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Rapid Commun Mass Spectrom. 2018 Aug 7. doi: 10.1002/rcm.8258. [Epub ahead of print]

MEHP and MEOHP but not DEHP bind productively to the peroxisome proliferator-activated receptor γ.

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Department of Molecular Systems Biology, UFZ, Helmholtz-Centre for Environmental Research, Permoserstraße 15, 04318, Leipzig, Germany.
Interdisciplinary research center HALOmem, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 3, 06120, Halle (Saale), Germany.
Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden, Budapester Straße 27, 01069, Dresden, Germany.
Department of Cell Toxicology, UFZ, Helmholtz-Centre for Environmental Research, Permoserstraße 15, 04318, Leipzig, Germany.
Center for Structural Biology, Vanderbilt University, Nashville, TN, 37212, USA.
Institute of Bioanalysis, University of Applied Sciences and Arts of Coburg, 96450, Coburg, Germany.
Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.



The most frequently occurring phthalate, di-(2-ethylhexyl) phthalate (DEHP) causes adverse effects on glucose homeostasis and insulin sensitivity in several cell models and epidemiological studies. However, there is no information on the molecular interaction of phthalates and one of the key regulators of the metabolism, the peroxisome proliferator-activated receptor gamma (PPARγ) available thus far. Since the endogenous ligand of PPARγ 15-deoxy-delta-12,14-prostaglandin J2 (15Δ-PGJ2 ) features structural similarity to DEHP and its main metabolites produced in human hepatic metabolism mono(2-ethylhexyl) phthalate (MEHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), we tested the hypothesis of direct interactions between PPARγ and DEHP or its transformation products.


Hydrogen/deuterium exchange mass spectrometry (HDX-MS) and docking were conducted to obtain structural insights into the interactions and surface plasmon resonance (SPR) analysis to reveal information about binding levels. To confirm the activation of PPARγ upon ligand binding on the cellular level, the GeneBLAzer® bioassay was performed.


HDX-MS and SPR analyses demonstrated that the metabolites MEHP and MEOHP, but not DEHP itself bind to the ligand binding pocket of PPARγ. This binding lead to typical activation-associated conformational changes, as observed with its endogenous ligand 15Δ-PGJ2 . Furthermore, the reporter gene assay confirmed productive interaction. DEHP was inactive up to a concentration of 14 μM, while the metabolites MEHP and MEOHP were active at low micromolar concentrations.


In summary, this study gives structural insights into the direct interaction of PPARγ with MEHP and MEOHP and shows that the DEHP transformation products may modulate the lipid metabolism through PPARγ pathways.


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