Sexually dimorphic epigenetic regulation of fetal brain development by environmental stressors

环境应激源对胎儿大脑发育的性别二态性表观遗传调控

基本信息

批准号：
9905527
负责人：
BRUCE K KRUEGER
金额：
$ 19.31万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-02 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905527
关键词：
Address Affect Air Pollution Antiepileptic Agents Anxiety Appearance Attention deficit hyperactivity disorder BDNF gene Behavior Behavior Disorders Biological Brain Brain-Derived Neurotrophic Factor Characteristics Chlorpyrifos Code Cognition Conceptions DNA Development Disease Environment Environmental Risk Factor Enzymes Epigenetic Process Etiology Experimental Designs Exposure to Female Fetus Future Gene Expression Genes Goals Gonadal Hormones Gonadal Steroid Hormones Human Ice Immunoblotting Insecticides Intellectual functioning disability Laboratory Study Lead Lysine Major Depressive Disorder Measures Mediating Mental disorders Messenger RNA Methylation Molecular Moods Mus Neurodevelopmental Disorder Organophosphates Pathogenicity Pathway Analysis Pesticides Pharmaceutical Preparations Poison Pregnancy Prevalence Prevention Protein Isoforms Proteins Publishing Quantitative Reverse Transcriptase PCR Randomized Regulator Genes Research Rodent Rodent Model Scheme Sex Bias Sex Chromosomes Sex Differences Signal Pathway Statistical Data Interpretation Statistical Models Testing Therapeutic Tissue-Specific Gene Expression Up-Regulation Valproic Acid Variant Western Blotting Work X Chromosome Y Chromosome autism spectrum disorder base brain abnormalities chromatin immunoprecipitation delta protein developmental disease differential expression environmental stressor enzyme activity epigenetic regulation fetal gene interaction genotypic sex innovation interest male mouse model nerve stem cell organophosphorus insecticide pregnant prenatal exposure programs promoter relating to nervous system response sex sexual dimorphism transcriptome sequencing

Address Affect Air Pollution Antiepileptic Agents Anxiety Appearance Attention deficit hyperactivity disorder BDNF gene Behavior Behavior Disorders Biological Brain Brain-Derived Neurotrophic Factor Characteristics Chlorpyrifos Code Cognition Conceptions DNA Development Disease Environment Environmental Risk Factor Enzymes Epigenetic Process Etiology Experimental Designs Exposure to Female Fetus Future Gene Expression Genes Goals Gonadal Hormones Gonadal Steroid Hormones Human Ice Immunoblotting Insecticides Intellectual functioning disability Laboratory Study Lead Lysine Major Depressive Disorder Measures Mediating Mental disorders Messenger RNA Methylation Molecular Moods Mus Neurodevelopmental Disorder Organophosphates Pathogenicity Pathway Analysis Pesticides Pharmaceutical Preparations Poison Pregnancy Prevalence Prevention Protein Isoforms Proteins Publishing Quantitative Reverse Transcriptase PCR Randomized Regulator Genes Research Rodent Rodent Model Scheme Sex Bias Sex Chromosomes Sex Differences Signal Pathway Statistical Data Interpretation Statistical Models Testing Therapeutic Tissue-Specific Gene Expression Up-Regulation Valproic Acid Variant Western Blotting Work X Chromosome Y Chromosome autism spectrum disorder base brain abnormalities chromatin immunoprecipitation delta protein developmental disease differential expression environmental stressor enzyme activity epigenetic regulation fetal gene interaction genotypic sex innovation interest male mouse model nerve stem cell organophosphorus insecticide pregnant prenatal exposure programs promoter relating to nervous system response sex sexual dimorphism transcriptome sequencing

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项目摘要

PROJECT SUMMARY The prevalence of neurodevelopmental disorders of behavior and cognition such as autism spectrum disorders (ASDs) is increased by prenatal exposure to pathogenic environmental stressors such as the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) and organophosphate insecticides such as chlorpyrifos. The under- lying cellular and molecular mechanisms are not known. Many mental disorders are sexually dimorphic. Some (e.g., ASD and ADHD) are more common in males whereas others (e.g., major depression and anxiety) are more common in females. A goal of this research program is to investigate the biological basis for these sex differences in fetal mouse brain exposed to environmental stressors during early gestation, prior to the appear- ance of sex hormones. Published work by the PI has identified VPA-induced sex differences in the activating epigenetic mark, H3K4me3, leading to sexually-dimorphic expression of Bdnf, the gene encoding brain-derived neurotrophic factor. These studies with Bdnf establish an experimental paradigm for identifying other sexually- dimorphic proteins that regulate brain development and that may mediate the pathogenic effects of environ- mental stressors on brain development. An important clue to the underlying mechanism is that the enzymes that regulate H3K4me3, the H3K4-demethylases, JARID1C and JARID1D, are encoded by genes on the X and Y-chromosomes, respectively, and are therefore postulated to be differentially expressed in the two sexes. The specific aims of this research program are to 1) identify genes involved in early brain development (in addition to Bdnf) that are expressed differently in males and females in response to VPA due to sexually dimorphic H3K4 trimethylation and 2) test the hypothesis that JARID1 gene expression and enzyme activity are greater in males than in females, thereby providing a plausible mechanism for sexually dimorphic gene expression in the fetal brain. Identification of such genes, particularly if found to be associated with one or more developmentally relevant signaling pathways, will lead to a clearer understanding of the etiology of neurodevelopmental disor- ders such as ASDs and provide the basis for future, hypothesis driven initiatives to determine the pathogenic mechanisms of action of other environmental stressors acting during early gestation.

项目摘要行为和认知的神经发育障碍的流行，例如自闭症谱系障碍（ASD）通过产前暴露于致病性环境应激源（例如抗癫痫病）来增加（ASDS）情绪稳定药物，丙戊酸（VPA）和有机磷酸盐杀虫剂（如毒死rif）。低下分子和分子机制尚不清楚。许多精神障碍是性二态性的。一些（例如，ASD和ADHD）在男性中更常见，而其他人（例如，重度抑郁和焦虑）是在女性中更常见。该研究计划的目标是调查这些性别的生物学基础在出现之前，在妊娠期间暴露于环境压力源的胎儿小鼠大脑的差异 - 在出现之前性激素的ance。 PI发表的工作已经确定了VPA引起的性别差异表观遗传标记，H3K4me3，导致BDNF的性二态表达，该基因编码大脑衍生神经营养因子。这些对BDNF的研究建立了一个实验范式，以识别其他性行为调节大脑发育的二态蛋白质，可能介导环境的致病作用精神压力源对大脑发育。基础机制的重要线索是酶调节H3K4me3，H3K4-二甲基酶，JARID1C和JARID1D，由x和x上的基因编码 Y染色体分别分别是在两个性别中差异表达的。这该研究计划的具体目的是1）确定与早期大脑发育有关的基因（此外对bdnf）在男性和女性中对VPA的响应二态性二态的表达方式有所不同 H3K4三甲基化和2）检验了JARID1基因表达和酶活性更大的假设男性比女性中的男性，从而提供了一种合理的机制，用于在胎儿大脑。识别此类基因，特别是发现与一个或多个发育相关相关信号通路，将使对神经发育的病因有更清晰的理解诸如ASDS之类的DERS，并为假设驱动的倡议提供了确定致病性的基础早期妊娠期间作用的其他环境压力的作用机制。