The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.
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.
Feige
Jérôme N
JN
Center for Integrative Genomics, University of Lausanne, Genopode, 1015 Lausanne, Switzerland.
Gelman
Laurent
L
Rossi
Daniel
D
Zoete
Vincent
V
Métivier
Raphaël
R
Tudor
Cicerone
C
Anghel
Silvia I
SI
Grosdidier
Aurélien
A
Lathion
Caroline
C
Engelborghs
Yves
Y
Michielin
Olivier
O
Wahli
Walter
W
Desvergne
Béatrice
B
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000737:chemistry / Q000378:metabolism
D004785:Environmental Pollutants; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate