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

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.