A toxicity pathway-oriented approach to develop adverse outcome pathway: AHR activation as a case study.

Area of Science:

• Environmental Toxicology
• Systems Biology
• Computational Chemistry

Background:

• Environmental chemical risk assessment faces challenges due to the constant introduction of new substances.
• The Adverse Outcome Pathway (AOP) framework offers a promising approach by integrating in vitro testing for toxicity assessment.
• A systems biology approach is crucial for understanding the toxic mechanisms of environmental chemicals via AOPs.

Purpose of the Study:

• To develop a novel, reliable method for constructing AOPs using integrated biological and chemical data.
• To explore toxic mechanisms of environmental chemicals through the AOP framework.
• To validate the developed AOP networks using known chemical stressors.

Main Methods:

• Utilized chemical-gene interactions, toxicity pathways, molecular regulations, and phenotype data from the Comparative Toxicogenomics Database (CTD) and Ingenuity Pathway Analysis (IPA).
• Employed Benzo(a)pyrene (BaP) as a model chemical to identify key pathways, molecular initiating events (MIEs), and candidate key events (KEs) for liver and lung AOPs.
• Validated AOP networks using CTD data for various AHR-ligands, including TCDD, valproic acid, quercetin, and particulate matter.

Main Results:

• Successfully structured AOPs for liver and lung toxicity using BaP, identifying pivotal pathways and key events.
• Validated the developed AOP networks, demonstrating their reliability for understanding toxic mechanisms.
• The method efficiently integrated fragmented bioinformation from published studies.

Conclusions:

• The novel AOP development approach accelerates the process, offering a time- and cost-efficient solution.
• This method enhances the understanding of environmental chemical toxicity mechanisms.
• It provides new insights for screening critical pathways within AOP networks for improved risk assessment.