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Experimental Studies of Endocrine Disrupting Compounds in Vascular Cells and Tissues
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Drug Safety and Toxicology)
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 [en]
Endocrine disrupting compounds, endothelium, vascular toxicity
National Category
Pharmaceutical Sciences
Research subject
Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-160662ISBN: 978-91-554-8217-6 (print)OAI: oai:DiVA.org:uu-160662DiVA: diva2:452827
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
List of papers
1. 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
Open this publication in new window or tab >>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
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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.

Keyword
1-Nitropyrene, ER stress, DNA damage, HUVEC, Endothelium, Diesel exhaust
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-119883 (URN)10.1016/j.tox.2009.05.008 (DOI)000268383900046 ()19460413 (PubMedID)
Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2017-12-12Bibliographically approved
2.
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3. Proangiogenic Effects of Environmentally Relevant Levels of Bisphenol A in Human Primary Endothelial Cells
Open this publication in new window or tab >>Proangiogenic Effects of Environmentally Relevant Levels of Bisphenol A in Human Primary Endothelial Cells
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.

Keyword
Bisphenol A, endothelium, HUVEC, angiogenesis, tube formation, nitric oxide
National Category
Environmental Health and Occupational Health
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-160660 (URN)10.1007/s00204-011-0766-2 (DOI)000300575900012 ()22045264 (PubMedID)
Projects
Helén Andersson
Available from: 2011-10-28 Created: 2011-10-28 Last updated: 2017-12-08Bibliographically approved
4. Increased expression of genes encoding proangiogenic and vasoconstriction factors in the cardiac tissues of rats following long‑term exposure to bisphenol A
Open this publication in new window or tab >>Increased expression of genes encoding proangiogenic and vasoconstriction factors in the cardiac tissues of rats following long‑term exposure to bisphenol A
(English)Manuscript (preprint) (Other academic)
National Category
Environmental Health and Occupational Health
Identifiers
urn:nbn:se:uu:diva-160661 (URN)
Available from: 2011-10-28 Created: 2011-10-28 Last updated: 2012-01-03
5. Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands
Open this publication in new window or tab >>Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands
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2010 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 38, no 1, 200-207 p.Article in journal (Refereed) Published
Abstract [en]

The beneficial effects of tamoxifen in the prevention and treatment of breast cancer are compromised by an increased risk of endometrial polyps, hyperplasia, and cancer. Tamoxifen is metabolized to an array of metabolites with estrogenic effects but also to reactive intermediates that may form protein and DNA adducts. The aim of this study was to investigate cellular [(3)H]tamoxifen adduct formation by light microscopic autoradiography and cell stress by immunohistochemical analysis of glucose-regulating protein 78 (GRP78), nuclear factor kappaB (NF-kappaB), and caspase 3 in human endometrial explants after short-term incubation with tamoxifen. The cellular expression of tamoxifen-metabolizing enzymes in human endometrial biopsy samples was also determined by immunohistochemistry. The results showed selective [(3)H]tamoxifen adduct formation in glandular and surface epithelia after incubation with a nontoxic concentration of [(3)H]tamoxifen (6 nM). There was also a selective expression of the endoplasmic reticulum stress chaperone GRP78 and activated caspase 3 at these sites after incubation with cytotoxic concentrations of tamoxifen (10-100 microM). The cell stress was preferentially observed in samples from women in the proliferative menstrual phase. No treatment-related expression of NF-kappaB was observed. Constitutive expression of the tamoxifen-metabolizing enzymes CYP1B1, CYP2A6, CYP2B6, CYP2C8/9/19, CYP2D6, and SULT2A1 in glandular and surface epithelia was shown, but there was a large interindividual variation. The colocalization of [(3)H]tamoxifen adducts, expression of GRP78, caspase 3, and tamoxifen-metabolizing enzymes in human glandular and surface epithelia suggest a local bioactivation of tamoxifen at these sites and that epithelial cells are early target sites for tamoxifen-induced cell stress.

National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-119884 (URN)10.1124/dmd.109.029488 (DOI)000272758300023 ()19812351 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2017-12-12Bibliographically approved

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