Differential effects of phthalates on the testis and the liver

Biol Reprod. 2005 Mar;72(3):745-54. doi: 10.1095/biolreprod.104.031583. Epub 2004 Nov 24.


Phthalates have been shown to elicit contrasting effects on the testis and the liver, causing testicular degeneration and promoting abnormal hepatocyte proliferation and carcinogenesis. In the present study, we compared the effects of phthalates on testicular and liver cells to better understand the mechanisms by which phthalates cause testicular degeneration. In vivo treatment of rats with di-(2-ethylhexyl) phthalate (DEHP) caused a threefold increase of germ cell apoptosis in the testis, whereas apoptosis was not changed significantly in livers from the same animals. Western blot analyses revealed that peroxisome proliferator-activated receptor (PPAR) alpha is equally abundant in the liver and the testis, whereas PPAR gamma and retinoic acid receptor (RAR) alpha are expressed more in the testis. To determine whether the principal metabolite of DEHP, mono-(2-ethylhexyl) phthalate (MEHP), or a strong peroxisome proliferator, 4-chloro-6(2,3-xylindino)-2-pyrimidinylthioacetic acid (Wy-14,643), have a differential effect in Sertoli and liver cells by altering the function of RAR alpha and PPARs, their nuclear trafficking patterns were compared in Sertoli and liver cells after treatment. Both MEHP and Wy-14,643 increased the nuclear localization of PPAR alpha and PPAR gamma in Sertoli cells, but they decreased the nuclear localization of RAR alpha, as previously shown. Both PPAR alpha and PPAR gamma were in the nucleus and cytoplasm of liver cells, but RAR alpha was predominant in the cytoplasm, regardless of the treatment. At the molecular level, MEHP and Wy-14,643 reduced the amount of phosphorylated mitogen-activated protein kinase (activated MAPK) in Sertoli cells. In comparison, both MEHP and Wy-14,643 increased phosphorylated MAPK in liver cells. These results suggest that phthalates may cause contrasting effects on the testis and the liver by differential activation of the MAPK pathway, RAR alpha, PPAR alpha, and PPAR gamma in these organs.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Environmental Pollutants / toxicity*
  • Germ Cells / drug effects
  • Hepatocytes / drug effects
  • Liver / cytology
  • Liver / drug effects*
  • Male
  • Mitogen-Activated Protein Kinases / drug effects*
  • PPAR gamma / drug effects
  • Phthalic Acids / toxicity*
  • Rats
  • Receptors, Retinoic Acid / drug effects
  • Retinoic Acid Receptor alpha
  • Sertoli Cells / drug effects
  • Signal Transduction / drug effects
  • Testis / cytology
  • Testis / drug effects*


  • Environmental Pollutants
  • PPAR gamma
  • Phthalic Acids
  • Rara protein, rat
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Mitogen-Activated Protein Kinases