Advancing the Effect-Directed Identification in Combined Pollution: Using Pathways to Link Effects and Toxicants

Area of Science:

• Environmental Toxicology
• Molecular Toxicology
• Systems Toxicology

Background:

• Identifying specific toxicants in complex pollution mixtures is challenging due to mixture effects.
• Traditional methods struggle to link observed adverse effects to causative agents at a molecular level.

Purpose of the Study:

• To develop and validate a pathway-based approach for mechanism-driven identification of toxicants in combined pollution.
• To link molecular mechanisms, identified through transcriptomics, to biological effects and causative agents.

Main Methods:

• Utilized concentration-dependent transcriptomics to evaluate 135 pathways across 6 biological processes.
• Constructed a toxicant-pathway interaction database (2413 interactions) and identified active pathway fragments (72 pathways).
• Applied the method to industrial (OB) and municipal (HL) wastewater, followed by suspect and non-targeted screening for toxicants.

Main Results:

• Pathway analysis revealed distinct molecular mechanisms for OB (cardiotoxicity, genotoxicity) and HL (neurotoxicity, environmental information processing).
• Identified 59 and 86 causative toxicants in OB and HL, with 29 confirmed toxicants interacting with >90% of enriched pathways and contributing >50% of effects.
• Upgraded wastewater treatments based on identified toxicants led to consistent removal of toxicants, pathway effects, and individual effects.

Conclusions:

• Pathway mediation enables mechanism-based identification of toxicants in combined pollution.
• This approach supports more effective environmental risk assessment and management strategies for complex pollutant mixtures.
• The study demonstrates the utility of integrating transcriptomics, pathway analysis, and toxicant identification for environmental monitoring and remediation.