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Cadmium-induced changes in apoptotic gene expression levels and DNA damage in mouse embryos are blocked by zinc.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2003 In: Toxicological Sciences, Vol. 76, 162-170 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. Vol. 76, 162-170 p.
URN: urn:nbn:se:uu:diva-93849OAI: oai:DiVA.org:uu-93849DiVA: diva2:167465
Available from: 2005-11-28 Created: 2005-11-28Bibliographically approved
In thesis
1. Mechanisms behind Cadmium-Induced Teratogenicity
Open this publication in new window or tab >>Mechanisms behind Cadmium-Induced Teratogenicity
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heavy metals polluting our environment cause concern for developing organisms. Among them, cadmium with extremely slow elimination from the body, causes lower birth weight in humans but has not been classify as a human teratogen. Studies in different laboratory animals have shown that cadmium indeed is a potent teratogen. Exposure to cadmium during early mouse embryonic stages (e.g. day 7-8 post-coitus) interferes with the closure of the anterior neural pore producing exencephalic embryos. The underlying mechanisms are not understood, but the heavy accumulation of cadmium in extra- and intraembryonic endoderm and chorioallantoic placenta, however not in the neuroepithelium, suggests that the effects on neural tube closure is due to indirect mechanisms. In this thesis, the disruption in the mouse embryo at the time of neural tube closure of the hierarchies of some signalling pathways and gene regulatory networks that control embryonic development has been studied after cadmium exposure. Cadmium was shown to cause DNA damage as measured by Comet assay, and to activate genes and proteins in the apoptotic pathways (p53, p21, Bcl-2, Bax, and caspase-3), increasing the number of apoptotic cells mostly in areas of physiological cell death, especially in the neuroepithelium. Many of these effects could be reversed by zinc pre-treatment, known to counteract the teratogenic effect of cadmium. Cadmium was also shown to affect Zn-transport and –regulatory proteins in the embryo, but perhaps more importantly in yolk sac placenta, and in the decidua (ZnT-1, MT-I, and ZIP-4). Using gene arrays, cadmium was found to considerably affect gene expression of rather few genes, such as those of metallothioneins and stress-related proteins, supporting in principle an extraembryonic site of action of cadmium. In addition, a number of genes expressed in the anterior visceral endoderm (Hesx1, HNF3β, Cerl, Otx2 and Sox2) where cadmium accumulates, and known to signal to the anterior neuroepithelium, was affected by cadmium. This finding may suggest a new principle for chemical teratogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 49 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 24
Toxicology, Cadmium, Teratogenesis, Exencephaly, Mechanisms, Toxikologi
National Category
Pharmacology and Toxicology
urn:nbn:se:uu:diva-6223 (URN)91-554-6421-1 (ISBN)
Public defence
2005-12-19, , Biomedical Center, Husargatan 3, Uppsala, 09:00
Available from: 2005-11-28 Created: 2005-11-28Bibliographically approved

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