Bisphenol A exposure promotes HTR-8/SVneo cell migration and impairs mouse placentation involving upregulation of integrin-β1 and MMP-9 and stimulation of MAPK and PI3K signaling pathways

Xi Lan; Li-Juan Fu; Jun Zhang; Xue-Qing Liu; Hui-Jie Zhang; Xue Zhang; Ming-Fu Ma; Xue-Mei Chen; Jun-Lin He; Lian-Bing Li; Ying-Xiong Wang; Yu-Bin Ding

doi:10.18632/oncotarget.17882

Bisphenol A exposure promotes HTR-8/SVneo cell migration and impairs mouse placentation involving upregulation of integrin-β1 and MMP-9 and stimulation of MAPK and PI3K signaling pathways

Oncotarget. 2017 May 16;8(31):51507-51521. doi: 10.18632/oncotarget.17882. eCollection 2017 Aug 1.

Authors

Xi Lan¹, Li-Juan Fu^{1

2}, Jun Zhang³, Xue-Qing Liu¹, Hui-Jie Zhang⁴, Xue Zhang¹, Ming-Fu Ma⁵, Xue-Mei Chen¹, Jun-Lin He¹, Lian-Bing Li⁵, Ying-Xiong Wang¹, Yu-Bin Ding¹

Affiliations

¹ Department of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, P.R. China.
² Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260, USA.
³ Center of Molecular Diagnostic Medicine, Life Science Institute, Chongqing Medical University, Chongqing, 400016, P.R. China.
⁴ Ministry of Education Key Laboratory of Diagnostic Medicine, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.
⁵ The Key Laboratory of Birth Defects and Reproductive Health of the National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing, 401147, P.R. China.

Abstract

In this study, we investigated the effect of Bisphenol A (BPA), an endocrine-disrupting chemical, on the migration of human trophoblasts and mouse placentation by using the primary extravillous trophoblast (EVT) and its cell line HTR-8/SVneo, villous explant cultures, and pregnant mice. BPA increased EVT motility and the outgrowth of villous explants in a dose-dependent manner. BPA also increased the protein levels of integrin-β1 and matrix metalloproteinase (MMP)-9 in human EVTs. Low-dose BPA (≤50 mg) increased the protein levels of MMP-9 and MMP-2 as well as integrin-β1 and integrin-α5 in mouse placenta and decreased the proportion of the labyrinth and spongiotrophoblast layers. Inhibitors of mitogen-activated protein kinase (MAPK) U0126 and phosphatidylinositol-3-kinases (PI3K) LY294002 reversed the protein levels of integrin-β1 and MMP-9 as well as the migratory ability induced by BPA. In conclusion, these results indicated that BPA can enhance trophoblast migration and impair placentation in mice by a mechanism involving upregulation of integrin(s) and MMP(s) as well as the stimulation of MAPK and PI3K/Akt (protein kinase B) signaling pathways.

Keywords: MAPK/PI3K signaling pathway; bisphenol A; cell migration; extravillous trophoblasts; placentation.