Urinary volatile organic compound metabolites and depressive symptoms among U.S. adults with cardiovascular-kidney-metabolic syndrome stages 0-3: NHANES-based associations and in silico multi-omics insights.

BACKGROUND

Depression is a major global public health burden, and environmental pollutants are increasingly associated with depressive symptoms. Volatile organic compounds (VOCs) are ubiquitous environmental contaminants with known neurotoxic potential; however, their associations with depressive symptoms, particularly in metabolically vulnerable populations such as those with cardiovascular-kidney-metabolic (CKM) syndrome, remain insufficiently characterized.

METHODS

We conducted a population-based study of adults with CKM stages 0-3 using data from NHANES 2011-2018, assessing associations between urinary levels of 16 VOC metabolites and PHQ-9-defined depressive symptoms using multivariable logistic regression, dose-response modeling, and mixture analyses. Machine learning identified key exposures, network toxicology revealed shared molecular targets and pathways, single-cell RNA sequencing characterized cell-type-specific expression and functional states, and molecular docking assessed interactions between prioritized mVOCs and protein targets.

RESULTS

Higher urinary levels of CYMA, MHBMA3, and HMPMA were significantly associated with increased odds of depressive symptoms after full adjustment, with approximately linear or nonlinear dose-response relationships. Mixture analysis indicated that these metabolites were the main contributors to the joint VOC exposure effect. Network toxicology identified enrichment of depression-related targets in neuronal signaling, synaptic transmission, and immune regulation pathways. Exploratory analysis of public scRNA-seq datasets suggested higher PIK3R1 expression in PBMC CD8 + T cells from depression-related samples and indicated altered immune-related transcriptional programs. Molecular docking suggested plausible binding interactions between the prioritized VOCs and PIK3R1.

CONCLUSIONS

Higher urinary VOC metabolite levels were associated with higher odds of PHQ-9-defined depressive symptoms among adults with CKM stages 0-3. In silico multi-omics analyses suggested potential involvement of PI3K/AKT-related neuroimmune pathways.