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Cadmium-induced changes in apoptotic gene expression levels and DNA damage in mouse embryos are blocked by zinc
Estibaliz L Fernández1, Anne-Lee Gustafson, Maria Andersson
1Department of Pharmaceutical Biosciences, Division of Toxicology, Biomedical Center, Uppsala University, 75124 Uppsala, Sweden.
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 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.
Insights
Cadmium exposure causes DNA damage and apoptosis in developing embryos. Zinc pretreatment mitigates these harmful effects, suggesting a link between cadmium teratogenicity and zinc metabolism.
Area of Science:
- Developmental toxicology
- Environmental health
- Molecular biology
Background:
- Cadmium is a known teratogen, but its precise molecular mechanisms of toxicity remain unclear.
- Understanding cadmium's teratogenic effects is crucial for public health and risk assessment.
Purpose of the Study:
- To investigate the molecular mechanisms of cadmium-induced teratogenicity in mouse embryos.
- To evaluate the protective role of zinc against cadmium toxicity during early embryonic development.
Main Methods:
- C57BL/6 pregnant mice were exposed to saline, cadmium, or zinc plus cadmium at 8 days post-coitus.
- Embryonic cells were analyzed for DNA damage, gene expression (p53, p21, Bax, Bcl-2), apoptosis, and pro-caspase-3 activation.
- Morphological assessments of embryonic development were performed.
Main Results:
- Cadmium exposure induced significant DNA damage, growth retardation, and apoptosis in embryonic cells.
- Cadmium altered the expression of key apoptosis-related genes (p53, p21, Bax, Bcl-2), favoring cell death.
- Zinc pretreatment effectively protected against cadmium-induced DNA damage and apoptosis, normalizing gene expression and morphology.
Conclusions:
- Cadmium teratogenicity involves primary DNA damage and activation of the apoptotic pathway.
- Zinc pretreatment ameliorates cadmium-induced developmental toxicity, indicating a potential role for zinc metabolism in cadmium's teratogenic effects.
