Urinary biomarkers of emerging contaminants in relation to prevalent Parkinson's disease: An exploratory mixture and network toxicology study.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with a multifactorial etiology, in which environmental chemical exposures have been increasingly implicated. However, the health effects of complex mixtures of contaminants of emerging concern (CECs) and their underlying mechanisms remain poorly understood. In this study, we applied an integrated, exploratory exposome-wide association and mechanism-oriented framework to investigate the associations between exposure to 71 CECs and odds of prevalent PD. Exposome-wide association study (ExWAS) and complementary mixture models (WQS, QGC and BKMR) consistently identified organophosphate ester metabolites, particularly dibutyl phosphate (DBP) and diphenyl phosphate (DPHP), together with ultraviolet filters, especially benzophenone-8 (BP-8) and benzophenone-1 (BP-1), as the chemicals most strongly associated with higher odds of prevalent PD. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), an established biomarker of oxidative stress, was significantly elevated in PD patients, and mediation analysis indicated that oxidative stress mediated 28.25% of the association between mixed exposure to the identified CECs and the odds of prevalent PD. Network toxicology further suggested that endocrine signaling perturbation, oxidative stress, apoptosis, and inflammatory signaling may represent biological processes potentially associated with CEC exposure and PD. These findings were subsequently organized into a proposed adverse outcome pathway (AOP) framework, presenting a mechanistic link between environmental CEC exposure and PD development. Overall, the results provide exploratory, population-based evidence that complex mixtures of emerging environmental contaminants may contribute to PD risk through oxidative stress-related neurodegenerative processes and offer mechanistic insights relevant to environmental risk assessment and PD prevention.