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Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Eva Brittebo)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2009 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 262, no 1, 57-64 p.Article in journal (Refereed) Published
Abstract [en]

Both epidemiological and experimental studies suggest that exposure to high levels of air pollution is a risk factor associated with cardiovascular disease. Traffic emission is a major source of exposure to persistent air pollutants such as nitrated polycyclic aromatic hydrocarbons (nitro-PAHs). 1-Nitropyrene (1-NP), one of the most abundant nitro-PAHs in diesel exhausts, was selected as a model nitro-PAH for the present study. The aim of the study was to investigate the effects of 1-NP in human umbilical vein endothelial cells (HUVECs) and the metabolic pathways involved. The nitroreductase inhibitor dicoumarol and the coplanar aryl hydrocarbon receptor (AhR) ligand PCB 126 were used to modulate the metabolism of 1-NP. The results revealed that low levels (< or =10microM) of 1-NP induced DNA damage, increased levels of reactive oxygen species (ROS) and increased protein expression of the endoplasmic reticulum (ER) stress chaperone GRP78. A decrease in cell viability was only observed following exposure to a higher level of 1-NP (15microM). Inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction. Our findings suggest that the human blood vessel endothelium is a sensitive target tissue for the major nitro-PAH constituent in diesel exhaust.

Place, publisher, year, edition, pages
2009. Vol. 262, no 1, 57-64 p.
Keyword [en]
1-Nitropyrene, ER stress, DNA damage, HUVEC, Endothelium, Diesel exhaust
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-119883DOI: 10.1016/j.tox.2009.05.008ISI: 000268383900046PubMedID: 19460413OAI: oai:DiVA.org:uu-119883DiVA: diva2:301147
Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2017-12-12Bibliographically 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)
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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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