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Placental epigenetic mechanisms contributing to sex-specific impacts of maternal stress on fetal development

胎盘表观遗传机制导致母体压力对胎儿发育的性别特异性影响

基本信息

批准号：
10359743
负责人：
Tracy L Bale
金额：
$ 24.81万
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：
2019-03-11 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359743
关键词：
Affect Attention deficit hyperactivity disorder Biochemical Birth Brain Cells Development EZH2 gene Environment Epigenetic Process Female Fetal Development Fetus Gene Expression Gene Targeting Genes Genetic Genetic Transcription Glucocorticoids Growth Histones Human Hypothalamic structure Link Metabolic Metabolic dysfunction Methods Methylation Methyltransferase MicroRNAs Mitochondria Modeling Molecular Molecular Target Mus Neurons Nuclear O-GlcNAc transferase Outcome Perfusion Phenotype Placenta Predictive Factor Pregnancy Proteomics Puberty Regulation RiboTag Risk Sex Bias Sex Chromosomes Sex Differences Sex Ratio Signal Transduction Stress Testing Time Tissues Transcriptional Regulation Transferase Transgenic Mice Transgenic Organisms Weaning Weight autism spectrum disorder boys disorder risk ex vivo perfusion fetal gene repression genome wide screen genome-wide girls in utero innovation male maternal stress metabolomics mitochondrial dysfunction mitochondrial messenger RNA mouse model offspring outcome prediction prenatal prenatal stress resilience response sex steroid hormone transcriptome trophoblast

项目摘要

Defining the mechanisms by which stress in the environment during pregnancy promotes changes in development is critical in identifying factors predictive of disease risk or resilience. One major consistency across prenatal insults is the increased vulnerability of males. In this proposal, we utilize our mouse model of early prenatal stress (EPS) to examine sex-specific placental transcriptional regulation. In our EPS model, male, but not female, offspring present with increased stress sensitivity, including increased HPA stress axis activity, reduced post-weaning growth, and hypothalamic mitochondrial dysfunction. Sex differences in the placental function are likely to produce sex-specific transplacental signals to the developing fetal brain. Sex differences in the placenta begin with sex chromosomes. Through a genome-wide screen following maternal stress, we identified the X-linked gene, OGT, as causal in programming the male-specific stress phenotype via its regulation of the histone transcriptional repressive mark, H3K27me3. This proposal uses innovative approaches to determine the mechanisms by which the female placenta is able to restrict transcriptional responses to stress in the environment, where males are not, thus placing the male developing brain at greater risk prenatally. The transplacental signals received by the developing brain appear to be related to energy availability and impact metabolic and mitochondrial programming. Of key translational importance, we have also found the same biochemical and molecular outcomes are predicted by fetal sex in human placental tissue. Therefore, our proposal will focus on defining the causal importance of H3K27me3 in risk for developmental changes in response to stress, identify the sex-specific transplacental signals resulting from these changes in placental function using ex vivo perfusion, and determine the cellular compartment and mechanism by which these changes promote hypothalamic mitochondrial reprogramming and the EPS phenotype.

确定怀孕期间环境中的压力促进改变的机制