Revisiting the obesogenic potential of legacy pollutants: Epidemiological, toxicogenomic, and benchmark dose-based evidence.

Legacy pollutants remain detectable in human populations despite decades of regulatory control, yet whether they continue to pose biologically relevant health risks under contemporary exposure scenarios remains unclear. Here we integrated epidemiology, toxicogenomics, and benchmark dose (BMD)-based risk assessment to re-evaluate the obesogenic potential of legacy pollutants in 665 adolescents. Among 97 quantified environmental chemicals in serum samples, hexachlorobenzene (HCB) and pentachlorophenol (PCP) were consistently identified as the principal contributors to overweight/obesity by generalized linear and weighted quantile sum models. Toxicogenomics, molecular docking, and adverse outcome pathway analyses indicate that both chemicals converge on endocrine and metabolic disruption and oxidative stress through key regulators including PPARγ, INS, ESR1, TNF, and TP53. In vitro validation confirmed dose-dependent perturbations of obesity-related biomarkers, yielding biologically relevant points of departure through BMD modeling. Margin-of-exposure (MOE) analysis integrating these thresholds with human biomonitoring data revealed generally moderate-to-low risk for HCB, whereas approximately 4% of participants exhibited high-risk PCP exposure. These findings demonstrate that certain legacy pollutants remain biologically active and risk-relevant despite long-term regulation and highlight the value of integrating epidemiological evidence with mechanistic and quantitative toxicology for prioritizing chemicals of public health concern in the exposome era.