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ToxSci Advance Access published online on August 13, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh253
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received July 6, 2004
Accepted August 5, 2004

In Vitro Toxicology

Activation of Mouse and Human Peroxisome Proliferator-Activated Receptors (PPARs) by Phthalate Monoesters

Moses T. Bility 1, Jerry T. Thompson 1, Richard H. McKee 2, Raymond M. David 3, John H. Butala 4, John P. Vanden Heuvel 1, Jeffrey M. Peters 1*

1 Department of Veterinary Science and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802
2 ExxonMobil Biomedical Sciences Inc, Annandale, NJ 08801-0971
3 Consultant to Eastman Chemical Company, Rochester, New York 14652-6272
4 Toxicology Consultants Inc, 7 Glasgow Road, Gibsonia, PA 15044

* To whom correspondence should be addressed. E-mail: jmp21{at}psu.edu.


  Abstract

Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of PPARs, and the monoesters appear to be the active metabolites that function as ligands of PPARs. There is evidence that PPARs exhibit significant species differences in response to ligand activation. In this study, the activation of mouse and human PPAR{alpha}, PPAR{beta}, and PPAR{gamma} by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPAR{alpha} target gene expression, and a PPAR{gamma}-mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPAR{alpha}, with the mouse PPAR{alpha} generally being activated at lower concentrations and exhibiting a greater response than human PPAR{alpha}. Similarly, a range in the trans-activation of mouse PPAR{beta} by phthalate monoesters was also observed, but this effect was not found with human PPAR{beta}. A number of phthalate monoesters activated both mouse and human PPAR{gamma}, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPAR{alpha} and PPAR{gamma} increases with increasing side-chain length. These studies also show that mouse PPAR{alpha} and PPAR{beta} are generally activated at lower concentrations of phthalate monoesters than human PPAR{alpha} and PPAR{beta}; and that both mouse and human PPAR{gamma} exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPAR{alpha} and PPAR{gamma}, and the relative induction of PPAR{alpha} target gene mRNA and PPAR{gamma}-mediated adipocyte differentiation respectively.

Keywords: Peroxisome proliferator-activated receptors (PPARs); phthalate monoesters.
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