Integrative network toxicology and multi-omics analyses reveal divergent molecular programs underlying...

Area of Science:

• Environmental Toxicology
• Reproductive Toxicology
• Molecular Toxicology

Background:

• Pyrethroid insecticides are widely used globally, with common low-level human exposure.
• Previous research suggests pyrethroid exposure may cause ovarian dysfunction, but the specific molecular mechanisms remain unclear.
• Understanding compound-specific effects is crucial for accurate reproductive risk assessment.

Purpose of the Study:

• To investigate the molecular mechanisms of ovarian dysfunction induced by three representative pyrethroids: permethrin (Type I), cypermethrin, and deltamethrin (Type II).
• To determine if structurally related pyrethroids share common or distinct molecular pathways in causing ovarian toxicity.
• To explore the potential for cross-tissue immune-context correspondence in pyrethroid-induced effects.

Main Methods:

• Integrated analysis of population data (National Health and Nutrition Examination Survey).
• Network toxicology, phenotype-matched mouse models, ovarian transcriptomics, and protein-level validation.
• Exploratory single-cell transcriptomic projection of peripheral blood mononuclear cells.

Main Results:

• All three pyrethroids impaired ovarian reserve, but elicited divergent molecular responses.
• Cypermethrin activated cell-cycle, inflammatory, and stress pathways; deltamethrin showed an attenuated Type II pattern; permethrin induced suppression and stromal remodeling.
• A common CDK4-centered cell-cycle/E2F regulatory node was perturbed differently by each compound.
• Cypermethrin-associated molecular programs showed the strongest immune-context correspondence in peripheral blood cells.

Conclusions:

• Pyrethroid-induced ovarian toxicity exhibits phenotypic convergence but mechanistic divergence.
• Distinct molecular programs are activated by different pyrethroids, necessitating mechanism-oriented risk assessment.
• Findings support refining reproductive risk assessment frameworks beyond chemical-class-based approaches.