Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in

为了与发育毒性这一方案主题保持一致，这些研究的目标是确定 环境化学物质损害哺乳动物免疫发育的分子机制 系统。我们以前的研究表明，环境中普遍存在的芳烃受体(AhR) 激动剂通过诱导骨髓前B淋巴细胞和前/前B淋巴细胞深刻影响免疫系统发育 死亡。在确定这种免疫毒性表现的分子机制的过程中，我们 发现包括在该机构指定的优先化学品清单上的其他环境化学品 有毒物质和疾病登记，特别是过氧化物酶体增殖物激活受体激动剂/ (PPARy)，如邻苯二甲酸二(2-乙基己基)/邻苯二甲酸单(2-乙基己基)酯，传递一个有效的死亡信号 涉及不同于AhR配体激活的细胞内信号通路。此外，一个 内源性骨髓源性PPARy激动剂，15-脱氧-Al2|I4-前列腺素J2，或自然产生的 RXRA激动剂9-CW-维甲酸可增强对B细胞增殖的抑制。我们的PPARy工作模式 激动剂诱导的死亡基于相当多的新信息，提出了一种途径， 涉及半胱氨酸天冬氨酸氨基转移酶的激活和相互作用、信号转导通路和核因子-kB。因此， 1.MAP PPARy激动剂诱导依赖caspase的骨髓B细胞凋亡 信号通路。2.绘制PPARy激动剂诱导的死亡过程中的激酶激活级联图，并定义其 与半胱氨酸天冬氨酸氨基转移酶和核因子-KB活化的关系。3.明确化学协同作用的分子机制 发展中的B细胞凋亡。这些研究不仅有助于我们理解分子效应 PPARy激动剂对B细胞发育的影响，但也将验证一个易于应用于研究的平台 其他免疫毒性环境化学品，无论是单独还是以复杂混合物的形式，在分子水平上。

In keeping with the programmatic theme of developmental toxicity, the goal of these studies is to determine the molecular mechanisms by which environmental chemicals impair the development of the mammalian immune system. Our previous studies demonstrated that environmentally ubiquitous aryl hydrocarbon receptor (AhR) agonists profoundly affect immune system development by inducing bone marrow pro- and pro/pre-B lymphocyte death. In the course of defining the molecular mechanisms through which this immunotoxicity is manifest, we found that other environmental chemicals included on the list of priority chemicals designated by the Agency for Toxic Substances and Disease Registry, notably agonists of the peroxisome proliferator activated receptor/ (PPARy) such as di-(2-ethylhexyl) phthalate/ mono-(2-ethylhexyl) phthalate, deliver a potent death signal that involves intracellular signaling pathways distinct from those activated by AhR ligands. Furthermore, an endogenous bone marrow-derived PPARy agonist, 15-deoxy-Al2|I4-prostaglandin J2, or a naturally occurring RXRa agonist, 9-cw-retinoic acid, enhances the inhibition of B cell proliferation. Our working model of PPARy agonist-induced death, which is based on a considerable foundation of new information, proposes a pathway that involves the activation of and interaction between caspases, kinase signaling cascades and NF-KB. Accordingly, three specific aims are proposed: 1. Map PPARy agonist-induced caspase-dependent bone marrow B cell apoptosis signaling pathways. 2. Map the kinase activation cascade in PPARy agonist-induced death and define its relationship to caspase and NF-KB activation. 3. Define the molecular mechanisms of chemical synergy resulting in developing B cell apoptosis. These studies not only will contribute to our understanding of the molecular effects of PPARy agonists on developing B cells, but also will validate a platform that is easily applicable to the study of other immunotoxic environmental chemicals, either individually or in complex mixtures, at the molecular level.