Nägeli Group

Group Nägeli

Molecular Toxicology

Toxicology is an interdisciplinary scientific approach to assess the risk to living organisms arising from exposure to hazardous chemicals, drugs, their metabolites or harmful biological substances. Reliable toxicological risk assessments are based on a profound molecular knowledge of biological receptors, signaling networks and downstream effectors that determine the endpoint of toxic stress. We are interested in the molecular toxicology of low-dose exposures to chemical carcinogens, endogenous genotoxic agents and persistent contaminants encountered in foods or the environment. We take advantage of advanced methods of molecular and cellular biology combined with real-time imaging as well as large-scale transcriptomics and metabolomics platforms to study how human cells respond to toxic insults.

DNA Repair

One focus of our research is the mechanism by which the nucleotide excision repair (NER) pathway removes carcinogen-DNA adducts, thereby preventing the lifelong accumulation of genetic damage and mutations causing aging, cancer or inherited diseases. Although the basic biochemical steps of the NER reaction are well understood (Figure 1), it is still not clear how this key cytoprotective system operates in the complex chromatin environment of mammalian cells and how it is coordinated with transcription or DNA replication. Indeed, how the whole human genome is constantly inspected for DNA damage and effectively repaired is still a major unanswered question.

Figure 1: The human nucleotide excision repair (NER) system is a versatile multi-component DNA repair machinery that eliminates DNA damage by an enzymatic cut-and-patch mechanism (adapted from F.C. Clement et al., 2010)

Biomarker Discovery

We are applying large-scale methods of transcriptomics and metabolomics (Figure 2) to identify multiplex profiles characteristic of particular toxicants or active metabolic products. The resulting molecular “fingerprints” at the level of RNA transcripts (describing changes in the gene expression program) or metabolites (describing an altered composition of body tissues or fluids) provide insights into the mechanisms of toxicity or pathogenesis of diseases. Also, they constitute an important basis for the discovery of biomarkers to be used as new diagnostic or prognostic tools, as indicators of toxic stress or disease predisposition, and as predictors of therapeutic responses.

Figure 2: Metabolomic profiling of adipose tissue by liquid chromatography/time-of-flight mass spectrometry (M. Olson, unpublished results). The metabolomic fingerprint represents the final outcome of complex interactions between genes and xenobiotics.