; folic acid supplementation; genome wide methylation; genomic data; health plan; high risk; improved outcome; in utero; macrophage; methyl group; methylation biomarker; methylation pattern; methylome; mouse model; neurodevelopment; neurotoxic; offspring; phenotypic data; predictive marker; prenatal; prenatal exposure; prospective; response; tool; transcriptome; transcriptome sequencing; whole genome

Placental tissue, which is normally discarded at birth, is a molecular time capsule that captures 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 (PCBs) and neurodevelopmental outcomes at age three years. In the MARBLES cohort, we have shown that taking folic acid in the form of prenatal vitamins specifically in the first month of pregnancy was associated with a 50% reduction in the risk for autism. Our human studies and the work of others also show evidence that folic acid supplementation can counter epigenetic and neurodevelopmental effects of environmental contaminants. Furthermore, 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 proposed PCB Epigenomic Brain & Behavior Lasting Effects Study (PEBBLES) combines WGBS analysis of human placental samples from the high-risk MARBLES cohort with a more extensive epigenomic 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. The hypothesis to be tested in the parent PEBBLES grant is that perinatal PCB exposures adversely impact neurodevelopment and leave a lasting molecular signature over genes relevant to neurodevelopment that can be detected in placenta. The hypothesis to be tested in the nutritional supplement to PEBBLES is that dietary folic acid supplementation will be protective against the adverse effects of PCB exposures at the level of the epigenome in an experimental animal model and human placenta. 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 brain and behavioral outcomes in humans. !

胎盘组织，通常在出生时被丢弃，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， 在表观基因组的水平上被揭示出来。在出生时识别表观遗传生物标志物， 子宫暴露或预测不良神经发育结果是一个重要的目标， 受到现有技术或缺乏相关组织可用性的限制。我们的团队目前 儿童环境健康中心计划中的跨学科科学家合作 使用来自前瞻性高风险队列研究（MARBLES）的现有胎盘样本， 出生时子宫内暴露于多氯联苯的表观遗传生物标志物， 三岁时的神经发育结果。在MARBLES队列中，我们已经表明， 特别是在怀孕的第一个月以产前维生素的形式服用叶酸， 与自闭症风险降低50%有关。我们的人类研究和其他人的工作 也有证据表明，叶酸补充剂可以对抗表观遗传， 环境污染物对神经发育的影响。此外，使用无偏整体 基因组亚硫酸氢盐测序（WGBS），我们以前已经证明， 保留了植入前胚胎的独特DNA甲基化模式，因此可以捕获 非常早期发育的分子状态，这是哺乳动物中保守的特征 物种，包括老鼠。拟议的PCB表观基因组大脑和行为持久效应研究 （PEBBLES）结合了来自高危MARBLES的人胎盘样本的WGBS分析 对胎盘和脑组织以及分选细胞进行更广泛的表观基因组分析的队列 来自围产期接触相同多氯联苯同系物混合物的小鼠模型的类型 在大理石母亲身上检测到。在PEBBLES母基金中要检验的假设是， 围产期PCB暴露对神经发育产生不利影响， 在胎盘中可以检测到的与神经发育相关的基因的签名。的 在PEBBLES的营养补充剂中待检验的假设是膳食叶酸 补充将保护免受多氯联苯暴露的不利影响， 实验动物模型和人类胎盘中的表观基因组。生物信息和统计 分析将整合基因组数据集与行为和分子结果的措施， 并确定是否在胎盘中观察到类似的表观遗传标记， 预测人类长期的大脑和行为结果。 !