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ToxSci Advance Access originally published online on August 12, 2003
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Toxicological Sciences 76, 162-170 (2003)
Copyright © 2003 by the Society of Toxicology

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY

Cadmium-Induced Changes in Apoptotic Gene Expression Levels and DNA Damage in Mouse Embryos Are Blocked by Zinc

Estíbaliz L. Fernández, Anne-Lee Gustafson1, Maria Andersson, Bjorn Hellman and Lennart Dencker2

Department of Pharmaceutical Biosciences, Division of Toxicology, Biomedical Center, Uppsala University, 75124 Uppsala, Sweden

Cadmium is a potent teratogen in laboratory animals, causing exencephaly when administered at early stages of development. Due to its heterogenicity with respect to molecular targets, the mechanisms behind cadmium toxicity are not well understood. In the present study, C57BL/6 pregnant mice were treated with saline, cadmium, or zinc plus cadmium at 8 days post-coitus and studied 24 h after exposure. Cadmium induced significant DNA damage in the embryonic cells. Cadmium also induced embryonic growth retardation, as well as a significant upregulation of p53, p21, and Bax transcription levels. At the same time, there was a downregulation of Bcl-2, shifting the equilibrium Bcl-2/Bax toward the apoptotic pathway. There was an increase in apoptotically stained cells in the cadmium-treated embryos, and pro-caspase-3 was significantly activated. Zinc pretreatment maintained DNA damage at the control levels. It also prevented cadmium-induced effects on the expression levels of p53 and p21. The cadmium-induced decrease in Bcl-2 was inhibited, whereas the Bax levels were maintained closer to the control values. The Bad transcripts did not change at any experimental condition. Morphologically, zinc could maintain the embryological development, where apoptotic areas were as in the controls, and decrease por-caspase-3 activation. In summary, cadmium administered to pregnant mice increased primary DNA damage and activated the apoptotic pathway. These effects could be ameliorated by zinc pretreatment, and, because of that, it is possible that the mechanisms of cadmium-induced teratogenicity are related to zinc metabolism.

Key Words: cadmium; zinc; apoptosis; DNA damage.


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