Environmental PPAR Agonists Accelerate Aging of Bone and Impair Lymphopoiesis

描述（由申请人提供）：越来越多的环境污染物被认为有能力激活脂肪细胞分化的主要调节剂，过氧化物酶体增殖物激活受体（PPAR），包括邻苯二甲酸盐和有机素。三丁基锡（TBT）作为一种防污剂，一直是海洋环境中备受关注的污染物；然而，在农业农药、木材防腐剂和塑料制造中使用TBT已导致这种污染物的大量陆地来源，以至于在房屋灰尘中甚至可以测量到有机锡。我们的数据表明，TBT在骨髓基质细胞中是一种高效的PPAR激活剂。脂肪细胞分化的EC50为~10 nM，完全在人体肝脏和血液中检测到的有机素（0.1 ~ 500 nM）的浓度范围内。骨髓是一个支持骨形成和淋巴生成的多功能器官，随着年龄的增长，这两种功能都会受到损害。单个间充质干细胞祖细胞同时产生脂肪细胞和成骨细胞，导致脂肪细胞和成骨细胞分化之间的相互关系。随着哺乳动物年龄的增长，骨髓中脂肪量的增加与成骨细胞的减少有关。此外，暴露于治疗性PPAR3激活剂治疗II型糖尿病会导致患者脂肪骨形成并增加骨折风险。最近的文献表明，1)成骨细胞是最佳淋巴细胞生成所必需的，2)脂肪细胞是淋巴细胞生成的负调节因子。骨髓中基质元素和B细胞前体的复杂平衡需要B细胞在整个生命中持续发育，这对衰老的哺乳动物尤其重要，因为它们骨髓中脂肪的积累与淋巴生成的衰老同时发生。因此，我们假设污染物驱动的PPAR激活和脂肪细胞分化将导致骨骼过早衰老，骨髓中脂肪细胞的积累和成骨细胞分化的抑制导致淋巴细胞生成能力的丧失，以及骨骼完整性的丧失。以下具体目标旨在检验这一假设：1。确定环境和治疗性PPAR（/RXR1）激动剂改变骨髓间充质干细胞分化的分子机制。2. 观察tbt诱导骨髓间充质干细胞分化改变对B淋巴生成的影响。3. 确定长期低剂量TBT暴露对体内骨生理和B淋巴生成的影响。总的来说，这些研究将有助于对淋巴生成和骨髓微环境之间相互关系的基本理解，并为治疗方法和环境污染物如何改变骨髓生理学导致过早衰老提供新的基于机制的信息。

DESCRIPTION (provided by applicant): A growing number of environmental contaminants are being recognized for their ability to activate the master regulator of adipocyte differentiation, peroxisome proliferator activated receptor ( (PPAR(), including phthalates and organotins. Tributyltin (TBT) has been a pollutant of concern in the marine environment due to its use as an anti-fouling agent; however the use of TBT in agricultural pesticides, wood preservatives and the manufacturing of plastics has resulted in significant land-based sources of this contaminant such that organotins are even measurable in house dust. Our data indicate that TBT is a highly potent activator of PPAR( in bone marrow stromal cells. The EC50 for adipocyte differentiation is ~10 nM, a concentration well within the range of organotins measured in human in liver and blood (0.1-500 nM). The bone marrow is a multifunctional organ that supports bone formation, as well as lymphopoiesis, and both functions are compromised during aging. A single mesenchymal stem cell progenitor produces both adipocytes and osteoblasts, resulting in a reciprocal relationship between adipocyte and osteoblast differentiation. As mammals age, there is an increase in fat mass within the bone marrow associated with a concomitant loss of osteoblasts. Additionally, exposure to therapeutic PPAR3 activators for treatment to Type II diabetes causes fatty bone formation in patients and increases risk for fracture. Recent literature has shown that 1) osteoblasts are necessary for optimal lymphopoiesis and 2) adipocytes are negative regulators of lymphopoiesis. A complicated balance of stromal elements and B cell precursors in the bone marrow is required to perpetuate B cell development throughout life that is particularly critical in aging mammals, in whom accumulation of fat in the bone marrow occurs concurrently with senescence of lymphopoiesis. Thus, we hypothesize that contaminant-driven activation of PPAR( and adipocyte differentiation will lead to premature aging in the bone and that accumulation of adipocytes in bone marrow and suppression of osteoblast differentiation results in loss of the ability to generate lymphocytes, as well as in loss of bone integrity. The following specific aims are designed to examine this hypothesis: 1. Determine molecular mechanisms of alteration of bone marrow mesenchymal stem cell differentiation by environmental and therapeutic PPAR(/RXR1 agonists. 2. Examine effects of TBT-induced alteration of bone marrow mesenchymal stem cell differentiation on B lymphopoiesis. 3. Define impact of long-term, low-dose TBT exposure on bone physiology and B lymphopoiesis in vivo. Collectively, these studies will contribute to both the basic understanding of the inter-relationship between lymphopoiesis and the bone marrow microenvironment, as well as contribute new mechanism-based information on how therapeutics and environmental contaminants alter the physiology of the bone marrow leading to premature aging.