A curated gene and biological system annotation of adverse outcome pathways related to human health.

Adverse outcome pathways (AOPs) are emerging as a central framework in modern toxicology and other fields in biomedicine. They serve as an extension of pathway-based concepts by depicting biological mechanisms as causally linked sequences of key events (KEs) from a molecular initiating event (MIE) to an adverse outcome. AOPs guide the use and development of new approach methodologies (NAMs) aimed at reducing animal experimentation. While AOPs model the systemic mechanisms at various levels of biological organisation, toxicogenomics provides the means to study the molecular mechanisms of chemical exposures. Systematic integration of these two concepts would improve the application of AOP-based knowledge while also supporting the interpretation of complex omics data. Hence, we established this link through rigorous curation of molecular annotations for the KEs of human relevant AOPs. We further expanded and consolidated the annotations of the biological context of KEs. These curated annotations pave the way to embed AOPs in molecular data interpretation, facilitating the emergence of new knowledge in biomedicine.

Toxicogenomics Data for Chemical Safety Assessment and Development of New Approach Methodologies: An Adverse Outcome Pathway-Based Approach.

Mechanistic toxicology provides a powerful approach to inform on the safety of chemicals and the development of safe-by-design compounds. Although toxicogenomics supports mechanistic evaluation of chemical exposures, its implementation into the regulatory framework is hindered by uncertainties in the analysis and interpretation of such data. The use of mechanistic evidence through the adverse outcome pathway (AOP) concept is promoted for the development of new approach methodologies (NAMs) that can reduce animal experimentation. However, to unleash the full potential of AOPs and build confidence into toxicogenomics, robust associations between AOPs and patterns of molecular alteration need to be established. Systematic curation of molecular events to AOPs will create the much-needed link between toxicogenomics and systemic mechanisms depicted by the AOPs. This, in turn, will introduce novel ways of benefitting from the AOPs, including predictive models and targeted assays, while also reducing the need for multiple testing strategies. Hence, a multi-step strategy to annotate AOPs is developed, and the resulting associations are applied to successfully highlight relevant adverse outcomes for chemical exposures with strong in vitro and in vivo convergence, supporting chemical grouping and other data-driven approaches. Finally, a panel of AOP-derived in vitro biomarkers for pulmonary fibrosis (PF) is identified and experimentally validated.