ToxSci Advance Access originally published online on June 12, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Toxicological Sciences 74, 297-308 (2003)
Copyright © 2003 by the Society of Toxicology
ENVIRONMENTAL TOXICOLOGY |
Activation of PPAR
and PPAR
by Environmental Phthalate Monoesters
Department of Biology, Division of Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215
Phthalate esters are widely used as plasticizers in the manufacture of products made of polyvinyl chloride. Mono-(2-ethylhexyl)-phthalate (MEHP) induces rodent hepatocarcinogenesis by a mechanism that involves activation of the nuclear transcription factor peroxisome proliferator-activated receptor-alpha (PPAR
). MEHP also activates PPAR-gamma (PPAR
), which contributes to adipocyte differentiation and insulin sensitization. Human exposure to other phthalate monoesters, including metabolites of di-n-butyl phthalate and butyl benzyl phthalate, is substantially higher than that of MEHP, prompting this investigation of their potential for PPAR activation, assayed in COS cells and in PPAR-responsive liver (PPAR) and adipocyte (PPAR) cell lines. Monobenzyl phthalate (MBzP) and mono-sec-butyl phthalate (MBuP) both increased the COS cell transcriptional activity of mouse PPAR, with effective concentration for half-maximal response (EC50) values of 21 and 63 µM, respectively. MBzP also activated human PPAR (EC50 = 30 µM) and mouse and human PPAR (EC50 = 75–100 µM). MEHP was a more potent PPAR activator than MBzP or MBuP, with mouse PPAR more sensitive to MEHP (EC50 = 0.6 µM) than human PPAR (EC50 = 3.2 µM). MEHP activation of PPAR required somewhat higher concentrations, EC50 = 10.1 µM (mouse PPAR) and 6.2 µM (human PPAR). No significant PPAR activation was observed with the monomethyl, mono-n-butyl, dimethyl, or diethyl esters of phthalic acid. PPAR activation was verified in FAO rat liver cells stably transfected with PPAR, where expression of several endogenous PPAR target genes was induced by MBzP, MBuP, and MEHP. Similarly, activation of endogenous PPAR target genes was evidenced for all three phthalates by the stimulation of PPAR-dependent adipogenesis in the 3T3-L1 cell differentiation model. These findings demonstrate the potential of environmental phthalate monoesters for activation of rodent and human PPARs and may help to elucidate the molecular basis for the adverse health effects proposed to be associated with human phthalate exposure.
Key Words: PPAR; MEHP; phthalate monoesters.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Grun and B. Blumberg Minireview: The Case for Obesogens Mol. Endocrinol., August 1, 2009; 23(8): 1127 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Adibi, R. Hauser, P. L. Williams, R. M. Whyatt, A. M. Calafat, H. Nelson, R. Herrick, and S. H. Swan Maternal Urinary Metabolites of Di-(2-Ethylhexyl) Phthalate in Relation to the Timing of Labor in a US Multicenter Pregnancy Cohort Study Am. J. Epidemiol., April 15, 2009; 169(8): 1015 - 1024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Feige, L. Gelman, D. Rossi, V. Zoete, R. Metivier, C. Tudor, S. I. Anghel, A. Grosdidier, C. Lathion, Y. Engelborghs, et al. The Endocrine Disruptor Monoethyl-hexyl-phthalate Is a Selective Peroxisome Proliferator-activated Receptor {gamma} Modulator That Promotes Adipogenesis J. Biol. Chem., June 29, 2007; 282(26): 19152 - 19166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Plummer, R. M. Sharpe, N. Hallmark, I. K. Mahood, and C. Elcombe Time-Dependent and Compartment-Specific Effects of In Utero Exposure to Di(n-butyl) Phthalate on Gene/Protein Expression in the Fetal Rat Testis as Revealed by Transcription Profiling and Laser Capture Microdissection Toxicol. Sci., June 1, 2007; 97(2): 520 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I Martinelli, N. O Mocchiutti, and C. A Bernal Dietary di(2-ethylhexyl)phthalate-impaired glucose metabolism in experimental animals Human and Experimental Toxicology, September 1, 2006; 25(9): 531 - 538. [Abstract] [PDF]
|
|
|
|
|
|
M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wyde, S. E. Kirwan, F. Zhang, A. Laughter, H. B. Hoffman, E. Bartolucci-Page, K. W. Gaido, B. Yan, and L. You Di-n-Butyl Phthalate Activates Constitutive Androstane Receptor and Pregnane X Receptor and Enhances the Expression of Steroid-Metabolizing Enzymes in the Liver of Rat Fetuses Toxicol. Sci., August 1, 2005; 86(2): 281 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Latini, M. Massaro, and C. De Felice Prenatal Exposure to Phthalates and Intrauterine Inflammation: A Unifying Hypothesis Toxicol. Sci., May 1, 2005; 85(1): 743 - 743. [Full Text] [PDF]
|
|
|
|
|
|
J. C. Corton and P. J. Lapinskas Peroxisome Proliferator-Activated Receptors: Mediators of Phthalate Ester-Induced Effects in the Male Reproductive Tract? Toxicol. Sci., January 1, 2005; 83(1): 4 - 17. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Bility, J. T. Thompson, R. H. McKee, R. M. David, J. H. Butala, J. P. Vanden Heuvel, and J. M. Peters Activation of Mouse and Human Peroxisome Proliferator-Activated Receptors (PPARs) by Phthalate Monoesters Toxicol. Sci., November 1, 2004; 82(1): 170 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Schlezinger, G. J. Howard, C. H. Hurst, J. K. Emberley, D. J. Waxman, T. Webster, and D. H. Sherr Environmental and Endogenous Peroxisome Proliferator-Activated Receptor {gamma} Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-{Delta}12,14-prostaglandin J2 J. Immunol., September 1, 2004; 173(5): 3165 - 3177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Shipley, C. H. Hurst, S. S. Tanaka, F. L. DeRoos, J. L. Butenhoff, A. M. Seacat, and D. J. Waxman trans-Activation of PPAR{alpha} and Induction of PPAR{alpha} Target Genes by Perfluorooctane-Based Chemicals Toxicol. Sci., July 1, 2004; 80(1): 151 - 160. [Abstract] [Full Text] [PDF]
|
|