Proteomics in systems toxicology

Proteins are the ultimate product of gene expression. As they hinge between gene transcription and phenotype, they offer a more realistic perspective of toxicopathic effects, responses and even susceptibility to insult than targeting genes and mRNAs while dodging some inter-individual variability that hinders measuring downstream endpoints like metabolites or enzyme activity. Toxicologists have long focused on proteins as biomarkers but the advent of proteomics shifted risk assessment from narrow single-endpoint analyses to whole-proteome screening, enabling deriving protein-centric adverse outcome pathways (AOPs), which are pivotal for the derivation of Systems Biology informally named Systems Toxicology. Especially if coupled pathology, the identification of molecular initiating events (MIEs) and AOPs allow predictive modeling of toxicological pathways, which now stands as the frontier for the next generation of toxicologists. Advances in mass spectrometry, bioinformatics, protein databases and top-down proteomics create new opportunities for mechanistic and effects-oriented research in all fields, from ecotoxicology to pharmacotoxicology.