title: TCDD induces the hypoxia-inducible factor (HIF)-1α regulatory pathway in human trophoblastic JAR cells.
abstract: The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development.
authors.affiliation: Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. pneumoniae0909@gmail.com.
authors.forename: Tien-Ling
authors.initials: TL
authors.lastname: Liao
authors.affiliation: Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 110, Taiwan. chanduki49@gmail.com.
authors.forename: Su-Chee
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Center for Reproductive Medicine & Sciences Taipei Medical University Hospital, Taipei 110, Taiwan. tzengcr@tmu.edu.tw.
authors.forename: Chii-Reuy
authors.initials: CR
authors.lastname: Tzeng
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan. kaosh@tmu.edu.tw.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Kao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000111:Acetylcysteine; D000730:Androstadienes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020780:Matrix Metalloproteinase 9; D009569:Nitric Oxide; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D000077191:Wortmannin