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SO174

The nonlinear association between DEHP exposure and cognitive decline in older adults: integrating NHANES data with multi-omics analysis

NON-LINEAR ASSOCIATION OF DEHP EXPOSURE WITH COGNITIVE DECLINE IN OLDER ADULTS: INTEGRATING NHANES EVIDENCE WITH MULTI-OMICS ANALYSIS

Urinary DEHP metabolites showed a nonlinear association with cognitive function in older adults, with the steepest decline occurring at levels below approximately 31.9 ng/mg creatinine.

The aim was to elucidate the shape of the dose–response relationship between di-(2-ethylhexyl) phthalate (DEHP), a common environmental neurotoxicant, and cognitive decline in older adults, and to integrate NHANES data with multi-omics analyses. The methods included restricted cubic spline (RCS) analysis, sample weighting, and mediation analysis using the systemic inflammation response index (SIRI), applied to NHANES data from N = 916 older adults (mean age 69.3 years; 51.5% female; DEHP 53.2 ± 109.4 ng/mg creatinine); mechanistic investigations used machine learning, immune and single-nucleus RNA sequencing (snRNA-seq) data, brain expression analysis, and molecular docking. At the epidemiological level, beta = -0.918 was found for CERAD immediate recall and beta = -2.33 for DSST processing speed, with these associations reaching statistical significance at p = 0.029 and p = 0.038, respectively. Both the overall and nonlinear associations were significant in these two cognitive domains (CERAD: P overall < 0.01 and P nonlinear < 0.01; DSST: P overall < 0.0001 and P nonlinear < 0.001). Across all four cognitive domains, the steepest decline occurred below a shared changepoint of approximately 31.9 ng/mg creatinine. Mechanistic analyses found SIRI-mediated proportions of 6.8% and 7.3%, an area under the curve (AUC) of 0.804 for the nine-gene signature, a false discovery rate (FDR) of 0.028 for BCL2, and a docking binding energy of -6.3 kcal/mol between DEHP and BCL2; the microglia-enriched genes PTPRC and CTSB indicated concurrent neuroinflammatory involvement. In conclusion, the effect on memory appears to be mediated by SIRI, whereas the effect on processing speed appears to be direct, suggesting that even low-level exposure may carry a significant neurotoxic risk; the cross-sectional design is the principal limitation.

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