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J. Biol. Chem., Vol. 282, Issue 26, 19152-19166, June 29, 2007

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The Endocrine Disruptor Monoethyl-hexyl-phthalate Is a Selective Peroxisome Proliferator-activated Receptor Modulator That Promotes Adipogenesis^*

Jérôme N. Feige¹, Laurent Gelman¹², Daniel Rossi, Vincent Zoete, Raphaël Métivier^¶, Cicerone Tudor^||, Silvia I. Anghel, Aurélien Grosdidier, Caroline Lathion, Yves Engelborghs^||, Olivier Michielin, Walter Wahli, and Béatrice Desvergne³

From the Center for Integrative Genomics, University of Lausanne, Genopode, 1015 Lausanne, Switzerland, the Ludwig Institute, National Research Center "Molecular Oncology," University of Lausanne, 1015 Lausanne, Switzerland, the ^¶SPARTE (Spatiotemporal Regulation of Transcription in Eukaryotes), UMR CNRS 6026, Université de Rennes I, 35042 Rennes Cedex, France, and the ^||Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, 3001 Heverlee, Belgium

The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of endocrine disrupting chemical interference with PPAR signaling. We thus performed structural and functional analyses that demonstrate how monoethyl-hexyl-phthalate (MEHP) directly activates PPAR and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPAR target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPAR coregulators that includes Med1 and PGC-1, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.

Received for publication, March 30, 2007 , and in revised form, April 25, 2007.

^* This work was supported by grants from the National Research Project 50, the Swiss National Science Foundation, the Etat de Vaud and the National Center for competence in Research "Frontiers in Genetics" (to W. W. and B. D.), the Swiss National Science Foundation and Oncosuisse (to O. M.), CNRS and ARC (to R. M.), the Research Council of the Katholieke Universiteit Leuven (to C. T.), and project G.0584.06 of the Fund for Scientific Research Flanders (to Y. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the reported work.

² Present address: Facility for Advanced Imaging and Microscopy, Friedrich Miescher Institut, Basel, Switzerland.

³ To whom correspondence should be addressed: Center for Integrative Genomics, Université de Lausanne, Génopode, CH-1015 Lausanne, Switzerland. Tel.: 41-0-21-692-41-40; Fax: 41-0-21-692-41-15; E-mail: beatrice.desvergne{at}unil.ch.

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