Is bisphenol A diglycidyl ether (BADGE) and obesogen?

描述(由申请人提供)：这是一种R21应用，旨在测试双酚A二缩水甘油醚(BAGE)在体内通过独立于PPAR3的途径作为致肥剂的假设。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1470亿美元的损失，主要是通过增加医疗保健费用。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。我们的初步结果表明，BAGE通过一条似乎不涉及关键成脂基因--过氧化物酶体增殖物激活受体γ(PPAR3)的途径诱导小鼠和人类多能间充质干细胞(MSCs)成脂。我们希望在活体内测试BAGE作为肥胖来源的假设。提出了两个特定的目标来验证这一假设：1)BAGE暴露是否使小鼠容易增加脂肪生成和肥胖，如果是这样，它是否改变了MSC室的谱系分配？2)BAGE通过什么分子途径影响脂肪生成和肥胖？这项拟议的工作将促进在了解大剂量化学物质BAGE在体内是否在环境相关剂量下作为致肥剂发挥作用方面取得快速进展，并将为深入了解内分泌干扰物如何影响脂肪生成和肥胖提供见解。 与公共健康相关：肥胖是一个主要的公共健康问题。我们建议阐明双酚A二缩水甘油醚(BAGE)是如何影响母体和脂肪组织发育的早期生命规划的。这项研究的成功完成将为理解肥胖的发育编程、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 an R21 application intended to test the hypothesis that bisphenol A diglycidyl ether (BADGE) acts as an obesogen, in vivo through a pathway that is independent of PPAR3. 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 $147 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 preliminary results demonstrate that BADGE induces adipogenesis in both mouse and human multipotent mesenchymal stem cells (MSCs) through a pathway that appears not to involve a key adipogenic gene - the peroxisome proliferator activated receptor gamma (PPAR3). We wish to test the hypothesis that BADGE acts as an obesogen, in vivo. Two specific aims are proposed to test this hypothesis: 1) Does BADGE exposure predispose mice to increased adipogenesis and obesity and if so, does it alter lineage allocation in the MSC compartment? 2) What molecular pathway does BADGE act through to influence adipogenesis and obesity? The proposed work will facilitate rapid progress in understanding whether the high volume chemical, BADGE, acts as an obesogen, in vivo, at environmentally relevant doses and will provide insights into how endocrine disrupting chemicals influence adipogenesis and obesity. PUBLIC HEALTH RELEVANCE: Obesity is a major public health problem. We propose to elucidate how maternal and early life programming of adipose tissue development is influenced by the endocrine disrupting chemical, bisphenol A diglycidyl ether (BADGE). The successful completion of this research will make important contributions to understanding the developmental programming of obesity, how obesogens affect this process, and what is the contribution of altered stem cell programming.