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Nitrofen induces a redox-dependent apoptosis associated with increased p38 activity in P19 teratocarcinoma cells

D E Kling1, J T Aidlen, J C Fisher

  • 1Pediatric Surgical Research Laboratories, Pediatric Surgical Services, The Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, WRN 1122, Boston, MA 02114-2696, USA. dkling@partners.org

Toxicology in Vitro : an International Journal Published in Association with BIBRA
|December 8, 2004
PubMed

Insights

Nitrofen herbicide causes cell death by inducing apoptosis, a process dependent on cellular redox state and reactive oxygen species (ROS). This mechanism may contribute to nitrofen-induced birth defects.

Area of Science:

  • Toxicology
  • Developmental Biology
  • Cellular Biology

Background:

  • Nitrofen is a diphenyl ether herbicide known to cause fetal abnormalities in rodents.
  • Understanding the cellular mechanisms underlying nitrofen's teratogenicity is crucial.

Purpose of the Study:

  • To investigate the molecular mechanisms of nitrofen-induced birth defects at the cellular level.
  • To explore nitrofen's effects on undifferentiated P19 teratocarcinoma cells.

Main Methods:

  • Assessed nitrofen's impact on P19 cell viability and apoptosis using TUNEL assays and caspase-3 cleavage analysis.
  • Investigated the role of p38 MAP kinase and reactive oxygen species (ROS) in nitrofen toxicity.
  • Examined the effect of antioxidants like N-acetyl cysteine on nitrofen-induced apoptosis.

Main Results:

  • Nitrofen induced time-dependent apoptosis in P19 cells, evidenced by increased TUNEL-positivity and caspase-3 cleavage, which was caspase-dependent.
  • Nitrofen treatment elevated p38 MAP kinase activity but did not affect caspase-3 cleavage, indicating p38-independent apoptosis.
  • Nitrofen increased ROS production and decreased the reduced/oxidized glutathione ratio, altering the cellular redox state.
  • N-acetyl cysteine treatment reduced nitrofen-mediated caspase-3 cleavage, confirming a cell-redox-dependent apoptotic pathway.

Conclusions:

  • Nitrofen induces P19 cell apoptosis through a cell-redox-dependent mechanism associated with increased ROS.
  • The observed apoptosis is linked to p38 MAP kinase activity but is p38-independent.
  • These cellular events provide insights into the potential mechanisms of nitrofen-induced birth defects.

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