Plasticizers induce central precocious puberty via dysregulation of EGFR/MYC/PTEN/mTOR-mediated HPG axis activation.

The incidence of central precocious puberty (CPP) has been steadily increasing, and plasticizers have been implicated in the onset of CPP. A thorough understanding of these mechanisms could enable early intervention to prevent CPP from its root cause, offering valuable directions for future basic research and treatment strategies. This study identified CPP-relevant targets for plasticizers via public databases, screening biomarkers with eight algorithms. Furthermore, GeneMANIA network analysis, chromosome localization, subcellular localization, ceRNA network analysis, and functional enrichment analysis were included to ascertain the molecular function of biomarkers. Molecular docking and molecular dynamics analyses provided valuable insights into ligand-target interaction mechanisms. A DEHP-induced CPP mouse model was validated by morphological, histological, hormonal, and molecular markers. EGFR, MYC, PTEN and MTOR were identified as CPP biomarkers, involved in cell cycle regulation and PI3K/AKT signaling. These targets were enriched in stress responses and cancer-related pathways. EGFR exhibited the broadest plasticizer binding spectrum, with EGFR-butyl benzyl phthalate showing the highest binding affinity (-8.0 kcal/mol); molecular dynamics confirmed stable target-plasticizer complexes. The DEHP-induced CPP model was successfully established, with model mice exhibiting an advanced vaginal opening time, increased absolute weights and indices of ovaries and uterus, accelerated estrous cycles, altered ovarian follicle developmental phenotypes, elevated serum FSH/LH/E2 (p < 0.001) and dysregulated biomarker expression (downregulated PTEN, upregulated EGFR/MYC/MTOR) in the HPG axis. The increased expression of canonical pubertal regulators indicates premature activation of the KNDy/kisspeptin-GnRH neuroendocrine axis in DEHP-induced CPP. Our study identified EGFR, MYC, PTEN and mTOR as core targets of plasticizer-triggered CPP, clarifying their regulatory mechanisms and providing novel molecular insights for CPP management.