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-

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-PGJ2 (15d-PGJ2), on developing B cells. MEHP inhibited [H]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 [H]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 M for primary pro-B cells and a pro/pre-B cell line, respectively), inhibition of [H]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 [H]thymidine incorporation seen with MEHP alone, potentially mimicking exposure in the bone marrow microenvironment where PG concentrations are high. Finally, MEHPand 15d-PGJ2-induced death does not result from a decrease in NFB 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. The Journal of Immunology, 2004, 173: 3165–3177.