Transgenerational actions of the endocrine disrupting compound Bisphenol A

内分泌干​​扰物双酚 A 的跨代作用

• 批准号: 8870353
• 负责人: Emilie F. Rissman
• 金额: $ 33.85万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870353
• 关键词: Affect; Age; Animals; Antibodies; Anxiety; Behavior; Behavior Disorders; Behavioral; Bioinformatics; Brain; Brain region; Breeding; C57BL/6 Mouse; Candidate Disease Gene; Cell Count; Cell Nucleus; Centers for Disease Control and Prevention (U.S.); Chemicals; Chromatin; Cognitive; Complex; DNA Methylation; DNA Sequence; Data; Development; Diet; Disease; Dose; Embryo; Endocrine; Endocrine Disruptors; Enzymes; Epigenetic Process; Ethnic Origin; Exposure to; Female; Fostering; Gene Expression; Gene Targeting; Gene-Modified; Generations; Genes; Genetic; Genetic Transcription; Genomics; Germ Cells; Goals; Health; Heritability; Histones; Human; Inbred Mouse; Individual; Industrial fungicide; Ingestion; Inherited; Knowledge; Lead; Maps; Maternal Behavior; Measures; Mediating; Mental Depression; Messenger RNA; Methods; Mission; Modeling; Modification; Mus; Mutation; National Institute of Environmental Health Sciences; Neurodevelopmental Disorder; Neuropeptides; Oxytocin; Parents; Partner in relationship; Perinatal; Phenotype; Plastics; Population; Pregnancy; Preoptic Areas; Procedures; Property; Proteins; RNA Sequences; Recruitment Activity; Research; Social Behavior; Stress; Structure of primordial sex cell; Techniques; Testing; Testis; Time; Tissues; Transcript; Untranslated RNA; Urine; Vasopressins; Water; Work; base; birth control; bisphenol A; brain behavior; chromatin immunoprecipitation; emotional behavior; epigenetic variation; epigenome; epigenomics; histone modification; human data; human disease; improved; male; man; nano; next generation; next generation sequencing; novel; nutrition; offspring; pregnant; programs; pup; relating to nervous system; research study; sex; social; sperm cell; transcriptome sequencing; transgenerational epigenetic inheritance; transmission process; vinclozolin

DESCRIPTION (provided by applicant): Many endocrine disrupting compounds (EDCs) have immediate effects on exposed individuals, but more complex concerns surround their long term actions on subsequent generations. The limited data from humans concur with the animal work suggesting that exposure to EDCs, particularly exposure during development, produce subtle increases in disease states, along with evidence for transgenerational effects. The precise epigenetic and/or genetic actions of EDCs on specific target genes, which produce stable modifications in subsequent generations, are unknown. The first goal of this program is to understand the mechanisms underlying transgenerational inheritance produced by human-relevant levels of the ubiquitous EDC, Bisphenol A (BPA). The work proposed is the first to test transgenerational actions of human-relevant exposures of BPA on brain and behaviors. Pregnant inbred mice are exposed to EDCs via voluntary ingestion of maternal diet. At birth, control and BPA pups are fostered to dams on control diet to isolate the actions of BPA to gestation and control for any consequences of these compounds on maternal behavior. We have shown that several social behaviors in the first and fourth generation (F4) of mice the BPA lineage differ significantly from control mice. Moreover, mRNA for two genes that regulate social behavior, vasopressin (Avp) and oxytocin (Oxt), are decreased in brains of the F4 BPA-exposed mice. Experiment one will determine the parent of origin for transmission of BPA's actions. In addition we will assess a number of cognitive and emotional behaviors in these mice to improve our ability to predict which human diseases may be sensitive to BPA. In the next study brains regions are probed with next generation sequencing techniques to establish target genes. Brains from F3 mice will be dissected into the nuclei that compose the social behavior network. A combination of Chromatin Immunoprecipitation (ChiP-) and RNA-sequencing will be conducted. These data provide targets for the epigenetic modifications found in brain. The mechanisms revealed will be applicable to other target tissues and thus a variety of diseases. This research plan will provide the field with a model for transgenerational actions of BPA and an epigenomic map of the consequences of these exposures.

描述（由申请人提供）：许多内分泌干扰化合物（EDCs）对暴露的个体有直接影响，但更复杂的问题是它们对后代的长期影响。来自人类的有限数据与动物研究一致，表明暴露于EDCs，特别是在发育期间暴露，会导致疾病状态的微妙增加，并有证据表明存在跨代影响。EDCs对特定靶基因的精确表观遗传和/或遗传作用，在后代中产生稳定的修饰，是未知的。该项目的第一个目标是了解与人类相关的普遍存在的EDC双酚A （BPA）水平产生的跨代遗传的机制。这项研究首次测试了BPA暴露对人类大脑和行为的跨代影响。怀孕的近交系小鼠通过自愿摄入母体饮食暴露于EDCs。在出生时，对照组和双酚a幼崽被饲养在控制饮食的坝中，以隔离双酚a对妊娠的作用，并控制这些化合物对母亲行为的任何后果。我们已经证明，BPA谱系的第一代和第四代（F4）小鼠的一些社会行为与对照小鼠有显著差异。此外，在F4 bpa暴露小鼠的大脑中，抗利尿激素（Avp）和催产素（Oxt）这两个调节社会行为的基因的mRNA含量下降。实验一将确定BPA行为传播的母体。此外，我们将评估这些小鼠的一些认知和情感行为，以提高我们预测哪些人类疾病可能对BPA敏感的能力。在接下来的研究中，将使用下一代测序技术对大脑区域进行探测，以建立目标基因。F3小鼠的大脑将被解剖成构成社会行为网络的细胞核。将进行染色质免疫沉淀（ChiP-）和rna测序的结合。这些数据为在大脑中发现的表观遗传修饰提供了靶标。揭示的机制将适用于其他靶组织，从而适用于各种疾病。这项研究计划将为该领域提供双酚a跨代作用的模型和这些暴露后果的表观基因组图谱。