Prediction of Molecular Initiating Events for Adverse Outcome Pathways Using High-Throughput Identification of...

Area of Science:

• Environmental Health Sciences
• Toxicology
• Proteomics

Background:

• Chemical exposure poses risks to human and environmental health, necessitating robust assessment frameworks.
• The Adverse Outcome Pathway (AOP) method requires precise identification of molecular initiating events (MIEs) and chemical-protein interactions, which remains a challenge.
• Current omics and mass spectrometry methods can identify protein targets but struggle to pinpoint the specific MIE.

Purpose of the Study:

• To develop and validate a combined methodology for predicting prioritized molecular initiating events (MIEs).
• To bridge the gap between high-throughput target identification and MIE prediction in chemical safety.
• To support the development and integration of Adverse Outcome Pathways (AOPs).

Main Methods:

• Coupling the proteome integral solubility alteration assay (PISA) for target identification with the analytical hierarchy process (AHP) for MIE prioritization.
• Analysis of 2824 human hepatic proteins to identify chemical-protein interactions.
• Validation using a test compound, TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin).

Main Results:

• The PISA assay identified eight potential protein targets interacting with the test compound.
• The AHP successfully prioritized the most suitable protein target for an AOP from the identified set.
• The combined methodology effectively linked high-throughput target identification to MIE prediction.

Conclusions:

• The integrated PISA and AHP approach provides a novel solution for identifying and prioritizing MIEs in chemical risk assessment.
• This method enhances the development of Adverse Outcome Pathways (AOPs).
• The approach promises more sustainable, time-efficient, and resource-saving chemical assessment strategies.