The gut-brain axis mediates precocious puberty induced by environmentally relevant low-dose endocrine-disrupting chemical mixtures

Background: The global rise in precocious puberty (PP) is increasingly linked to exposure to endocrine-disrupting chemicals (EDCs). However, the mechanisms by which environmentally relevant, low-dose mixtures of EDCs influence PP remain inadequately explained by direct endocrine disruption. Objective: This systematic review evaluates a novel hypothesis: that disruption of the gut-brain axis (GBA) serves as a pivotal mechanism in EDC mixture-induced PP. Methods: ) following PRISMA 2020 guidelines. An exploratory Random Forest analysis was employed to identify key mediators and estimate the relative contribution of the GBA pathway. Results: Perinatal exposure to low-dose EDC mixtures consistently induced gut dysbiosis, characterized by reduced microbial diversity (Shannon Δ = -1.8), a 40% decrease in Lactobacillus, and a 1.5-fold increase in Bacteroides. This dysbiosis was linked to impaired production of butyrate (↓50%) and secondary bile acids, increased intestinal permeability (FITC-dextran ↑80%), and systemic inflammation (IL-6 ↑1.8-fold). Fecal microbiota transplantation from PP donors into germ-free mice recapitulated early pubertal onset, supporting a causal role for gut microbiota. Exploratory modeling suggested that mediators within the GBA pathway could be associated with a large share (approximately 68%) of the model-internal variance explanation for PP risk at low experimental doses (≤1 μg/kg/day), indicating its potential prominence over direct endocrine disruption in this analysis. Significant synergistic effects (Synergy Index > 2.3) were observed under mixture exposures. Conclusion: This review identifies the GBA as a critical and previously underappreciated mechanism for low-dose EDC mixture-induced precocious puberty in a dose-dependent manner. Our findings underscore the need for regulatory paradigms and future research to integrate this pathway when assessing the risks of complex, real-world chemical mixtures.