Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters

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

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of peroxisome proliferator-activated receptors (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 PPARα, PPARβ, and PPARγ by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARα target gene expression, and a PPARγ -mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARα, with the mouse PPARα generally being activated at lower concentrations and exhibiting a greater response than human PPARα. Similarly, a range in the trans-activation of mouse PPARβ by phthalate monoesters was also observed, but this effect was not found with human PPARβ. A number of phthalate monoesters activated both mouse and human PPARγ, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARα and PPARγ increase with increasing side-chain length. These studies also show that mouse PPARα and PPARβ are generally activated at lower concentrations of phthalate monoesters than human PPARα and PPARβ, and that both mouse and human PPARγ exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARα and PPARγ, and the relative induction of PPARα target gene mRNA and PPARγ-mediated adipocyte differentiation, respectively.

Original languageEnglish (US)
Pages (from-to)170-182
Number of pages13
JournalToxicological Sciences
Volume82
Issue number1
DOIs
StatePublished - Nov 1 2004

Fingerprint

Peroxisome Proliferator-Activated Receptors
Chemical activation
phthalic acid
Assays

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Bility, Moses T. ; Thompson, Jerry T. ; McKee, Richard H. ; David, Raymond M. ; Butala, John H. ; Vanden Heuvel, John P. ; Peters, Jeffrey M. / Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. In: Toxicological Sciences. 2004 ; Vol. 82, No. 1. pp. 170-182.
@article{198b51aa417946fa8cbef484060c9c39,
title = "Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters",
abstract = "Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of peroxisome proliferator-activated receptors (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 PPARα, PPARβ, and PPARγ by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARα target gene expression, and a PPARγ -mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARα, with the mouse PPARα generally being activated at lower concentrations and exhibiting a greater response than human PPARα. Similarly, a range in the trans-activation of mouse PPARβ by phthalate monoesters was also observed, but this effect was not found with human PPARβ. A number of phthalate monoesters activated both mouse and human PPARγ, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARα and PPARγ increase with increasing side-chain length. These studies also show that mouse PPARα and PPARβ are generally activated at lower concentrations of phthalate monoesters than human PPARα and PPARβ, and that both mouse and human PPARγ exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARα and PPARγ, and the relative induction of PPARα target gene mRNA and PPARγ-mediated adipocyte differentiation, respectively.",
author = "Bility, {Moses T.} and Thompson, {Jerry T.} and McKee, {Richard H.} and David, {Raymond M.} and Butala, {John H.} and {Vanden Heuvel}, {John P.} and Peters, {Jeffrey M.}",
year = "2004",
month = "11",
day = "1",
doi = "10.1093/toxsci/kfh253",
language = "English (US)",
volume = "82",
pages = "170--182",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "1",

}

Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. / Bility, Moses T.; Thompson, Jerry T.; McKee, Richard H.; David, Raymond M.; Butala, John H.; Vanden Heuvel, John P.; Peters, Jeffrey M.

In: Toxicological Sciences, Vol. 82, No. 1, 01.11.2004, p. 170-182.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters

AU - Bility, Moses T.

AU - Thompson, Jerry T.

AU - McKee, Richard H.

AU - David, Raymond M.

AU - Butala, John H.

AU - Vanden Heuvel, John P.

AU - Peters, Jeffrey M.

PY - 2004/11/1

Y1 - 2004/11/1

N2 - Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of peroxisome proliferator-activated receptors (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 PPARα, PPARβ, and PPARγ by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARα target gene expression, and a PPARγ -mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARα, with the mouse PPARα generally being activated at lower concentrations and exhibiting a greater response than human PPARα. Similarly, a range in the trans-activation of mouse PPARβ by phthalate monoesters was also observed, but this effect was not found with human PPARβ. A number of phthalate monoesters activated both mouse and human PPARγ, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARα and PPARγ increase with increasing side-chain length. These studies also show that mouse PPARα and PPARβ are generally activated at lower concentrations of phthalate monoesters than human PPARα and PPARβ, and that both mouse and human PPARγ exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARα and PPARγ, and the relative induction of PPARα target gene mRNA and PPARγ-mediated adipocyte differentiation, respectively.

AB - Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of peroxisome proliferator-activated receptors (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 PPARα, PPARβ, and PPARγ by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARα target gene expression, and a PPARγ -mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARα, with the mouse PPARα generally being activated at lower concentrations and exhibiting a greater response than human PPARα. Similarly, a range in the trans-activation of mouse PPARβ by phthalate monoesters was also observed, but this effect was not found with human PPARβ. A number of phthalate monoesters activated both mouse and human PPARγ, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARα and PPARγ increase with increasing side-chain length. These studies also show that mouse PPARα and PPARβ are generally activated at lower concentrations of phthalate monoesters than human PPARα and PPARβ, and that both mouse and human PPARγ exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARα and PPARγ, and the relative induction of PPARα target gene mRNA and PPARγ-mediated adipocyte differentiation, respectively.

UR - http://www.scopus.com/inward/record.url?scp=8444220827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=8444220827&partnerID=8YFLogxK

U2 - 10.1093/toxsci/kfh253

DO - 10.1093/toxsci/kfh253

M3 - Article

C2 - 15310864

AN - SCOPUS:8444220827

VL - 82

SP - 170

EP - 182

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 1

ER -