Associations of Environmental Phenols Exposure with Cognitive Function in Middle-Aged and Older Adults: A Nested...

Global aging amplifies cognitive impairment prevalence, with environmental phenols emerging as neurotoxic risk factors. Ubiquitous endocrine disruptors like bisphenols and synthetic phenolic antioxidants (SPAs) impair cognitive function, evidenced by epidemiological and experimental studies linking phenols exposure to memory deficits and neurodevelopmental disruption. To address the paucity of data on phenolic exposure and cognitive function in aging populations, as well as the lack of mixture effect evaluations, this study aimed to quantify urinary levels of ten environmental phenols (including SPAs, nitrophenol, ultraviolet stabilizer, bisphenols and novel bisphenol analogues) in 122 adults aged ≥45 years from the SCOPA-China cohort, explore their single and combined associations with cognitive function assessed by the Mini-Mental State Examination (MMSE), and identify key phenolic components driving cognitive impairment risk using advanced statistical models. Single-exposure effects were estimated through multivariable conditional logistic regression model (CLRM), while weighted quantile sum regression (WQS), Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp) were employed to evaluate joint and component-specific effects. The highest quartile of tert-butylhydroquinone (TBHQ) (Q4 vs. Q1, OR = 16.70, 95% CI: 1.39-200.10) and even moderate 4,4'-dihydroxy-diphenylether (DHDPE) exposure (Q2 vs. Q1, OR = 6.13, 95% CI: 1.15-32.63) were associated with increased cognitive impairment risk. Phenolic mixtures were significantly associated with elevated risk (WQS OR = 3.62, 95% CI: 1.00-13.33), with TBHQ, DHDPE, and butylated hydroxytoluene (BHT) accounting for 83% of the total risk. Consistent findings were observed in BKMR and qgcomp analyses. BKMR model not only revealed increased cognitive risk above the median mixture exposure level, but also confirmed monotonic risk escalation patterns for BHT and TBHQ. Qgcomp identified BHT as the predominant risk driver, followed by TBHQ and DHDPE. This study provides novel evidence that exposure to SPAs (TBHQ, BHT) and DHDPE is related to cognitive decline in middle-aged and older adults, supporting the neurotoxic potential of environmental phenolic mixtures.