The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms

Environ Health Perspect. 2010 Feb;118(2):234-41. doi: 10.1289/ehp.0901217.


Background: The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferator-activated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.

Objectives: In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action.

Methods: As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses.

Results: DEHP-treated mice were protected from diet-induced obesity via PPARalpha-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARbeta nor PPARgamma was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARalpha-humanized mice. These species differences are associated with a different pattern of coregulator recruitment.

Conclusion: These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARalpha signaling and highlight the metabolic importance of the species-specific activation of PPARalpha by xenobiotic compounds.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Diethylhexyl Phthalate / pharmacology*
  • Energy Metabolism / drug effects*
  • Fatty Acids / metabolism
  • Glucose Tolerance Test
  • Liver / drug effects*
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Obesity / chemically induced
  • Obesity / prevention & control*
  • Oxidation-Reduction / drug effects
  • PPAR alpha / metabolism*
  • Phenotype
  • Plasticizers / pharmacology*


  • Fatty Acids
  • PPAR alpha
  • Plasticizers
  • Diethylhexyl Phthalate