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Bisphenol A exposure promotes HTR-8/SVneo cell migration and impairs mouse placentation involving upregulation of integrin-?1 and MMP-9 and stimulation of MAPK and PI3K signaling pathways.

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-?1 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-?1 and integrin-?5 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-?1 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.

SUBMITTER: Lan X

PROVIDER: S-EPMC5584264 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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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.

Lan Xi X Fu Li-Juan LJ Zhang Jun J Liu Xue-Qing XQ Zhang Hui-Jie HJ Zhang Xue X Ma Ming-Fu MF Chen Xue-Mei XM He Jun-Lin JL Li Lian-Bing LB Wang Ying-Xiong YX Ding Yu-Bin YB

Oncotarget 20170516 31

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 ( ...[more]

PMID: 28881663

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Project description:BackgroundValproate, thalidomide and alcohol (ethanol) exposure during the first trimester of pregnancy is known to cause several developmental disorders. All these teratogens are known to pass the placental barrier and interfere directly with the normal development of the fetus. However, these teratogens also alter the formation and function of the placenta itself which may in turn affect the proper nourishment and development of the fetus. Optimum development of the placenta requires adequate invasion of trophoblast into the maternal uterine tissues. Changes in the migratory behavior of trophoblast by maternal exposure to these teratogens during placentogenesis may therefore alter the structure and function of the placenta.MethodsIn the present study, the effects of sodium valproate, thalidomide and alcohol on the migration of human first trimester trophoblast cell line (HTR-8/SVneo) were examined in vitro. Cells were cultured in the wells of 48-well culture plates as mono or multilayers. Circular patches of cells were removed from the center of the wells by suction, and the migration of cells into the wound was studied using microscopy. Effects of low and high concentrations of valproate, thalidomide and alcohol were examined on the healing of wounds and on the migration rate of cells by determining the wound areas at 0, 3, 6, 12, 24 and 48 h. Effects of drugs and alcohol on the proliferation and the expression levels of integrin subunits beta1 and alpha5 in cells were examined.ResultsThe migration rates of trophoblast differed between wounds created in mono and multilayers of cells. Exposure to teratogens altered the migration of trophoblast into mono and multilayer wounds. The effects of valproate, thalidomide and alcohol on the proliferation of cells during the rapid migratory phase were mild. Drug exposure caused significant changes in the expression levels of beta1 and alpha5 integrin subunits.ConclusionResults suggest that exposure to valproate, thalidomide or alcohol during the first trimester of pregnancy may change the ultrastructure of the placenta by altering the migration of trophoblast cells and this effect may be mediated by drug- or alcohol-induced changes in the expression levels of beta1 and alpha5 integrin subunits.

Project description:BackgroundHow nutrition and growth factor restriction due to serum depletion affect trophoblast function remains poorly understood. We performed a proteomic differential study of the effects of serum depletion on a first trimester human immortalized trophoblast cell line.MethodsThe viability of HTR-8/SVneo trophoblast cells in culture with 0, 0.5 and 10 % fetal bovine serum (FBS) were assayed via MTT at 24, 48 and 64 h. A comparative proteomic analysis of the cells grown with those FBS levels for 24 h was performed using two-dimensional electrophoresis (2DE), followed by mass spectrometry for protein spot identification, and a database search and bioinformatics analysis of the expressed proteins. Differential spots were identified using the Kolmogorov-Smirnov test (n = 3, significance level 0.10, D > 0.642) and/or ANOVA (n = 3, p < 0.05).ResultsThe results showed that low serum doses or serum depletion differentially affect cell growth and protein expression. Differential expression was seen in 25 % of the protein spots grown with 0.5 % FBS and in 84 % of those grown with 0 % FBS, using 10 % serum as the physiological control. In 0.5 % FBS, this difference was related with biological processes typically affected by the serum, such as cell cycle, regulation of apoptosis and proliferation. In addition to these changes, in the serum-depleted proteome we observed downregulation of keratin 8, and upregulation of vimentin, the glycolytic enzymes enolase and pyruvate kinase (PKM2) and tumor progression-related inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) enzyme. The proteins regulated by total serum depletion, but not affected by growth in 0.5 % serum, are members of the glycolytic and nucleotide metabolic pathways and the epithelial-to-mesenchymal transition (EMT), suggesting an adaptive switch characteristic of malignant cells.ConclusionsThis comparative proteomic analysis and the identified proteins are the first evidence of a protein expression response to serum depletion in a trophoblast cell model. Our results show that serum depletion induces specific changes in protein expression concordant with main cell metabolic adaptations and EMT, resembling the progression to a malignant phenotype.

Project description:Preeclampsia (PE) is a common pregnancy complication, and placental hypoxia is one of its causes. We aimed to identify the transcriptional profile and construct a long non-coding RNAs (lncRNA)-centered competing endogenous RNAs (ceRNA) network in hypoxia-induced HTR8/SVneo cells. We used datasets from the GEO database to identify important pathways in PE. We performed microarray profiling and functional analysis to identify differentially expressed long non-coding RNAs (lncRNAs), differentially expressed profiles of microRNA (miRNAs), and differentially expressed profiles of messenger RNA (mRNAs) in hypoxia-induced HTR8/SVneo cells. The candidates were validated using quantitative reverse transcription polymerase chain reaction. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were performed to understand the functional significance of differentially expressed genes. Finally, we constructed an lncRNA-centered ceRNA network. Several hub genes were validated both in placentas from PE and normal pregnancy, and in hypoxia-induced HTR8/SVneo cells. The hypoxic response pathway was involved in the pathophysiology of PE. Subsequently, we identified 536 differentially expressed profiles of lncRNAs (183 upregulated and 353 downregulated), 46 differentially expressed profiles of miRNAs (35 upregulated and 11 downregulated), and 2782 differentially expressed profiles of mRNAs (DEmRNAs) (1031 upregulated and 1751 downregulated) in hypoxia-induced HTR8/SVneo cells. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed potential pathways affected by these genes, such as angiogenesis, the HIF-1 signaling pathway, and the PI3K-Akt signaling pathway. The ceRNA network comprised 35 lncRNAs, 11 miRNAs, 27 mRNAs, and 2 hub lncRNAs, which might play a vital role in placental functions and PE. Our results revealed the transcriptome profile and constructed an lncRNA-centered ceRNA network in hypoxia-induced HTR8/SVneo cells, thereby providing potential therapeutic targets for PE.

Dataset Information

Bisphenol A exposure promotes HTR-8/SVneo cell migration and impairs mouse placentation involving upregulation of integrin-?1 and MMP-9 and stimulation of MAPK and PI3K signaling pathways.

Publications

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.

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