The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis
Feige, Jerome N × Gelman, Laurent Rossi, Daniel Zoete, Vincent Metivier, Raphael Tudor, Cicerone Anghel, Silvia I Grosdidier, Aurelien Lathion, Caroline Engelborghs, Yves Michielin, Olivier Wahli, Walter Desvergne, Beatrice #
American Society for Biochemistry and Molecular Biology
Journal of Biological Chemistry vol:282 issue:26 pages:19152-19166
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 gamma 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 gamma 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 gamma coregulators that includes Med1 and PGC-1 alpha, 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.