During the last two decades, striking progress in metabolomics, computer sciences and improvement of in vitro experiments have been made. The application of these promising tools has been driven mostly by two major factors: a better understanding of the biochemical changes provoked by a toxic insult in a defined and controllable experimental system and the increasing need to move towards the use of human-relevant non-animal alternatives in toxicology in accordance with policies endorsing the 3Rs concept (Reduction, Refinement, and Replacement of animal testing).
Apart from the evident benefits of reducing animal testing and getting better insights into the molecular targets of xenobiotics and their mode of action (MoA), the application of these tools to in vitro systems allows their application at a high throughput level based not only on the correlation of results of test and reference model but using mechanistic validation and supporting the development of Adverse Outcome Pathways (AOPs).
In the 2021 – 2024 SCAHT research programme the bioanalytical and metabolomic expertise has been integrated in a cross-sectional project that applies the advancements made in these scientific areas to the toxicological questions of the four other core projects.
P5 – Bioanalytical and metabolomic readouts for toxicology
During the last two decades, metabolomics has become a mature and widely recognised discipline applied in life sciences research. Because of its ability to characterise the phenotype at the molecular level, metabolomics can be considered as the most functional omics, thus playing a pivotal role in System Toxicology. It also enables the study of how the small molecules constituting the metabolome can regulate the activity of upstream biomolecules such as genes, transcripts, or proteins. The high sensitivity of metabolite concentrations to external insults makes them an excellent readout in many toxicology risk assessment scenarios.
When it comes to supporting regulatory toxicology, four major strengths of metabolomics have been highlighted: a) discovery of toxicological pathways and molecular key events (KEs); b) direct measurement of a system’s molecular phenotype allowing its association to Adverse Outcome Pathways (AOP); c) quantitation of a chemical and discovery of its metabolic biotransformation products in a cell/organism (toxicokinetics), and d) chemical grouping of substances based on their induced phenotypic responses.
This project takes the advancements made in the analytical domain one step further by directly applying its methods to the toxicological questions raised in the different SCAHT research areas. The project supports all other four major SCAHT research projects, with the focus set on extended steroid profile (steroidomics), untargeted and targeted metabolomic readouts, and absolute quantification including toxicokinetics.