Deciphering the molecular mechanisms of metabolism-disrupting chemicals during the interplay of adipocytes and macrophages

• Applicant: Dr. Kristin Schubert
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530364326

Over 50% of the population in the European Union is overweight or obese, and the trend is increasing worldwide. Obesity is accompanied by the development of metabolic syndrome, which leads to increased morbidity and mortality. Metabolism-disrupting chemicals (MDCs) have been associated with the development of obesity and metabolic syndrome. However, there are no regulatory guidelines to assess the risk of MDCs concerning obesity as an endpoint due to a lack of data on the underlying molecular modes of action. Particularly in adipose tissue, adipocyte function may be affected by MDCs. Since obesity is associated with low-grade inflammation of adipose tissue, mainly caused by macrophages, it is essential to consider macrophages a vital player in characterizing MDC-mediated effects. Nevertheless, how MDCs affect the interaction of both cell types is not yet understood. Therefore, this project aims to gain a mechanistic understanding of the effects of MDCs on adipogenesis and the interplay between adipocytes and macrophages and their functions. A co-culture model of adipocytes and macrophages will be established to study the direct and indirect effects of MDCs, which may serve as New Approach Method (NAM) in future risk assessment. Using innovative omics methods, such as bulk and single-cell proteomics, thermal proteome profiling and post-translational modification analysis, molecular initiation events and key events will be identified, providing data for AOP development. Besides deciphering the modes of action of MDCs, this approach will define molecular signatures that explain the effects of MDCs and provide biomarkers for human biomonitoring. In summary, this project will fill data gaps of chemical-induced metabolic disruption in adipose tissue and contribute new approach methods (NAMs) for animal-free risk assessment. Detecting biomarkers, particularly biomarkers of effects (BoE), will support human biomonitoring and advance establishing and validating adipogenesis/adipose tissue inflammation and dysfunction as an endpoint in regulatory risk assessment.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: Elutriation centrifuge