HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schlezinger, J. J. Articles by Sherr, D. H. Search for Related Content PubMed PubMed Citation Articles by Schlezinger, J. J. Articles by Sherr, D. H.

Environmental and Endogenous Peroxisome Proliferator-Activated Receptor Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-^12,14-prostaglandin J₂¹

Jennifer J. Schlezinger^2,*, Gregory J. Howard^*, Christopher H. Hurst, Jessica K. Emberley^*, David J. Waxman, Thomas Webster^* and David H. Sherr^*

^* Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118; and Department of Biology, Division of Cell and Molecular Biology, Boston University, Boston, MA 02215

The common commercial use of phthalate esters has resulted in significant human exposure to these bioactive compounds. The facts that phthalate ester metabolites, like endogenous PGs, are peroxisome proliferator-activated receptor (PPAR) agonists, and that PPAR agonists induce lymphocyte apoptosis suggest that phthalate esters are immunosuppressants that could act together with PGs to modulate early B cell development. In this study we examined the effects of a metabolite of one environmental phthalate, mono(2-ethylhexyl)phthalate (MEHP), and 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂), on developing B cells. MEHP inhibited [³H]thymidine incorporation by primary murine bone marrow B cells and a nontransformed murine pro/pre-B cell line (BU-11). Cotreatment with a retinoid X receptor ligand, 9-cis-retinoic acid, decreased [³H]thymidine incorporation synergistically, thereby implicating activation of a PPAR-retinoid X receptor complex. These results were similar to those obtained with the natural PPAR ligand 15d-PGJ₂. At moderate MEHP concentrations (25 or 100 µM for primary pro-B cells and a pro/pre-B cell line, respectively), inhibition of [³H]thymidine incorporation resulted primarily from apoptosis induction, whereas at lower concentrations, the inhibition probably reflected growth arrest without apoptosis. Cotreatment of bone marrow B cells with 15d-PGJ₂ and MEHP significantly enhanced the inhibition of [³H]thymidine incorporation seen with MEHP alone, potentially mimicking exposure in the bone marrow microenvironment where PG concentrations are high. Finally, MEHP- and 15d-PGJ₂-induced death does not result from a decrease in NF-B activation. These data demonstrate that environmental phthalates can cooperate with an endogenous ligand, 15d-PGJ₂, to inhibit proliferation of and induce apoptosis in developing bone marrow B cells, potentially via PPAR activation.

This article has been cited by other articles:

				S. L. Bissonnette, J. E. Teague, D. H. Sherr, and J. J. Schlezinger An Endogenous Prostaglandin Enhances Environmental Phthalate-Induced Apoptosis in Bone Marrow B Cells: Activation of Distinct but Overlapping Pathways J. Immunol., August 1, 2008; 181(3): 1728 - 1736. [Abstract] [Full Text] [PDF]

				J. J. Schlezinger, J. K. Emberley, S. L. Bissonnette, and D. H. Sherr An L-Tyrosine Derivative and PPAR{gamma} Agonist, GW7845, Activates a Multifaceted Caspase Cascade in Bone Marrow B Cells Toxicol. Sci., July 1, 2007; 98(1): 125 - 136. [Abstract] [Full Text] [PDF]

				J. J. Schlezinger, J. K. Emberley, and D. H. Sherr Activation of Multiple Mitogen-Activated Protein Kinases in Pro/Pre-B Cells by GW7845, a Peroxisome Proliferator-Activated Receptor {gamma} Agonist, and Their Contribution to GW7845-Induced Apoptosis Toxicol. Sci., August 1, 2006; 92(2): 433 - 444. [Abstract] [Full Text] [PDF]