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能够激活脂肪细胞分化的主要调节因子过氧化物酶体增殖物激活受体（（PPAR），包括邻苯二甲酸酯和有机锡。由于三丁基锡被用作防污剂，它一直是海洋环境中令人关注的污染物;然而，三丁基锡在农业杀虫剂、木材防腐剂和塑料制造中的使用导致了这一污染物的大量陆地来源，甚至在室内灰尘中也可以测量到有机锡。我们的数据表明，TBT是一种高效的过氧化物酶体增殖物激活剂（在骨髓基质细胞。脂肪细胞分化的EC 50约为10 nM，在人体肝脏和血液中测得的有机锡浓度范围内（0.1-500 nM）。骨髓是支持骨形成和淋巴细胞生成的多功能器官，这两种功能在衰老过程中都会受到损害。单个间充质干细胞祖细胞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，骨髓中的脂肪量增加，伴随着成骨细胞的损失。此外，暴露于用于治疗II型糖尿病的治疗性PPAR 3激活剂会导致患者的脂肪骨形成并增加骨折的风险。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。骨髓中基质成分和B细胞前体的复杂平衡是终生维持B细胞发育所必需的，这在衰老的哺乳动物中特别关键，其中骨髓中脂肪的积累与淋巴细胞生成的衰老同时发生。因此，我们假设污染物驱动的PPAR活化（和脂肪细胞分化）将导致骨的过早老化，骨髓中脂肪细胞的积累和成骨细胞分化的抑制导致产生淋巴细胞的能力丧失，以及骨完整性的丧失。以下具体目标是为了检验这一假设：1。确定环境和治疗性PPAR（/RXR 1激动剂改变骨髓间充质干细胞分化的分子机制。2.检测TBT诱导的骨髓间充质干细胞分化改变对B淋巴细胞生成的影响。3.确定长期、低剂量三丁基锡化合物接触对体内骨生理和B淋巴细胞生成的影响。总的来说，这些研究将有助于对淋巴细胞生成和骨髓微环境之间的相互关系的基本理解，以及关于治疗剂和环境污染物如何改变骨髓生理学导致过早衰老的新机制信息。 公共卫生相关性：我们假设暴露于环境污染物可导致骨骼过早老化。在这里，我们提出，参与的蛋白质受体，称为过氧化物酶体增殖物激活受体，塑料中的污染物改变了骨髓细胞的分化。由此产生的脂肪在骨骼中的积累，让人想起衰老，将导致支持新骨形成和支持新免疫细胞形成的细胞的损失。了解导致骨髓细胞分化改变的分子机制及其对免疫细胞形成的影响将使我们能够最大限度地减少污染物暴露的有害影响和也针对该受体的治疗剂的非预期影响。

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. PUBLIC HEALTH RELEVANCE: We hypothesize that exposure to environmental contaminants can lead to premature aging of bone. Here we propose that engagement of a protein receptor, called the peroxisome proliferator activated receptor, by contaminants in plastics alters the differentiation of cells in the bone marrow. The resulting accumulation of fat in the bone, reminiscent of aging, will cause the loss of cells that support formation of new bone and that support formation of new immune cells. Understanding the molecular mechanisms leading to altered bone marrow cell differentiation and its impact on immune cell formation will allow us to minimize the detrimental effects of contaminant exposure and the unintended effects of therapeutics that also target this receptor.