Development of an adverse outcome pathway network for nephrotoxicity

Area of Science:

• Toxicology
• Computational Biology
• Biochemistry

Background:

• Adverse Outcome Pathways (AOPs) provide structured, evidence-based representations of chemical toxicity mechanisms.
• Linear AOPs often fail to capture complex toxicological processes, necessitating network approaches.
• AOP networks help understand chemical interactions and predict adverse outcomes in complex exposure scenarios.

Purpose of the Study:

• To develop an Adverse Outcome Pathway (AOP) network for nephrotoxicity by connecting thirteen individual AOPs.
• To identify key events (KEs) central to various kidney-related adverse outcomes.
• To establish a foundation for developing in vitro and in silico methods for assessing chemical-induced nephrotoxicity.

Main Methods:

• Utilized established criteria to construct an AOP network from the AOP-Wiki database, focusing on nephrotoxicity.
• Analyzed the topological features of the modelled AOP network.
• Identified central and highly connected Key Events (KEs) within the network.

Main Results:

• Successfully developed an AOP network linking thirteen individual AOPs related to nephrotoxicity.
• Identified mitochondrial dysfunction, oxidative stress, and tubular necrosis as the most connected and central KEs.
• These central KEs are linked to adverse outcomes such as kidney failure and chronic kidney disease.

Conclusions:

• The developed AOP network provides a comprehensive model for understanding chemical-induced nephrotoxicity.
• Central KEs like mitochondrial dysfunction and oxidative stress are critical targets for further research.
• This network approach supports the development of novel in vitro and in silico assays to replace animal testing for kidney toxicity assessment.