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Bisphenol A promotes X-linked inhibitor of apoptosis protein-dependent angiogenesis via G protein-coupled estrogen receptor pathway.

Significance Statement

 

Bisphenol A (BPA), regarded as a kind of environment endocrine disrupts, has been widely used and becomes one of the high-volume chemicals permeated from various plastic consumer products. Evidence was shown that Bisphenol A exerted adverse biological effects at levels lower than those presently considered safe. Specially,epidemiological report supported Bisphenol A as a risk factor for mammary tumors, which demonstrated that exposure to BPA were correlated with breast cancer and angiogenesis in the glands of cycling rats.  Angiogenesis plays a crucial role in tumor growth, progression and metastasis. Reasonably, X-linked inhibitor of apoptosis protein (XIAP), which regulates cells proliferation and migration, may tightly associate with angiogenesis on the ground that it acts as a modulator of nitric oxide (NO) production by releasing endothelial NO synthase (eNOS) from caveolin-1 (Cav-1). It is known that NO shows importance to angiogenic response. Furthermore, G-protein coupled estrogen receptors (GPER) displays a higher affinity for Bisphenol A and its function related to mediate progression in various types of cancer cells has aroused much concerns. However, whether and how GPER or XIAP is involved in BPA-induced angiogenesis remains unclear  In the present study, we elucidated an indirect molecular mechanism that low levels of Bisphenol A stimulated GPER, resulted in increasing the expression of XIAP, promoting interactions with Cav-1 and leading to NO production by eNOS activation, which provided a novel insight on the potential role of XIAP in mediating the pro-angiogenic effects of Bisphenol A in endothelial cells.

Figure legend

 Schematic representation of the possible mechanisms of BPA-induced angiogenesis in bovine aortic endothelial cells. This schematic diagram shows that BPA-induced angiogenesis is mediated by GPER activation, followed by XIAP upregulation. Furthermore, interactions between XIAP and Cav-1 induce BPA to activate eNOS and then increase NO production. BPA, bisphenol A; Cav-1, caveolin-1; eNOS, endothelial nitric oxide synthase; GPER, G protein-coupled estrogen receptor; NO, nitric oxide; XIAP, X-linked inhibitor of apoptosis protein.

Bisphenol A promotes X-linked inhibitor of apoptosis protein-dependent angiogenesis via G protein-coupled estrogen receptor pathway. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Liu J, Jin X, Zhao N, Ye X, Ying C. J Appl Toxicol. 2015 Feb 7.

Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China.

Abstract

Bisphenol A (BPA), one of the high-volume chemicals worldwide, has a core structure resembling that of natural estradiol. Recent evidence has demonstrated that exposure to Bisphenol A has a relationship with the risk of cancer. The objective of our study is to investigate the mechanisms underlying the pro-angiogenic effects of Bisphenol A. We demonstrated that Bisphenol A markedly induces endothelial cell proliferation, migration and tube formation by activating endothelial nitric oxide synthase. BPA-induced nitric oxide generation appeared to be associated with the X-linked inhibitor of apoptosis protein (XIAP), which competes with endothelial nitric oxide synthase for caveolin-1. BPA was shown to exert its pro-angiogenic effect by upregulating XIAP expression via G protein-coupled estrogen receptor (ER) activation but not via ERα or ERβ. Our data suggest that 100 nM Bisphenol A promote  angiogenesis in a G protein-coupled ER-dependent genomic pathway, and provide a novel insight into the potential role of XIAP in mediating the pro-angiogenic effects of Bisphenol A in endothelial cells.

Copyright © 2015 John Wiley & Sons, Ltd.

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