title: Xenobiotic-induced TNF-alpha expression and apoptosis through the p38 MAPK signaling pathway.
abstract: 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-alpha (TNF-alpha) 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-alpha and apoptosis through a p38 MAPK-dependent mechanism.
authors.affiliation: Center for Bioenvironmental Research, Molecular and Cellular Biology Program, Tulane University Health Science Center, New Orleans, LA 70112, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
authors.forename: Katinka A
authors.initials: KA
authors.lastname: Vigh
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Struckhoff
authors.forename: Steven
authors.initials: S
authors.lastname: Elliott
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Beckman
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.forename: John A
authors.initials: JA
authors.lastname: McLachlan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D003634:DDT / Q000633:toxicity*; D006801:Humans; D007536:Isomerism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015262:Xenobiotics / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D015262:Xenobiotics; D045304:Cytochromes c; D003634:DDT; C016340:o,p'-DDT; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases