Cardiotoxicity adverse outcome pathway network: towards mechanistic and quantitative modelling.

Area of Science:

• Toxicology
• Biomedical Science
• Environmental Health

Background:

• Chemical-induced heart toxicity poses significant challenges in drug development and environmental safety.
• Current testing methods often fail to capture the complex biological progression of toxicities due to narrow, late-stage endpoints.

Purpose of the Study:

• To develop a comprehensive Adverse Outcome Pathway (AOP) network to map the progression of chemical-induced heart toxicity.
• To identify critical biological pathways and biomarkers for improved cardiotoxicity assessment.
• To create a practical, accessible resource for designing human-relevant, animal-free testing strategies.

Main Methods:

• Integrated data from the OECD AOP-Wiki to construct a network of 64 biological events and 94 relationships.
• Identified central biological events and 'crossroads' where different toxic chemicals converge.
• Developed a methods catalogue linking biological events to laboratory assays.
• Hosted the network on an interactive, FAIR-aligned web platform.

Main Results:

• Revealed a core set of biological events, including oxidative stress and mitochondrial dysfunction, as primary drivers of cardiac injury.
• Demonstrated how systemic factors and inter-organ interactions (e.g., with kidneys) contribute to cardiotoxicity.
• Established a network that moves beyond linear pathways to illustrate complex toxicological interactions.

Conclusions:

• The developed AOP network provides a clear scaffold for understanding heart safety.
• This resource facilitates the design of more human-relevant, animal-free testing strategies.
• Enables prioritization of impactful biomarkers for future safety assessments, enhancing drug development and environmental safety evaluations.