Integrating multi-omics, EWAS, and reverse network toxicology to explore environmental pollutant risks in erectile...

Area of Science:

• Integrative toxicology and multi-omics.
• Environmental health and disease mechanisms.
• Network pharmacology and bioinformatics.

Background:

• Erectile dysfunction (ED) prevalence is rising globally.
• ED stems from complex genetic and environmental factors.
• Environmental exposures involve chemical mixtures with synergistic toxicity.

Purpose of the Study:

• To systematically identify causal molecular targets and environmental pollutants linked to ED risk.
• To elucidate the mechanisms underlying ED development due to environmental factors.
• To integrate multi-omics data with reverse network toxicology for ED etiology.

Main Methods:

• Summary data-based Mendelian randomization (SMR) integrating proteomic (pQTL), transcriptomic (eQTL), and DNA methylation (mQTL) data.
• Identification and exclusion of false positives using HEIDI tests.
• Screening of environmental pollutants via Comparative Toxicogenomics Database, toxicity prediction (ADMETlab 3.0, ProTox-III), and molecular docking; functional assays in HUVECs.

Main Results:

• Identified 28 plasma proteins significantly associated with ED risk via pQTL-SMR analysis.
• Prioritized FIS1, TNFSF12, and CNP as core ED-linked targets across multi-omics levels.
• Linked four pollutants (bisphenol F, tetrabromobisphenol A, benzo[a]pyrene, chlorpyrifos) to ED; benzo[a]pyrene impaired HUVEC function and reduced FIS1 expression.

Conclusions:

• Delineated a potential mechanistic pathway: environmental pollutant-molecular target-ED.
• Provided novel insights into the environmental etiology of ED.
• Established a theoretical basis for ED risk assessment and targeted prevention strategies.