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Proangiogenic Effects of Environmentally Relevant Levels of Bisphenol A in Human Primary Endothelial Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Drug Safety and Toxicology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Drug Safety and Toxicology)
2012 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 86, no 3, 465-474 p.Article in journal (Refereed) Published
Abstract [en]

Bisphenol A (BPA) is widely used in the manufacturing of consumer products such as plastic food containers and food cans. Experimental studies suggest a relationship between exposure to BPA and changes in metabolic processes and reproductive organs. Also, epidemiological studies report an association between elevated exposure to BPA and cardiovascular disease and diabetes. Although alterations in the vascular endothelium are implicated in pathological conditions associated with BPA, little is known about the effects of BPA in the human endothelium. This study aimed to investigate the effects of 0.1 nM-1 μM of BPA on selected biomarkers of endothelial dysfunction, inflammation, and angiogenesis in human umbilical vein endothelial cells (HUVEC). The mRNA expression of biomarkers was assayed using qRT-PCR, and the production of nitric oxide and reactive oxygen species was measured using the H(2)DCFDA and the DAF-FM assays. The effect of BPA on phosphorylated eNOS was examined using Western blot and immunofluorescence, and the endothelial tube formation assay was used to investigate in vitro angiogenesis. BPA (≤1 μM) increased the mRNA expression of the proangiogenic genes VEGFR-2, VEGF-A, eNOS, and Cx43 and increased the production of nitric oxide in HUVEC. Furthermore, BPA increased the expression of phosphorylated eNOS and endothelial tube formation in HUVEC. These studies demonstrate that environmentally relevant levels of BPA have direct proangiogenic effects on human primary endothelial cells in vitro suggesting that the human endothelium may be an important target for BPA.

Place, publisher, year, edition, pages
2012. Vol. 86, no 3, 465-474 p.
Keyword [en]
Bisphenol A, endothelium, HUVEC, angiogenesis, tube formation, nitric oxide
National Category
Environmental Health and Occupational Health
Research subject
Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-160660DOI: 10.1007/s00204-011-0766-2ISI: 000300575900012PubMedID: 22045264OAI: oai:DiVA.org:uu-160660DiVA: diva2:452341
Projects
Helén Andersson
Available from: 2011-10-28 Created: 2011-10-28 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Experimental Studies of Endocrine Disrupting Compounds in Vascular Cells and Tissues
Open this publication in new window or tab >>Experimental Studies of Endocrine Disrupting Compounds in Vascular Cells and Tissues
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Epidemiological evidence suggest that exposure to endocrine disrupting compounds (EDCs) is a risk factor for diseases that involves the cardiovascular system but we know little about the mechanisms whereby these compounds can cause injury in the vasculature. The aim of this thesis was to characterize the effects and mechanisms of some EDCs in vascular cells and highly vascularized tissues.

Elevated exposure to environmental EDCs is associated with an increased risk for cardiovascular diseases. In vitro studies demonstrated that the environmental EDCs, 1-nitropyrene, PCB126 and bisphenol A, caused distinct changes in primary human endothelial cells. 1‑Nitropyrene induced cell stress and DNA damage, PCB126 caused changes that indicate endothelial dysfunction and vasoconstriction, and BPA induced changes that indicate angiogenesis and vasoconstriction. Further studies demonstrated that long-term exposure of rats to BPA induced changes in rat cardiac tissues in vivo similar to those observed in human endothelial cells in vitro. The type of cellular alterations that were demonstrated is known to play to play a role in cardiovascular disease in humans. These findings suggest that environmental EDCs can cause damage to the human endothelium that may contribute to the development of cardiovascular disease.

The beneficial effects of the pharmaceutical EDC tamoxifen in breast cancer treatment are compromised by an increased risk for bleedings, hyperplasia, and cancer in the endometrium. Ex vivo studies identified the glandular and surface epithelia as potential target sites for tamoxifen adduct formation and tamoxifen-induced cell stress the human endometrium. No signs of tamoxifen-induced changes were detected in the blood vessels. The results suggest that bioactivation of tamoxifen and subsequent cell injury in endometrial epithelial cells may play a role for tamoxifen’s side effects in the endometrium.

Taken together, this thesis provide evidence that may help understanding how exposure to EDCs can increase the risk for diseases in that involves the cardiovascular system.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 150
Keyword
Endocrine disrupting compounds, endothelium, vascular toxicity
National Category
Pharmaceutical Sciences
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-160662 (URN)978-91-554-8217-6 (ISBN)
Public defence
2011-12-17, B21, Uppsala Biomedical Centre, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2011-11-25 Created: 2011-10-28 Last updated: 2012-01-03Bibliographically approved

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Andersson, HelénBrittebo, Eva

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