Induction of apoptosis and CYP4A1 expression in Sprague-Dawley rats exposed to low doses of perfluorooctane sulfonate

J Toxicol Sci. 2011 Apr;36(2):201-10. doi: 10.2131/jts.36.201.


In previous studies, perfluorooctane sulfonate (PFOS), an environmental organic compound, was reported to cause hepatotoxicity and hypolipidemia in rodents. However, the low dose toxicity of PFOS and the toxic mechanisms involved remain to be determined. To clarify the low dose toxicity and action mechanism in the target organ toxicity, Sprague-Dawley (SD) rats were orally administered with PFOS at the doses of 0, 1.25, 5, 10 mg/kg/day for 28 days. As a result, no death or abnormal symptoms were observed in all groups. The significant loss of mean body weight was observed in female rats treated with 10 mg/kg PFOS and the relative liver weight of 10 mg/kg PFOS-treated group was significantly greater compared to control. Histopathological examination revealed that fatty change was evident in the liver of male rats treated with PFOS (5 and 10 mg/kg) and hypertrophy and cellular swellings in females at the dose of 10 mg/kg, which showed different pattern of pathological lesions. In addition, we demonstrated the expression induction of hepatic caspase-3 and cytochrome P450 4A1 (CYP4A1) related with apoptosis and lipid metabolism, respectively. This study suggested that no-observed-adverse-effect level (NOAEL) of PFOS was 1.25 mg/kg in 28-day repeated toxicity study and, however, the toxic response showed gender differences. The possible toxic mechanism of PFOS was the induction of apoptosis and altering lipid metabolism which resulted in hepatotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alkanesulfonic Acids / toxicity*
  • Animals
  • Apoptosis / drug effects*
  • Body Weight / drug effects
  • Caspase 3 / biosynthesis
  • Caspase 3 / genetics
  • Cell Survival / drug effects
  • Cytochrome P-450 CYP4A / biosynthesis
  • Cytochrome P-450 CYP4A / genetics*
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P450 Family 4
  • Environmental Pollutants / toxicity*
  • Fatty Liver / chemically induced
  • Fatty Liver / pathology
  • Female
  • Fluorocarbons / toxicity*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / pathology
  • Humans
  • Lipid Metabolism / drug effects
  • Liver / drug effects
  • Liver / enzymology
  • Liver / pathology
  • Male
  • Organ Size / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Toxicity Tests


  • Alkanesulfonic Acids
  • Cyp4a1protein, rat
  • Environmental Pollutants
  • Fluorocarbons
  • Cytochrome P-450 Enzyme System
  • perfluorooctane sulfonic acid
  • Cytochrome P450 Family 4
  • Cytochrome P-450 CYP4A
  • Caspase 3