Transgenerational inheritance of prenatal obesogen exposure

产前肥胖原暴露的跨代遗传

基本信息

批准号：
9116209
负责人：
BRUCE BLUMBERG
金额：
$ 67.03万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116209
关键词：
Address Adipocytes Adipose tissue Adolescence Adult Affect Animal Model Animals Biological Cells Chemical Exposure Chromatin Structure DNA DNA Methylation Data Development Discipline of Nursing Endocrine Disruptors Engravings Environmental Exposure Environmental Risk Factor Epidemic Epigenetic Process Event Exposure to Fatty acid glycerol esters Fetus Functional disorder Future Gene Expression Gene Targeting Generations Genes Genetic Genome Genomic DNA Genomics Goals Health Health Care Costs Healthcare Systems Individual Learning Life Mammals Measures Mediating Memory Mesenchymal Stem Cells Metabolic Modeling Modification Mus Mutation Obesity Obesity associated disease Osteocytes PPAR gamma Pathway interactions Pharmaceutical Preparations Predisposition Process Public Health Publishing Research Role Signal Pathway Specimen Stem cells Technology Testing Time Transcriptional Regulation Up-Regulation Weight Gain Work adipocyte differentiation base bone cost deep sequencing differential expression early life exposure environmental chemical epigenetic regulation epigenomics genome analysis histone modification in utero innovation lipid biosynthesis male mother nutrition novel obesity risk obesogen obesogenic offspring osteogenic postnatal pregnant prenatal prenatal exposure prevent programs promoter response sperm cell stem cell fate transcription factor transcriptomics transgenerational epigenetic inheritance tributyltin

项目摘要

DESCRIPTION (provided by applicant): This is an R01 application submitted in response to RFA-ES-12-006, "Transgenerational Inheritance in Mammals after Environmental Exposure". Prenatal and early postnatal events such as maternal nutrition, drug, and chemical exposure are received, remembered, and then manifested in health consequences later in life. The obesity epidemic costs more than $208 billion annually in the US in additional health care costs associated with obesity-related diseases. Emerging evidence supports an important role for environmental factors in obesity. Among these is exposure to endocrine disrupting chemicals (EDCs). Our published work identified tributyltin (TBT) as an environmental "obesogen" that predisposes exposed individuals to weight gain. In utero TBT exposure leads to long-term metabolic dysfunctions, enhanced fat accumulation, and increased risk of obesity. These data support the model that TBT acts via inappropriate modulation of the "master regulator" of mammalian adipocyte differentiation - the peroxisome proliferator activated receptor gamma (PPARγ) signaling pathway. Our published and preliminary results reveal that prenatal TBT exposure alters the fate of multipotent mesenchymal stem cells (MSCs) by diverting them to an adipocyte lineage at the expense of bone and that this reprogramming is transgenerational, persisting through at least the F3 generation after F0 exposure. The transgenerational inheritance of the effects of TBT exposure suggests that these effects are epigenetic and permanent and that epigenetic modification of the promoter leads to up-regulation of a key PPARγ target gene. We hypothesize that prenatal exposure to TBT is epigenetically engraved in the memory of the MSC compartment, reprogramming MSCs toward the adipogenic and away from the osteogenic lineage. Three specific aims are proposed to test this hypothesis: 1) which genes are epigenetically modified by prenatal TBT exposure to elicit altered expression in MSCs that promotes the adipocyte lineage at the expense of the osteogenic lineage? 2) How does TBT exert transgenerational effects on lineage allocation in MSCs?, 3) Are postnatal effects of TBT exposure mediated by epigenetic alterations? We will use state-of-the-art genomic, epigenomic and transcriptomic analyses to address these questions. The proposed work will provide a deep understanding of how TBT (and likely other obesogens) act transgenerationally to reprogram MSC fate and will identify critical developmental windows for TBT exposure.

描述（由应用程序提供）：这是针对RFA-ES-12-006提交的R01申请，“环境暴露后哺乳动物中的跨代遗传”。收到，记住，记住，然后表现出产后和早期产后事件，例如母体营养，药物和化学暴露，然后表现出生命后期的健康后果。肥胖流行病在美国每年的额外医疗费用与肥胖相关疾病有关。新兴证据支持肥胖中环境因素的重要作用。其中包括暴露于内分泌破坏化学物质（EDC）。我们已发表的工作确定了tributyltin（TBT）是一种环境“肥胖”，使人容易体重增加。在子宫内，TBT暴露会导致长期代谢功能障碍，增加脂肪的积累和肥胖风险增加。这些数据支持TBT通过对哺乳动物脂肪细胞分化的“主调节器”的不适当调制作用的模型 - 过氧化物体增殖物激活受体伽马（PPARγ）信号传导途径。我们发表的初步结果表明，产前TBT暴露改变了多能间充质干细胞（MSC）的脂肪，通过将其转移到脂肪细胞谱系上，以骨骼为代价，并且这种重编程是转变的，至少在F3后F3生成后持续使用F3生成。 TBT暴露作用的转化遗传表明，这些作用是表观遗传和永久性的，并且启动子的表观遗传修饰会导致关键PPARγ靶基因的上调。我们假设在MSC室的记忆中刻有产前暴露于TBT的TBT，将MSC重新编程为脂肪生成，并远离成骨谱系。提出了三个具体目的来检验这一假设：1）通过产前TBT暴露于MSC中的表达改变了哪些基因，以促进脂肪细胞谱系的表达改变，以造成成骨谱系为代价？ 2）TBT如何对MSC中的谱系分配执行转化影响？，3）TBT暴露的产后影响是否是由表观遗传改变介导的？我们将使用最先进的基因组，表观基因组和转录组分析来解决这些问题。拟议的工作将对TBT（以及其他可能的肥胖症）如何转化以重新编程MSC命运的方式深入了解，并将确定关键的TBT暴露窗口。