Background, challenges and main goals of the IP Exposome
Recent large-scale studies have indicated that chronic diseases are driven by genetic factors to only about 10-20 %, leaving 80-90 % for environmental factors. Accordingly, the exposome representing the cumulative and combined internal exposure to chemicals in the body has become a new focal point for systematic analyses of relationships between environmental factors and health impacts. In this context, the inner chemical milieu may be modified by both stress related to lifestyle, diet and previous diseases as well as through exposure to exogenous contaminants, with internally formed reactive oxygen and nitrogen species (ROS, RNS) being typical examples of external chemical stress resulting in modified endogenous chemistry.
The exposome includes chemically modified proteins and DNA, the totality of which is called adductome. Here, a prominent example is given by Michael acceptors as one class of organic electrophiles that may deplete cellular glutathione and form covalent adducts with nucleophilic protein sites. Quinones are both electrophilic and can act as redox cyclers generating ROS, the latter of which may contribute to lipid peroxidation, DNA damage and cancer. Both oxidative stress and perturbations of the one-carbon metabolism are linked to disease-relevant epigenetic modifications. Further xenobiotic metabolism may result in toxification or detoxification. All these processes are becoming accessible to computational chemistry and toxicology.
The challenge will be to identify perturbation-related and disease-relevant exposome components employing methods of molecular biology (omics), advanced analytics, bioinformatics, computational chemistry, and PBTK (physiologically based toxicokinetics) modelling of compartment-specific doses, with a focus on unravelling adverse outcome pathways (AOPs) that represent the sequential progression from the molecular initiating event to the disease outcome at the biological level of interest.
The overall goal is to unravel exposome signatures that link perturbation by environmental factors to chronic human or environmental health impact. To this end, the focus will be on relating external exposure to internal dose and effect, on identifiying molecular events that trigger AOPs of chronic health impacts initiated by perturbing environmental factors, and on designing AOP-informing in vitro screens for exposome-specific health impacts.