Xenobiotic-induced TNF-α expression and apoptosis through the p38 MAPK signaling pathway

Daniel E. Frigo, Katinka A. Vigh, Amanda P. Struckhoff, Steven Elliott, Barbara S. Beckman, Matthew E. Burow, John A. McLachlan

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Some xenobiotics, such as dichlorodiphenyltrichloroethane (DDT), bind to and activate estrogen receptors (ERs), eliciting estrogenic effects in both wildlife and humans. However, our laboratory and others have demonstrated that DDT and DDT-like compounds target non-ER pathways. In search for a molecular mechanism we recently established that DDT and its metabolites stimulate activator protein-1 (AP-1)-mediated gene expression through the p38 mitogen-activated protein kinase (MAPK) cascade. Here, we determined that DDT-induced p38 activity produces a novel environmental signaling pathway in endometrial Ishikawa and human embryonic kidney (HEK) 293 cells. Xenobiotic exposure stimulates expression of the death ligand, tumor necrosis factor-α (TNF-α) as demonstrated using RT-PCR and reporter gene assays. Furthermore, DDT-induced p38 activity led to the release of cytochrome c from the mitochondria and activation of caspase-3/7. Ultimately, DDT-treated cells underwent cell death. Taken together, these data demonstrate DDT induces both the expression of the death ligand TNF-α and apoptosis through a p38 MAPK-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)227-238
Number of pages12
JournalToxicology Letters
Issue number2
StatePublished - Feb 15 2005


  • Apoptosis
  • DDT
  • HEK 293
  • Ishikawa
  • p38 MAPK
  • TNF-α

ASJC Scopus subject areas

  • Toxicology


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