Endocrine-Disrupting Chemicals and Polycystic Ovary Syndrome: A Systems Toxicology Perspective on Mechanistic Pathways

This review presents a novel conceptual framework—the Multi-Hit, Multi-Level Cascade Model—that systematically integrates evidence from systems toxicology, molecular endocrinology, and epidemiology. Our model posits that chronic exposure to real-world EDC mixtures initiates a cascade of events wherein cellular perturbations (oxidative stress and low-grade inflammation) are amplified within the uniquely vulnerable ovarian microenvironment. This cascade then escalates into a systemic, self-perpetuating metabolic-endocrine-inflammatory vicious cycle, ultimately manifesting as the diverse clinical phenotypes of PCOS. Within this model, we formally propose three novel, testable hypotheses: the PCOS-specific vulnerability hypothesis, the cumulative susceptibility window hypothesis, and the mixture-driven synergistic toxicity hypothesis. By integrating fragmented evidence into a cohesive narrative, this framework not only provides a mechanistic understanding of EDC-induced PCOS pathogenesis but also identifies critical knowledge gaps and charts a roadmap for future research and targeted prevention strategies. • Proposes a novel 'Multi-Hit, Multi-Level Cascade Model' to explain the link between EDCs and PCOS. • Introduces three testable hypotheses on ovarian vulnerability, cumulative exposure, and synergistic toxicity. • Provides a systems toxicology perspective on the complex etiology of PCOS. • Bridges the gap between environmental EDC exposure and the clinical manifestations of PCOS. • Synthesizes fragmented evidence into a coherent, mechanistically-driven framework for future research.