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Cadmium, gene regulation, and cellular signalling in mammalian cells
1Department of Biology and Chemistry, University of Bremen, Germany.
Abstract:
Effects of the carcinogenic metal cadmium on the regulation of mammalian gene expression are reviewed and discussed in the light of observations on interference with cellular signal transduction pathways. Cadmium ions are taken up through calcium channels of the plasma membrane of various cell types, and cadmium is accumulated intracellularly due to its binding to cytoplasmic and nuclear material. At elevated cytotoxic concentrations, cadmium inhibits the biosyntheses of DNA, RNA, and protein, and it induces lipid peroxidation, DNA strand breaks, and chromosome aberrations. Cadmium compounds as such are only weak mutagens and clastogens. However, cadmium at noncytotoxic doses interferes with DNA repair processes and enhances the genotoxicity of directly acting mutagens. Hence, the inhibition of repair and detoxifying enzymes by this metal may partially explain the observed weak genotoxic properties of this metal. Nongenotoxic mechanisms upregulating intracellular signalling pathways leading to increased mitogenesis are discussed as major mechanisms for the interpretation of the carcinogenic activity by chronic cadmium exposure. About 1 microM cadmium stimulates DNA synthesis and cell proliferation in various cell lines, whereas more elevated concentrations are inhibitory. Cadmium enhances the expression of several classes of genes at concentrations of a few microM. It stimulates the expression of immediate early genes (c-fos, c-jun, and c-myc), of the tumor suppressor gene p53, and of genes coding for the syntheses of protective molecules, including metallothioneins, glutathione, and stress (heat shock) proteins. The mechanisms underlying the modulation of gene activity by cadmium are discussed in terms of interference with cellular signalling at the levels of cell surface receptors, cellular calcium and zinc homeostases, protein phosphorylation, and modification of transcription factors. In considering the available evidence, the carcinogenic properties of cadmium are interpreted using a multifactorial approach involving indirect genotoxicity (interference with DNA repair) and the upregulation of mitogenic signalling pathways.
Insights
Cadmium exposure disrupts mammalian gene expression by interfering with cellular signaling and DNA repair. This carcinogenic metal can upregulate cell proliferation and gene activity, contributing to its cancer-causing effects.
Area of Science:
- Environmental Toxicology
- Molecular Biology
- Carcinogenesis
Background:
- Cadmium is a carcinogenic metal that affects cellular processes.
- It enters cells via calcium channels and accumulates intracellularly.
- High concentrations are cytotoxic, inhibiting DNA, RNA, and protein synthesis.
Purpose of the Study:
- To review and discuss the effects of cadmium on mammalian gene expression.
- To explore cadmium's interference with cellular signal transduction pathways.
- To interpret cadmium's carcinogenic activity through genotoxic and non-genotoxic mechanisms.
Main Methods:
- Review of existing literature on cadmium's effects on gene expression and cellular signaling.
- Analysis of cadmium's interaction with DNA repair mechanisms.
- Discussion of non-genotoxic pathways involving mitogenesis and gene upregulation.
Main Results:
- Cadmium interferes with DNA repair, enhancing mutagenicity at non-cytotoxic doses.
- Low cadmium concentrations (approx. 1 microM) stimulate DNA synthesis and cell proliferation.
- Cadmium upregulates immediate early genes (e.g., c-fos, c-jun, c-myc) and tumor suppressor p53.
Conclusions:
- Cadmium's carcinogenicity involves indirect genotoxicity and upregulation of mitogenic signaling.
- Mechanisms include interference with cellular signaling, calcium/zinc homeostasis, and transcription factors.
- A multifactorial approach is necessary to understand cadmium's carcinogenic properties.