Journal Article

Activation of PPARα and PPARγ by Environmental Phthalate Monoesters

Christopher H. Hurst and David J. Waxman

in Toxicological Sciences

Volume 74, issue 2, pages 297-308
Published in print August 2003 | ISSN: 1096-6080
Published online August 2003 | e-ISSN: 1096-0929 | DOI:
Activation of PPARα and PPARγ by Environmental Phthalate Monoesters

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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 (PPARα). MEHP also activates PPAR-gamma (PPARγ), 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 (PPARα) and adipocyte (PPARγ) cell lines. Monobenzyl phthalate (MBzP) and mono-sec-butyl phthalate (MBuP) both increased the COS cell transcriptional activity of mouse PPARα, with effective concentration for half-maximal response (EC50) values of 21 and 63 μM, respectively. MBzP also activated human PPARα (EC50 = 30 μM) and mouse and human PPARγ (EC50 = 75–100 μM). MEHP was a more potent PPAR activator than MBzP or MBuP, with mouse PPARα more sensitive to MEHP (EC50 = 0.6 μM) than human PPARα (EC50 = 3.2 μM). MEHP activation of PPARγ required somewhat higher concentrations, EC50 = 10.1 μM (mouse PPARγ) and 6.2 μM (human PPARγ). No significant PPAR activation was observed with the monomethyl, mono-n-butyl, dimethyl, or diethyl esters of phthalic acid. PPARα activation was verified in FAO rat liver cells stably transfected with PPARα, where expression of several endogenous PPARα target genes was induced by MBzP, MBuP, and MEHP. Similarly, activation of endogenous PPARγ target genes was evidenced for all three phthalates by the stimulation of PPARγ-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.

Keywords: PPAR; MEHP; phthalate monoesters

Journal Article.  8155 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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