TCDD Induces the Hypoxia-Inducible Factor (HIF)-1α Regulatory Pathway in Human Trophoblastic JAR Cells

International Journal of Molecular Sciences

Tien-Ling Liao¹  Su-Chee Chen³  Chii-Reuy Tzeng²  Shu-Huei Kao⁴ 

[1] Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; E-Mail:;Center for Reproductive Medicine & Sciences; Taipei Medical University Hospital, Taipei 110, Taiwan; E-Mail:;Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 110, Taiwan; E-Mail:;School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan

关键词: dioxin;    trophoblastic cell;    hypoxia induction factor-1α;    reactive oxygen species;   

DOI  :  10.3390/ijms151017733

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.