Peroxisome proliferator activated receptor y (PPARy) is poised at the apex of a regulatory network that controls bone physiology, yet it remains unclear how activation of PPARy 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 PPARy and its heterodimerization partners the retinoid X receptors (RXR). Our long-term goal 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 objective here is to determine the role of PPARy activation in phthalate- and organotin-induced alteration of bone marrow physiology. We 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. We will investigate this hypothesis by pursuing three Specific Aims: 1) 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, 2) 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 3) 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. Critical knowledge will be gained to refine human risk assessment and to improve prevention of both bone loss and immune compromise.

Public Health Relevance

Aging is associated with an impaired immune response to infection, and exposure to environmental obesogens may mimic this phenomenon. Our data suggest that contaminant-induced fat formation in bone results not only in loss of bone quality but also in compromise ofthe microenvironment required to support immune cell development, similar to aging. Results from these studies will provide fundamental information on the interaction of the bone marrow environment and immune cell development and targets for intervention.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Boston University
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Aschengrau, Ann; Janulewicz, Patricia A; White, Roberta F et al. (2016) Long-term Neurotoxic Effects of Early-life Exposure to Tetrachloroethylene-contaminated Drinking Water. Ann Glob Health 82:169-79
Mahalingaiah, S; Hart, J E; Laden, F et al. (2016) Adult air pollution exposure and risk of infertility in the Nurses' Health Study II. Hum Reprod 31:638-47
Hewlett, Meghan; Chow, Erika; Aschengrau, Ann et al. (2016) Prenatal Exposure to Endocrine Disruptors: A Developmental Etiology for Polycystic Ovary Syndrome. Reprod Sci :
Girguis, Mariam S; Strickland, Matthew J; Hu, Xuefei et al. (2016) Maternal exposure to traffic-related air pollution and birth defects in Massachusetts. Environ Res 146:1-9
Reid, Noah M; Proestou, Dina A; Clark, Bryan W et al. (2016) The genomic landscape of rapid repeated evolutionary adaptation to toxic pollution in wild fish. Science 354:1305-1308
Mahalingaiah, Shruthi; Winter, Michael R; Aschengrau, Ann (2016) Association of prenatal and early life exposure to tetrachloroethylene (PCE) with polycystic ovary syndrome and other reproductive disorders in the cape cod health study: A retrospective cohort study. Reprod Toxicol 65:87-94
Padilla, Cindy M; Kihal-Talantikit, Wahida; Vieira, Verónica M et al. (2016) City-Specific Spatiotemporal Infant and Neonatal Mortality Clusters: Links with Socioeconomic and Air Pollution Spatial Patterns in France. Int J Environ Res Public Health 13:
Townley, Ian K; Karchner, Sibel I; Skripnikova, Elena et al. (2016) Sequence and functional characterization of hypoxia inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish, Fundulus heteroclitus. Am J Physiol Regul Integr Comp Physiol :ajpregu.00402.2016
Bolt, Alicia M; Grant, Michael P; Wu, Ting Hua et al. (2016) Tungsten Promotes Sex-Specific Adipogenesis in the Bone by Altering Differentiation of Bone Marrow-Resident Mesenchymal Stromal Cells. Toxicol Sci 150:333-46
Pennell, Kelly G; Scammell, Madeleine K; McClean, Michael D et al. (2016) Field data and numerical modeling: A multiple lines of evidence approach for assessing vapor intrusion exposure risks. Sci Total Environ 556:291-301

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