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.