Evaluation of acute hepatotoxic effects exerted by environmental estrogens nonylphenol and 4-octylphenol in immature male rats

Toxicology. 2002 Jun 14;175(1-3):49-62. doi: 10.1016/s0300-483x(02)00046-x.


Nonylphenol (NP) and 4-Octylphenol (4OP) have shown estrogenic properties both in vivo and in vitro. Researchers have known for years that estrogens induce a wide number of hepatotoxic actions in rodents. In order to study the acute hepatic effects exerted by NP and 4OP on rat liver the following endpoints were evaluated: relative liver weight (RLW), morphology, cell cycle and ploidy status, monooxygenase enzymes content and levels of both, cytosolic estrogen receptor (cER) and microsomal binding sites for estrogens (mEBS). Immature male Sprague-Dawley rats were injected intraperitoneally (i.p.) with 60 mg/kg of NP or 4OP for 1, 5 or 10 days. Despite the fact that RLW of the animals was not modified but any treatment, the histopathological study revealed the presence of an increase in the percentage of both, mitotic activity and Ki-67-labeling index (LI) in the livers from animals treated with alkylphenols in absence of any degenerative lesion. Furthermore, all the livers from alkylphenols-treated groups showed the presence of abnormal mitosis and c-mitosis. Although the levels of both, cER and cytochrome P450 (Cyt. P450) were not affected by any treatment, concentration of the mEBS was decreased after 10 days of treatment with alkylphenols. These findings taken together suggest that the exposition to alkylphenols induce cell proliferation and spindle disturbances and that these compounds are capable of modulating the expression of putative membrane receptors for estrogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemical and Drug Induced Liver Injury*
  • Cytochrome P-450 Enzyme System / metabolism
  • Estrogens, Non-Steroidal / toxicity*
  • Flow Cytometry
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Liver Diseases / metabolism
  • Liver Diseases / pathology
  • Male
  • Microscopy, Electron
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Organ Size / drug effects
  • Phenols / toxicity*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / metabolism


  • Estrogens, Non-Steroidal
  • Ki-67 Antigen
  • Phenols
  • Receptors, Estrogen
  • nonylphenol
  • 4-octylphenol
  • Cytochrome P-450 Enzyme System