Endocrine disruption by organotins in obesity and diabetes

描述(由申请人提供)：这是一份对父母拨款ES-015849的竞争性补充申请，以回应题为“美国国立卫生研究院宣布恢复法案资金可用于竞争性修订”的通知编号(NOTOD-09-058)。出生前和出生后早期的事件，如母亲的营养、药物和化学物质暴露，被接受、记住，然后在以后的生活中表现为健康后果。在美国，肥胖症的流行每年造成超过750亿美元的损失，主要是通过增加医疗保健成本。越来越多的证据支持环境因素在肥胖中的重要作用。其中之一是接触内分泌干扰性化学物质。我们发表的研究发现，三丁基锡(TBT)是一种环境“肥胖源”，容易使暴露于环境中的人体重增加。在子宫内接触TBT会导致长期代谢功能障碍，增加脂肪堆积，增加肥胖风险。这些数据支持TBT通过不适当地调节哺乳动物脂肪细胞分化的“主调节器”--过氧化体增殖物激活受体--γ(PPAR？)信号通路。初步结果显示，出生前暴露于TBT可改变多能间充质干细胞(MSCs)的命运，使其转向脂肪细胞系，并且其启动子的表观遗传修饰导致关键的PPAR？靶基因。我们假设PPAR的产前激活？通过TBT在表观遗传学上印记在干细胞间的记忆中，在发育过程中触发MSCs向脂肪库的迁移和分化。我们提出了两个特定的目标来验证这一假设：1)产前TBT暴露是否影响体内多能基质细胞的命运？2)产前TBT暴露是如何影响多潜能基质细胞的？拟议的工作将促进在理解控制MSC命运的产前编程的发育途径的调制以及暴露于环境致病菌如何改变这一命运方面取得快速进展。 与公共健康相关：肥胖是一个主要的公共健康问题。我们建议阐明激活PPAR的内分泌干扰化学物质如何影响母体对脂肪组织发育的编程？以及循环中的MSCs是否有助于脂肪的发育。这项研究的成功完成将为理解肥胖的母体编程、肥胖原因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。

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.