The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.
Détails
ID Serval
serval:BIB_D9F6F2FEDDB0
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.
Périodique
Journal of Biological Chemistry
ISSN
0021-9258[print], 0021-9258[linking]
Statut éditorial
Publié
Date de publication
2007
Peer-reviewed
Oui
Volume
282
Numéro
26
Pages
19152-19166
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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 PPARgamma and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARgamma target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARgamma coregulators that includes Med1 and PGC-1alpha, 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.
Mots-clé
3T3-L1 Cells, Adipocytes/cytology, Adipocytes/drug effects, Adipogenesis/drug effects, Adipogenesis/physiology, Animals, Binding Sites, COS Cells, Cercopithecus aethiops, Diethylhexyl Phthalate/analogs &, derivatives, Diethylhexyl Phthalate/chemistry, Environmental Pollutants/chemistry, Environmental Pollutants/metabolism, Fluorescence Resonance Energy Transfer, Hela Cells, Humans, Hypoglycemic Agents/chemistry, Hypoglycemic Agents/metabolism, Mice, PPAR gamma/chemistry, PPAR gamma/genetics, Promoter Regions, Genetic/physiology, Protein Structure, Tertiary, RNA, Small Interfering/pharmacology, Thiazolidinediones/chemistry, Thiazolidinediones/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/01/2008 12:22
Dernière modification de la notice
20/08/2019 16:59