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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
3P42ES007381-18S1
Application #
8908683
Study Section
Special Emphasis Panel (ZES1-JAB-J)
Program Officer
Henry, Heather F
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
18
Fiscal Year
2014
Total Cost
$4,867
Indirect Cost
$1,894
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Aschengrau, Ann; Gallagher, Lisa G; Winter, Michael et al. (2018) Modeled exposure to tetrachloroethylene-contaminated drinking water and the occurrence of birth defects: a case-control study from Massachusetts and Rhode Island. Environ Health 17:75
Weisskopf, Marc G; Seals, Ryan M; Webster, Thomas F (2018) Bias Amplification in Epidemiologic Analysis of Exposure to Mixtures. Environ Health Perspect 126:047003
Narasimhan, Supraja; Stanford Zulick, Elizabeth; Novikov, Olga et al. (2018) Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor. Int J Mol Sci 19:
Rothhammer, Veit; Borucki, Davis M; Kenison, Jessica E et al. (2018) Detection of aryl hydrocarbon receptor agonists in human samples. Sci Rep 8:4970
Lille-Langøy, Roger; Karlsen, Odd André; Myklebust, Line Merethe et al. (2018) Sequence variations in pxr (nr1i2) from zebrafish (Danio rerio) strains affect nuclear receptor function. Toxicol Sci :
Lemaire, Benjamin; Karchner, Sibel I; Goldstone, Jared V et al. (2018) Molecular adaptation to high pressure in cytochrome P450 1A and aryl hydrocarbon receptor systems of the deep-sea fish Coryphaenoides armatus. Biochim Biophys Acta Proteins Proteom 1866:155-165
Eide, Marta; Rydbeck, Halfdan; Tørresen, Ole K et al. (2018) Independent losses of a xenobiotic receptor across teleost evolution. Sci Rep 8:10404
Watt, James; Baker, Amelia H; Meeks, Brett et al. (2018) Tributyltin induces distinct effects on cortical and trabecular bone in female C57Bl/6J mice. J Cell Physiol 233:7007-7021
Aschengrau, Ann; Gallagher, Lisa G; Winter, Michael et al. (2018) Modeled exposure to tetrachloroethylene-contaminated drinking water and the risk of placenta-related stillbirths: a case-control study from Massachusetts and Rhode Island. Environ Health 17:58
Kim, Stephanie; Li, Amy; Monti, Stefano et al. (2018) Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models. Arch Toxicol 92:2859-2874

Showing the most recent 10 out of 398 publications