Integrated population-level and molecular evidence links nineteen aromatic amine antioxidants and six p-phenylenediamine quinones to thyroid homeostasis in older adults.

Aromatic amine antioxidants (AAs) and p-phenylenediamine quinones (PPD-Qs) are emerging environmental contaminants, yet little is known about their associations with human thyroid function, particularly among the elderly. We quantified 19 AAs and 6 PPD-Qs in urine samples from 479 Chinese older adults and assessed their associations with thyroid hormones and sensitivity indices using traditional linear models, mixed-exposure models (WQS), explainable machine learning (XGBoost-SHAP), and molecular docking. Individual exposure to (cyclohexylamino)diphenylamine (CPPD) was associated with elevated free thyroid hormones (FT3 (β = 0.051, p < 0.05) and FT4 (β = 0.034, p < 0.05)), while several PPD-Qs (e.g., CPPD-Q, DPPD-Q) were associated with increased thyroid-stimulating hormone (TSH) levels and reduced central thyroid sensitivity, with stronger associations observed in females and individuals aged over 70 years. Both WQS and XGBoost-SHAP analyses consistently indicated that mixed exposure to AAs and PPD-Qs was associated with elevated TSH levels and reduced central thyroid hormone sensitivity, with CPPD-quinone (CPPD-Q) and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) identified as the predominant contributors. Molecular docking suggested potential interactions of CPPD-Q and 6PPD with key thyroid-related proteins, including TRβ1 and TSHR, providing a plausible molecular basis for the observed epidemiological associations. Overall, this study provides integrated population-level evidence, complemented by exploratory molecular docking findings, suggesting that CPPD-Q and 6PPD warrant attention in environmental monitoring and thyroid health risk assessment among elderly populations.