Project 3: Environmental PPARγ Agonist-Mediated Toxicity in the Developing Immune System Jennifer Schlezinger Environmental Health Boston University Superfund.

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Project 3: Environmental PPARγ Agonist-Mediated Toxicity in the Developing Immune System Jennifer Schlezinger Environmental Health Boston University Superfund Research Program

Kawai M et al Am J Physiol Endocrinol Metab PPARγ Is a Key Transcription Factor in Bone PPAR  RXR HSC WBCs RBCs

Takada et al Nat. Rev. Rheumatol. Rzonca et al Endocrinology Aging also is associated with a reduced capacity to generate B cells! Osteoporosis: Obesity of the bone.

Long Term Goal: Determine molecular mechanisms by which Superfund chemicals (individually and as mixtures) impair ongoing development in the immune system. Current Objective: Determine the role of PPARγ (and other nuclear receptors) in phthalate- and organotin- induced alterations in bone marrow physiology. Hypothesis: Environmental PPAR/RXR ligands suppress B lymphopoiesis by two mechanisms: 1)directly, by inducing apoptosis in early B cells 2)indirectly, by altering the bone marrow microenvironment that supports lymphopoiesis, resulting in aging-like suppression of immune responses. Specific Aims: 1.Determine the relationship between PPAR and RXR activation and the functional consequences for MSC differentiation. In vitro. 2.Determine the mechanisms by which environmental PPAR/RXR agonists damage B lymphopoiesis, both directly and indirectly. In vitro. 3.Determine mechanisms by which in vivo exposure to PPAR/RXR agonists negatively affects bone physiology, lymphopoiesis and immune responses. In vivo.

In press: Pillai H, Fang M, Beglov D, Kozakov D, Vajda S, Stapleton H, Webster T, Schlezinger J The flame retardant Firemaster 550 contains PPARγ ligands that induce adipogenesis and suppress osteogenesis. Environ. Health Perspect. *Inter- and intra-SRP collaboration. *Core collaboration. *Trainee. Aim 1 Bragdon B, Burns R, Baker AH, Belkina AC, Morgan EF, Denis GV, Gerstenfeld LC and Schlezinger JJ Intrinsic sex-linked variations in osteogenic and adipogenic differentiation potential of bone marrow multipotent stromal cells. J. Cell. Physiol. *Trainee. Aim 1 Project 3: Publications

What’s happening this summer? 1. Finishing 16 months of making fat mice… Imaging VhTBT

What’s happening this summer? 3. Training – Lariah Extending adipogenesis/ osteogenesis studies to parabens. Working with Nrf2 and Wnt signaling.