Superfund Research Program
Environmental PPARγ Agonist-Mediated Toxicity in the Developing Immune System
Project Leader: Jennifer J. Schlezinger
Grant Number: P42ES007381
Funding Period: 2005-2020
Project Summary (2012-2017)
Peroxisome proliferator activated receptor γ (PPARγ) is poised at the apex of a regulatory network that controls bone physiology, yet it remains unclear how activation of PPARγ in the bone marrow may alter the microenvironment that supports life-long B cell development. This is an important problem, as a growing number of environmental contaminants, including Superfund chemicals such as phthalates and organotins, are being recognized for their ability to activate PPARγ and its heterodimerization partners the retinoid X receptors (RXR).
The long-term goal of Jennifer Schlezinger, Ph.D., and her team of researchers is to understand the molecular mechanisms by which individual and complex mixtures of Superfund chemicals impair development in the mammalian immune system, a system that requires ongoing development in the face of continuing pathogen exposures. The researchers’ objective is to determine the role of PPARγ activation in phthalate- and organotin-induced alteration of bone marrow physiology. They hypothesize that environmental PPAR/RXR ligands suppress B lymphopoiesis by two mechanisms, directly by inducing apoptosis in early B cells and indirectly by altering the bone marrow microenvironment that supports lymphopoiesis, resulting in aging-like suppression of immune responses. The research group is investigating this hypothesis by pursuing three specific goals:
- Determine the relationship between PPAR and RXR activation and the functional consequences for multipotent mesenchymal stromal cell differentiation by determining changes in the osteogenic transcriptome induced by a phthalate, an organotin, and contaminant mixtures,
- Determine the mechanisms by which environmental PPAR/RXR agonists damage B lymphopoiesis, both directly and indirectly by defining mechanisms of toxicant-induced apoptosis and by testing contaminant-altered bone marrow environments for the ability to support B cell development, and
- Determine mechanisms by which in vivo exposure to environmental PPAR/RXR agonists negatively affects bone physiology, lymphopoiesis and immune responses by examining organotin-induced defects in bone integrity, B cell development and B cell function.
From this research, the investigators will gain critical knowledge to refine human risk assessment and to improve prevention of both bone loss and immune compromise.