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

doi:10.18632/oncotarget.17882

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.

Highlights

Bisphenol A (BPA) is an endocrine-disrupting chemical that is used extensively in the production of polycarbonate plastics and epoxy resins
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
We confirmed that matrix metalloproteinase (MMP)-9 and MMP-2 were involved in BPAinduced EVTs migration

Summary

Introduction

Bisphenol A (BPA) is an endocrine-disrupting chemical that is used extensively in the production of polycarbonate plastics and epoxy resins. The general population, including women of reproductive age and pregnant women, is exposed to BPA in daily life [1]. Contamination by this chemical can occur, for example, through the consumer’s skin or by ingestion of personal care products [2]. It has been suggested that exposure to BPA may be a detrimental factor related to a decline in female fertility [4]. Oogenesis impairment, reduced embryo implantation sites, and even sociosexual behavioral changes in mice and rats were observed after BPA exposure [5,6,7,8]. BPA leads to compromised in vitro decidualization in human endometrial stromal cells [9]

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