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

为了与发育毒性的计划主题保持一致，这些研究的目标是确定 环境化学物质损害哺乳动物免疫系统发育的分子机制 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淋巴细胞而深刻地影响免疫系统发育 死亡在确定这种免疫毒性表现的分子机制的过程中，我们 发现其他环境化学品包括在优先化学品名单上指定的机构， 有毒物质和疾病登记处，特别是过氧化物酶体增殖物激活受体激动剂/ 例如邻苯二甲酸二-（2-乙基己基）酯/邻苯二甲酸单-（2-乙基己基）酯的PPARy，传递强有力的死亡信号， 涉及不同于AhR配体激活的细胞内信号传导途径。此外， 内源性骨髓源性PPAR γ激动剂，15-脱氧-Al 2| I4-前列腺素J2，或天然存在的 RXR α激动剂9-顺式-视黄酸增强了对B细胞增殖的抑制。我们的PPARy工作模型 激动剂诱导的死亡，这是基于相当基础的新信息，提出了一个途径， 涉及半胱天冬酶、激酶信号级联和NF-κ B的激活和相互作用。因此，委员会认为， 提出了三个具体目标：1。Map PPARy激动剂诱导的半胱天冬酶依赖性骨髓B细胞凋亡 信号通路2.在PPARy激动剂诱导的死亡中绘制激酶激活级联并定义其 与caspase和NF-κ B活化的关系。3.定义化学协同作用的分子机制， 在发展B细胞凋亡中。这些研究不仅有助于我们了解分子效应 PPARy激动剂对发育中的B细胞的作用，而且还将验证一个容易适用于研究 其他免疫毒性环境化学品，无论是单独或复杂的混合物，在分子水平。

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.