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
Carwile, Jenny L; Mahalingaiah, Shruthi; Winter, Michael R et al. (2014) Prenatal drinking-water exposure to tetrachloroethylene and ischemic placental disease: a retrospective cohort study. Environ Health 13:72
Lowe, Margaret M; Mold, Jeff E; Kanwar, Bittoo et al. (2014) Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production. PLoS One 9:e87877
Hoffman, Kate; Vieira, Veronica M; Daniels, Julie L (2014) Brief report: diminishing geographic variability in autism spectrum disorders over time? J Autism Dev Disord 44:712-8
Parks, Ashley J; Pollastri, Michael P; Hahn, Mark E et al. (2014) In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo. Mol Pharmacol 86:593-608
Morrison, Ann Michelle Stanley; Goldstone, Jared V; Lamb, David C et al. (2014) Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14*-demethylase. Biochim Biophys Acta 1840:1825-36
Pillai, Hari K; Fang, Mingliang; Beglov, Dmitri et al. (2014) Ligand binding and activation of PPAR? by Firemaster® 550: effects on adipogenesis and osteogenesis in vitro. Environ Health Perspect 122:1225-32
Reitzel, Adam M; Karchner, Sibel I; Franks, Diana G et al. (2014) Genetic variation at aryl hydrocarbon receptor (AHR) loci in populations of Atlantic killifish (Fundulus heteroclitus) inhabiting polluted and reference habitats. BMC Evol Biol 14:6
Bristow, Robert E; Chang, Jenny; Ziogas, Argyrios et al. (2014) Spatial analysis of adherence to treatment guidelines for advanced-stage ovarian cancer and the impact of race and socioeconomic status. Gynecol Oncol 134:60-7
Quintana, Francisco J; Sherr, David H (2013) Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 65:1148-61
Fraccalvieri, Domenico; Soshilov, Anatoly A; Karchner, Sibel I et al. (2013) Comparative analysis of homology models of the AH receptor ligand binding domain: verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor. Biochemistry 52:714-25

Showing the most recent 10 out of 279 publications