Plastic leachates induce astrocyte metabolism remodeling and risk assessment of depressive disorder.

Depressive disorders arise from various external stressors, and its progression involves metabolic heterogeneity that determines disease severity. Environmental exposure to plastic leachates may contribute to metabolic alterations relevant to depression, but the underlying mechanisms remain unclear. In this study, a depression-relevant model was established by treating astrocytes with 10 μM dexamethasone (Dex) for 24 h. Using LC-MS/MS based metabolomics and lipidomics, the effects of plastic leachates from food packaging on metabolic remodeling associated with depression were investigated. The results showed that the astrocyte depression-relevant model included decreased phenylalanine levels (fold change, FC 0.1), decreased hypoxanthine levels (FC 0.2), decreased glutathione levels (FC 0.3), and lipid metabolic disorder (upregulation of most GPs and downregulation of most SPs). Compared with the Dex group, plastic leachates exposure uniquely altered dihydrothymine levels (FC 3.4) and Cytidine triphosphate (FC 2.2) and decreased medium-chain fatty acid metabolism (hexanoylglycine, FC 0.4). Similarities between Dex and Dex+P groups included persistent decreased glutathione levels (FC 0.4) and minor overall lipid metabolism, though with an increase in lipid species diversity. Subsequently, correlation analyses were performed by integrating published metabolomic data from body fluids and tissues of depressed patients and clinical diagnostic criteria. The results indicated that the above-identified metabolites correlated with clinical depression metrics. Pyrimidine expression showed a significant strong positive correlation with suicidal ideation (Beck Depression Inventory, BDI, and Suicidal Ideation Questionnaire, SIQ, n = 192). Medium-chain fatty acid expression exhibited a significant strong negative correlation with depression severity (Patient Health Questionnaire, PHQ-9, n = 792). These metabolic changes were proposed as potential target metabolites mediating the neurotoxic effects of plastic leachates and as key data for risk assessment of depressive disorder. These findings provide insights into the targets through which environmental factors induce depression and offer data supporting a more realistic understanding of plastic leachates toxicity.