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ToxSci Advance Access published online on August 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg208
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received June 12, 2003; accepted July 22, 2003
© 2003 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 Supplementation

Estíbaliz L. Fernández 1, Anne-Lee Gustafson 1, Maria Andersson 1, Bjorn Hellman 1, and Lennart Dencker 1*

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

* To whom correspondence should be addressed. E-mail: Lennart.Dencker{at}farmbio.uu.se.


  Abstract

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 embryonic cells. Cadmium also induced embryonic growth retardation, as well as a significant up-regulation of p53, p21 and Bax transcription levels. At the same time, there was a down-regulation of Bcl-2, shifting the equilibrium Bcl-2/Bax towards the apoptotic pathway. There was an increased in apoptotically stained cells in cadmium-treated embryos and pro-caspase-3 was significantly activated. Zinc pre-treatment maintained DNA damage at 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 Bax levels were maintained closer to control values. Bad transcripts did not change at any experimental condition. Morphologically, zinc could maintain the embryological development, apoptotic areas were as in 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 pre-treatment, 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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