PCB Epigenomic Brain & Behavior Lasting Effects Study (PEBBLES)

PCB表观基因组脑

• 批准号: 10416017
• 负责人: Janine M LaSalle
• 金额: $ 46.3万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416017
• 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 通过环境相互作用和失调的分子和细胞途径 可以在表观基因组水平上揭示。在出生时识别表观遗传生物标记物 反映宫内暴露或预测不良神经发育结果是重要的 这一目标受到现有技术或缺乏相关组织供应的限制。我们的 目前在儿童中心内合作的跨学科科学家团队 环境健康计划使用来自预期高危人群的现有胎盘样本 队列研究(大理石)以确定出生时宫内暴露的表观遗传生物标志物 多氯联苯与三岁前的神经发育结果。vbl.使用 无偏全基因组亚硫酸盐测序(WGBS)，我们之前已经证明 胎盘组织保留着植入前独特的DNA甲基化模式 胚胎等可以在非常早期的发育中捕捉到分子状态，这是一个特征 在哺乳动物物种中保存，包括小鼠。有待检验的新假说 这项建议是，围产期接触多氯联苯对神经发育和 在与神经发育相关的基因上留下持久的分子签名 在胎盘中检测到。提出的多氯联苯表观组脑&行为持久效应 研究(鹅卵石)将结合分析来自高危人群的胎盘样本 大理石与胎盘、脑组织和分类细胞类型的分析 来源于围产期暴露于相同混合物的多氯联苯的小鼠模型 在母亲的弹珠中检测到。这项研究将利用现有的神经学和 行为分析与样本检验多氯联苯诱导的关系 DNA甲基化标记的扰动具有不良的神经毒性结果。表观基因组学 胎盘和脑的分析以及它们各自的分类细胞亚型 组织将包括用于甲基组的WGBS、用于转录组的RNA-seq和用于 染色质可及性。生物信息学和统计分析将整合基因组数据 具有行为和分子结果测量的集合，并确定是否类似 在胎盘中观察到的表观遗传标记可以用来预测长期的不良反应 人类的大脑和行为结果。 好了！

项目成果

Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study.

在一项前瞻性自闭症研究中，胎盘 DNA CYP2E1 和 IRS2 甲基化水平与儿童结局相关。

• DOI: 10.1093/hmg/ddz084
• 发表时间: 2019
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Zhu,Yihui;Mordaunt,CharlesE;Yasui,DagH;Marathe,Ria;Coulson,RochelleL;Dunaway,KeithW;Jianu,JuliaM;Walker,CherylK;Ozonoff,Sally;Hertz-Picciotto,Irva;Schmidt,RebeccaJ;LaSalle,JanineM
• 通讯作者: LaSalle,JanineM

Placenta keeps the score of maternal cannabis use and child anxiety.

胎盘记录母亲使用大麻和儿童焦虑的评分。

• DOI: 10.1073/pnas.2118394118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: LaSalle,JanineM

The Promise of DNA Methylation in Understanding Multigenerational Factors in Autism Spectrum Disorders.

• DOI: 10.3389/fgene.2022.831221
• 发表时间: 2022
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Mouat JS;LaSalle JM
• 通讯作者: LaSalle JM

Wilson Disease: Intersecting DNA Methylation and Histone Acetylation Regulation of Gene Expression in a Mouse Model of Hepatic Copper Accumulation.

• DOI: 10.1016/j.jcmgh.2021.05.020
• 发表时间: 2021
• 期刊: Cellular and molecular gastroenterology and hepatology
• 影响因子: 7.2
• 作者: Sarode GV;Neier K;Shibata NM;Shen Y;Goncharov DA;Goncharova EA;Mazi TA;Joshi N;Settles ML;LaSalle JM;Medici V
• 通讯作者: Medici V

Future Prospects for Epigenetics in Autism Spectrum Disorder.

• DOI: 10.1007/s40291-022-00608-z
• 发表时间: 2022-11
• 期刊: MOLECULAR DIAGNOSIS & THERAPY
• 影响因子: 4
• 作者: Williams, Logan A.;LaSalle, Janine M.
• 通讯作者: LaSalle, Janine M.