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

Pyrethroid insecticides are among the most widely used insecticide classes worldwide, and low-level exposure is common in the general population. Although previous studies have implicated pyrethroid exposure in ovarian dysfunction, whether structurally related pyrethroids impair ovarian function through shared or compound-specific molecular programs remains unclear. Here, we integrated National Health and Nutrition Examination Survey population analysis, network toxicology, phenotype-matched mouse models, ovarian transcriptomics, protein-level corroboration, and exploratory single-cell transcriptomic projection to investigate the mechanisms underlying ovarian dysfunction induced by three representative pyrethroids: the Type I pyrethroid permethrin and the Type II pyrethroids cypermethrin and deltamethrin. Population analysis showed a non-significant trend toward a higher prevalence of self-reported insecticide exposure among women with ovarian dysfunction. In vivo, all three pyrethroids converged on ovarian-reserve impairment yet elicited markedly divergent molecular responses at comparable phenotypic severity. Cypermethrin induced broad activation of cell-cycle, inflammatory, and stress-response programs; deltamethrin produced an attenuated Type II-like activation pattern; and permethrin preferentially induced a suppression-dominant program accompanied by collagen-associated stromal remodeling. Integrative network and transcriptomic analyses identified a CDK4-centered cell-cycle/E2F regulatory node that is commonly perturbed across all three compounds, but with compound-dependent directionality. Exploratory transcriptional projection of peripheral blood mononuclear cells further suggested cross-tissue immune-context correspondence, most robustly for the cypermethrin-associated program. Together, these findings reveal phenotypic convergence coupled with mechanistic divergence in pyrethroid-induced ovarian toxicity and support mechanism-oriented refinement of reproductive risk assessment beyond chemical-class-based frameworks.