DESCRIPTION (provided by applicant): A growing number of environmental contaminants are being recognized for their ability to activate the master regulator of adipocyte differentiation, peroxisome proliferator activated receptor ( (PPAR(), including phthalates and organotins. Tributyltin (TBT) has been a pollutant of concern in the marine environment due to its use as an anti-fouling agent; however the use of TBT in agricultural pesticides, wood preservatives and the manufacturing of plastics has resulted in significant land-based sources of this contaminant such that organotins are even measurable in house dust. Our data indicate that TBT is a highly potent activator of PPAR( in bone marrow stromal cells. The EC50 for adipocyte differentiation is ~10 nM, a concentration well within the range of organotins measured in human in liver and blood (0.1-500 nM). The bone marrow is a multifunctional organ that supports bone formation, as well as lymphopoiesis, and both functions are compromised during aging. A single mesenchymal stem cell progenitor produces both adipocytes and osteoblasts, resulting in a reciprocal relationship between adipocyte and osteoblast differentiation. As mammals age, there is an increase in fat mass within the bone marrow associated with a concomitant loss of osteoblasts. Additionally, exposure to therapeutic PPAR3 activators for treatment to Type II diabetes causes fatty bone formation in patients and increases risk for fracture. Recent literature has shown that 1) osteoblasts are necessary for optimal lymphopoiesis and 2) adipocytes are negative regulators of lymphopoiesis. A complicated balance of stromal elements and B cell precursors in the bone marrow is required to perpetuate B cell development throughout life that is particularly critical in aging mammals, in whom accumulation of fat in the bone marrow occurs concurrently with senescence of lymphopoiesis. Thus, we hypothesize that contaminant-driven activation of PPAR( and adipocyte differentiation will lead to premature aging in the bone and that accumulation of adipocytes in bone marrow and suppression of osteoblast differentiation results in loss of the ability to generate lymphocytes, as well as in loss of bone integrity. The following specific aims are designed to examine this hypothesis: 1. Determine molecular mechanisms of alteration of bone marrow mesenchymal stem cell differentiation by environmental and therapeutic PPAR(/RXR1 agonists. 2. Examine effects of TBT-induced alteration of bone marrow mesenchymal stem cell differentiation on B lymphopoiesis. 3. Define impact of long-term, low-dose TBT exposure on bone physiology and B lymphopoiesis in vivo. Collectively, these studies will contribute to both the basic understanding of the inter-relationship between lymphopoiesis and the bone marrow microenvironment, as well as contribute new mechanism-based information on how therapeutics and environmental contaminants alter the physiology of the bone marrow leading to premature aging.

PUBLIC HEALTH RELEVANCE: We hypothesize that exposure to environmental contaminants can lead to premature aging of bone. Here we propose that engagement of a protein receptor, called the peroxisome proliferator activated receptor, by contaminants in plastics alters the differentiation of cells in the bone marrow. The resulting accumulation of fat in the bone, reminiscent of aging, will cause the loss of cells that support formation of new bone and that support formation of new immune cells. Understanding the molecular mechanisms leading to altered bone marrow cell differentiation and its impact on immune cell formation will allow us to minimize the detrimental effects of contaminant exposure and the unintended effects of therapeutics that also target this receptor.