Impact of toxic and carcinogenic metal compounds on the cellular redox-regulation

• Applicant: Professorin Dr. Andrea Hartwig
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517723786

Many metal compounds have toxic and even carcinogenic properties; this also applies to trace elements such as iron, copper or zinc if homeostatic control, e.g. through non-physiological exposure pathways such as inhalation, is overridden. With the exception of chromates, indirect genotoxic effects and the induction of oxidative stress play an important role. Thus, interactions with all major DNA repair processes and other cellular responses to DNA damage, as well as an increase in reactive oxygen species (ROS) have been observed in previous studies. The overall aim of the project is to investigate whether, in addition to irreversible damage to DNA, lipids and proteins by toxic / carcinogenic metal compounds, metal ions also interfere with redox-regulated signaling pathways, which may contribute to their potentially carcinogenic effects. Experiments will be carried out in the SV40-immortalized human bronchial epithelial cell line BEAS-2B. In a first step, the impact of of cadmium chloride, arsenite as well as copper chloride and particulate CuO (especially CuO NP) on the cellular protein composition will be investigated. Further studies will focus on reversible oxidative modifications of cysteine residues, as these play a key role in the cellular redox regulation of signaling pathways. Initially, reversible and irreversible thiol oxidations will be identified upon treatment with H2O2 and characterized by a LC-MS/MS-based proteome analyzes. Subsequently, the impact of the metal compounds will be analyzed with respect to interactions with potentially redox-regulated structures as well as their impact on H2O2 mediated redox regulation. The specific aim is to identify particularly metal ion-sensitive thiol groups, i.e. those that are modified at particularly low concentrations of the respective metal compounds. The activation / inactivation of the corresponding signaling pathways will then be pursued further on the transcriptional level. In addition to basic knowledge about the mechanism of action, the investigations will also contribute to a scientific-based risk assessment for these metal compounds as a prerequisite for the derivation of health-based limit values.

• DFG Programme: Research Grants