TCDD induces the hypoxia-inducible factor (HIF)-1α regulatory pathway in human trophoblastic JAR cells

• Published in: International journal of molecular sciences 2014-09, Vol.15 (10), p.17733-17750
• Main Authors: Liao, Tien-Ling, Chen, Su-Chee, Tzeng, Chii-Reuy, Kao, Shu-Huei
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Androstadienes - pharmacology; Cell Line; Cell Movement - drug effects; dioxin; Humans; hypoxia induction factor-1α; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Nitric Oxide - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Polychlorinated Dibenzodioxins - toxicity; PPAR gamma - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; trophoblastic cell; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms151017733

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.