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

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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.