Endocrine disruption by organotins in obesity and diabetes

有机锡对肥胖和糖尿病的内分泌干扰

• 批准号: 7807840
• 负责人: BRUCE BLUMBERG
• 金额: $ 61.2万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2012-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807840
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Bone Marrow; Bone Marrow Transplantation; Budgets; Chemical Exposure; Data; Development; Diabetes Mellitus; Diet; Endocrine Disruptors; Endocrine disruption; Environmental Risk Factor; Epidemic; Epigenetic Process; Event; Exposure to; Fatty acid glycerol esters; Functional disorder; Funding; Future; Gene Targeting; Genes; Genomics; Goals; Growth; Health; Health Care Costs; Homing; Hour; Human Resources; Hyperplasia; Individual; Laboratories; Lead; Life; Mammals; Memory; Mesenchymal Stem Cells; Metabolic; Methylation; Modeling; Modification; Mus; Obesity; Occupations; PPAR gamma; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Positioning Attribute; Process; Public Health; Publishing; Recovery; Relative (related person); Research; Role; Signal Pathway; Stem cells; Stromal Cells; Testing; Time; Transgenic Mice; United States National Institutes of Health; Up-Regulation; Weight Gain; Work; adipocyte differentiation; base; bisphenol A; bisulfite; cell motility; chromatin immunoprecipitation; cost; imprint; in utero; in vivo; migration; mother nutrition; obesity risk; parent grant; phthalates; postnatal; prenatal; programs; promoter; public health relevance; research study; response; stem cell fate; tributyltin

DESCRIPTION (provided by applicant): This is a competitive supplemental application to parent grant ES-015849 in response to Notice Number (NOTOD-09-058) entitled: "NIH Announces the Availability of Recovery Act Funds for Competitive Revision". 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 $75 billion annually in the US, primarily by increasing health care costs. Emerging evidence supports an important role for environmental factors in obesity. Among these is exposure to endocrine disrupting chemicals. 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 (PPAR?) signaling pathway. Preliminary results reveal that prenatal TBT exposure alters the fate of multipotent mesenchymal stem cells (MSCs) by diverting them to an adipocyte lineage and that epigenetic modification of its promoter leads to up-regulation of a key PPAR? target gene. We hypothesize that prenatal activation of PPAR? by TBT is epigenetically imprinted in the stem cell compartment memory triggering the migration and differentiation of MSCs to fat depots during development. Two specific aims are proposed to test this hypothesis: 1) Does prenatal TBT exposure affect multipotent stromal cell fate in vivo? 2) How is prenatal TBT exposure imprinted in the multipotent stromal cell compartment? The proposed work will facilitate rapid progress in understanding the modulation of developmental pathways controlling the prenatal programming of MSC fate by and how exposure to environmental obesogens alters this fate. PUBLIC HEALTH RELEVANCE: Obesity is a major public health problem. We propose to elucidate how maternal programming of adipose tissue development is influenced by endocrine disrupting chemicals that activate PPAR? and whether circulating MSCs contribute to adipose development. The successful completion of this research will make important contributions to understanding the maternal programming of obesity, how obesogens affect this process, and what is the contribution of altered stem cell programming.

描述（由申请人提供）：这是一个有竞争力的补充申请，以母基金ES-015849响应通知编号（NOTOD-09-058），标题为：“NIH宣布恢复法资金的可用性竞争性修订”。产前和产后早期的事件，如母亲的营养，药物和化学品接触，接收，记住，然后在以后的生活中表现出健康后果。在美国，肥胖流行病每年花费超过750亿美元，主要是通过增加医疗保健费用。新出现的证据支持环境因素在肥胖中的重要作用。其中之一是接触干扰内分泌的化学品。我们已发表的工作确定三丁基锡（TBT）是一种环境“肥胖原”，易使暴露个体体重增加。在子宫内接触三丁基锡化合物会导致长期的代谢功能障碍、脂肪积累增加和肥胖风险增加。这些数据支持三丁基锡化合物通过不适当调节哺乳动物脂肪细胞分化的“主调节因子”--过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体？）信号通路初步结果显示，产前三丁基锡化合物暴露改变了多能间充质干细胞（MSC）的命运，将它们转移到脂肪细胞系，其启动子的表观遗传修饰导致上调的一个关键的过氧化物酶体增殖物激活受体？靶基因我们假设产前激活的过氧化物酶体增殖物激活体？通过TBT在干细胞隔室记忆中表观遗传印记，触发MSC在发育期间向脂肪库的迁移和分化。提出了两个具体目标来检验这一假设：1）产前三丁基锡化合物暴露是否影响体内多能基质细胞的命运？2)产前三丁基锡化合物暴露如何在多能基质细胞隔室中留下印记？拟议的工作将促进在了解控制MSC命运的产前编程的发育途径的调制以及暴露于环境肥胖剂如何改变这种命运方面的快速进展。 公共卫生相关性：肥胖是一个主要的公共卫生问题。我们建议阐明如何影响母体脂肪组织发育的编程内分泌干扰物激活过氧化物酶体增殖物激活受体？以及循环MSC是否有助于脂肪发育。这项研究的成功完成将为理解肥胖的母体编程，肥胖剂如何影响这一过程以及改变干细胞编程的贡献做出重要贡献。