Integrative Analysis Reveals Multi-Target Associations of Liquid Crystal Monomer in Ovulatory Dysfunction: Insights...

Area of Science:

• Environmental Health
• Genetics
• Toxicology

Background:

• Ovulatory dysfunction, encompassing polycystic ovary syndrome (PCOS), anovulation, and primary ovarian insufficiency (POI), presents a significant reproductive health challenge.
• The environmental impact of chemicals, such as the liquid crystal monomer EBCN, on reproductive health requires thorough investigation.
• Understanding the pathogenic mechanisms linking environmental exposures to ovulatory dysfunction is crucial for risk assessment and prevention.

Purpose of the Study:

• To investigate the potential pathogenic mechanisms of EBCN in ovulatory dysfunction using an integrative computational approach.
• To identify specific proteins and pathways mediating the association between EBCN exposure and ovulatory dysfunction phenotypes.
• To combine composite and subtype-specific Mendelian randomization with network toxicology and molecular docking.

Main Methods:

• An integrative computational strategy combining network toxicology, Mendelian randomization (MR), and molecular docking.
• MR analysis utilized large-scale genetic data from European ancestry cohorts for a composite ovulatory dysfunction phenotype and specific subtypes (PCOS, POI).
• In silico exposure to EBCN was used for target prediction, followed by genetically predicted plasma protein levels for causal inference.

Main Results:

• Network toxicology identified 150 overlapping targets between EBCN and ovulatory dysfunction, enriched in cancer, PI3K-Akt, MAPK signaling, inflammation, metabolism, and apoptosis pathways.
• Mendelian randomization revealed genetically elevated levels of JUN, CYP3A4, FGFR3, MET, and POLR1C were significantly associated with increased ovulatory dysfunction risk.
• Molecular docking confirmed stable binding interactions between EBCN and prioritized targets, notably CYP3A4 and JUN.

Conclusions:

• Inflammatory regulators, xenobiotic-metabolizing enzymes (e.g., CYP3A4), and cellular pathway proteins (e.g., JUN) are identified as potential mediators genetically linked to ovulatory dysfunction.
• The study provides prioritized targets and testable hypotheses for future experimental validation of EBCN's role in ovulatory pathology.
• Findings contribute to environmental risk assessment by highlighting potential molecular mechanisms underlying chemical-induced reproductive dysfunction.