Cadmium and Its Impact on Genomic Stability

Abstract

The carcinogenicity of cadmium for humans and experimental animals has been long established, most evident for tumors in the lung and kidney, but with increasing evidence also for other tumor locations. While cadmium does not interact directly with DNA, elevated levels of reactive oxygen species (ROS), the interference with the cellular response to DNA damage including all major DNA repair systems as well as the inactivation of tumor suppressor functions appear to be of major importance, thereby increasing the susceptibility towards exogenous and endogenous DNA damage. Furthermore, the deregulation of cell growth, the resistance to apoptosis, as well as epigenetic alterations have been demonstrated in diverse experimental systems. Particularly sensitive targets appear to be proteins with zinc-binding structures, present in many DNA repair proteins, transcription factors and in the tumor suppressor protein p53. The interaction with critical thiol groups and/or the enhanced generation of ROS may also provoke an interference with cellular redox regulation of critical signaling pathways. Especially the combination of these multiple mechanisms may give rise to a high degree of genomic instability in cadmium-adapted cells, relevant not only for tumor initiation but also for later steps in tumor development.