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Cadmium chloride alters mRNA levels of angiogenesis related genes in primary human endometrial endothelial cells grown in vitro
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
2010 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 3, 370-376 p.Article in journal (Refereed) Published
Abstract [en]

Cadmium, is known to cause adverse reproductive effects, and classified as an endocrine disrupting chemical (EDC). Human endometrial endothelial cells (HEEC) have a key role in the regulation of endometrial angiogenesis. These cells are known to express estrogen receptors, a feature that makes them potential targets for EDCs such as cadmium. We have designed a co-culture system, in which HEEC were grown in the same cell culture medium as endometrial stromal cells but in separate, communicating chambers. With quantitative PCR, we investigated changes in mRNA expression of genes associated with angiogenesis, sex steroids and endothelial cell specific functions. We found that cadmium altered the mRNA expression of the two important angiogenic molecules VEGF-A and PLGF. Cadmium might thus affect endometrial angiogenesis and as a consequence cause endometrial dysfunction with an increased risk for fertility problems.

Place, publisher, year, edition, pages
2010. Vol. 30, no 3, 370-376 p.
Keyword [en]
Angiogenesis; Cadmium chloride; Endocrine disruptor; Endometrium; Co-culture; In vitro; Human endometrial endothelial cells; qPCR
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-128933DOI: 10.1016/j.reprotox.2010.05.003ISI: 000282165000004PubMedID: 20580663OAI: oai:DiVA.org:uu-128933DiVA: diva2:332245
Available from: 2010-08-03 Created: 2010-08-03 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Effects of Endocrine Disrupting Chemicals on Human Endometrial Endothelial Cells In Vitro
Open this publication in new window or tab >>Effects of Endocrine Disrupting Chemicals on Human Endometrial Endothelial Cells In Vitro
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Evidence from an abundant number of studies suggests that human female reproductive functions have become impaired over the past half century and that there might be a relationship between endocrine disrupting chemicals (EDCs) and reduced fertility. It is, however, not known by what mechanisms EDCs affect different reproductive functions such as endometrial receptivity, embryo implantation and placentation.

The endometrium is continuously changing its morphological and functional properties, responding to cyclic changes of oestrogen and progesterone levels during the menstrual cycle. These changes include monthly preparation for embryo implantation through changed endometrial angiogenic activity and consequent changes in endometrial vasculature.

Use of primary human endometrial endothelial cells (HEECs) in this work was evaluated as a possible screening tool for effects caused by EDCs on human endometrial vasculature and subsequently on various endometrial functions.

In this study HEEC and endometrial stromal cells were isolated. HEECs were grown in monocultures, and together with stromal cells in co-cultures, and exposed to endocrine active substances. These were cadmium, which has oestrogenic properties, tamoxifen, with anti-oestrogenic effects, mifepristone, which is an anti-progestin, and bisphenol A, with oestrogenic properties. The effects were evaluated by using proliferation and viability assays, migration and tube formation assays, quantitative PCR (qPCR), immunohistochemistry and western blot.

Cadmium affected the expression of angiogenesis-related genes, and caused different effects in HEECs cultured alone vs. HEECs co-cultured with stromal cells. Tamoxifen altered the expression of angiogenesis-related genes and reduced HEEC migration, thus having an anti-angiogenic effect. Mifepristone caused reduced formation of tubular structures in tube-formation assays involving HEECs co-cultured with stromal cells. Bisphenol A promoted tube formation in co-cultured HEECs which was related to changes in the expression of several angiogenesis-related genes as well as up-regulated expression of VEGF-D protein.

In conclusion, we showed that EDCs have the ability to induce changes in endometrial angiogenic activity in vitro and may thus disturb normal endometrial functions related to fertility and pregnancy. HEECs grown in vitro may provide valuable information on the effects of EDCs on human endometrial functions. However, this model is not suitable as a large-scale screening tool.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 902
Keyword
endocrine disrupting chemicals, hormones, human endometrial endothelial cells, endometrium, estrogen, progesterone, cadmium, tamoxifen, mifepristone, bisphenol A, angiogenesis
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-196730 (URN)978-91-554-8663-1 (ISBN)
Public defence
2013-06-05, Auditorium Minus, Akademigatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-15 Created: 2013-03-13 Last updated: 2013-08-30Bibliographically approved

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