Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis
Background: The role of bisphenol S (BPS) in the pathogenesis of depression still unclear, particularly regarding its underlying mechanisms and causality. Methods: In this study, network toxicology approaches were employed to explore the mechanisms underlying BPS-induced depression, and Mendelian ra...
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Elsevier
2025-09-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325010620 |
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| author | Ni-ren Li Pai Xie Yi-xuan Zeng Bing-ying Deng Si-fan Lu Yu-feng Gu Yanhong Ma Chao-hua Luo Yi Liu |
| author_facet | Ni-ren Li Pai Xie Yi-xuan Zeng Bing-ying Deng Si-fan Lu Yu-feng Gu Yanhong Ma Chao-hua Luo Yi Liu |
| author_sort | Ni-ren Li |
| collection | DOAJ |
| description | Background: The role of bisphenol S (BPS) in the pathogenesis of depression still unclear, particularly regarding its underlying mechanisms and causality. Methods: In this study, network toxicology approaches were employed to explore the mechanisms underlying BPS-induced depression, and Mendelian randomization (MR) was utilized to validate the causal relationship between BPS-targeted proteins and depression. Clinical datasets were further analyzed to corroborate the identified proteins. Molecular docking and molecular dynamics (MD) simulations were conducted to assess the binding stability between BPS and its target proteins. To investigate potential mediating pathways through which BPS-targeted proteins might contribute to depression, multi-omics data were integrated, including proteome-wide association study datasets from the FINNGEN biobank, the UK Biobank Pharma Proteomics Project, and the Icelandic deCODE consortium, as well as human plasma metabolomic datasets. This enabled a systematic exploration of the mediating roles of plasma proteins and metabolites in the association between BPS-targeted proteins and depression. Finally, protein-protein docking simulations were performed to validate interactions among key proteins. All analyses adhered to rigorous scientific standards for reproducibility and validity. Results: BPS impaired the blood-brain barrier and exerted adverse effects on the brain. Network toxicology analysis revealed that BPS promotes the onset of depression by modulating pathways including neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, PI3K-Akt signaling pathway, and apoptosis. Using MR, molecular docking, MD simulations, and clinical data validation, we demonstrated that BPS stably binds to its target proteins, AZU1 and CTSD, and exhibits a significant causal relationship with depressive symptoms. Mediation MR analysis further revealed that AZU1 promotes depression by mediating the expression of plasma proteins CD302 and FGF19, as well as the production of the plasma metabolite phosphate to urate ratio. Similarly, CTSD mediates the depressive effects by regulating plasma metabolite levels, including cysteinylglycine disulfide, oxidized Cys-gly, X-11470, cysteinylglycine to taurine ratio, and aspartate to mannose ratio. Conclusions: This study elucidates the mechanistic pathways through which the plastic additive BPS induces depression, providing critical insights into its adverse effects on the brain. These findings hold significant implications for public health safety and offer a comprehensive research framework and novel perspectives for evaluating the safety of plastic additives. |
| format | Article |
| id | doaj-art-e1cb4ebfb7c14ee29aabcb65b0b6b76b |
| institution | DOAJ |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-e1cb4ebfb7c14ee29aabcb65b0b6b76b2025-08-20T03:05:34ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130211871710.1016/j.ecoenv.2025.118717Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysisNi-ren Li0Pai Xie1Yi-xuan Zeng2Bing-ying Deng3Si-fan Lu4Yu-feng Gu5Yanhong Ma6Chao-hua Luo7Yi Liu8Traditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaJiangmen Central Hospital, Jiangmen 529000, PR China; Corresponding authors.Jiangmen Central Hospital, Jiangmen 529000, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Corresponding authors.Traditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Corresponding authors.Background: The role of bisphenol S (BPS) in the pathogenesis of depression still unclear, particularly regarding its underlying mechanisms and causality. Methods: In this study, network toxicology approaches were employed to explore the mechanisms underlying BPS-induced depression, and Mendelian randomization (MR) was utilized to validate the causal relationship between BPS-targeted proteins and depression. Clinical datasets were further analyzed to corroborate the identified proteins. Molecular docking and molecular dynamics (MD) simulations were conducted to assess the binding stability between BPS and its target proteins. To investigate potential mediating pathways through which BPS-targeted proteins might contribute to depression, multi-omics data were integrated, including proteome-wide association study datasets from the FINNGEN biobank, the UK Biobank Pharma Proteomics Project, and the Icelandic deCODE consortium, as well as human plasma metabolomic datasets. This enabled a systematic exploration of the mediating roles of plasma proteins and metabolites in the association between BPS-targeted proteins and depression. Finally, protein-protein docking simulations were performed to validate interactions among key proteins. All analyses adhered to rigorous scientific standards for reproducibility and validity. Results: BPS impaired the blood-brain barrier and exerted adverse effects on the brain. Network toxicology analysis revealed that BPS promotes the onset of depression by modulating pathways including neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, PI3K-Akt signaling pathway, and apoptosis. Using MR, molecular docking, MD simulations, and clinical data validation, we demonstrated that BPS stably binds to its target proteins, AZU1 and CTSD, and exhibits a significant causal relationship with depressive symptoms. Mediation MR analysis further revealed that AZU1 promotes depression by mediating the expression of plasma proteins CD302 and FGF19, as well as the production of the plasma metabolite phosphate to urate ratio. Similarly, CTSD mediates the depressive effects by regulating plasma metabolite levels, including cysteinylglycine disulfide, oxidized Cys-gly, X-11470, cysteinylglycine to taurine ratio, and aspartate to mannose ratio. Conclusions: This study elucidates the mechanistic pathways through which the plastic additive BPS induces depression, providing critical insights into its adverse effects on the brain. These findings hold significant implications for public health safety and offer a comprehensive research framework and novel perspectives for evaluating the safety of plastic additives.http://www.sciencedirect.com/science/article/pii/S0147651325010620Network toxicologyMendelian randomizationMolecular dynamicsAZU1/CTSD proteinBisphenol SDepression |
| spellingShingle | Ni-ren Li Pai Xie Yi-xuan Zeng Bing-ying Deng Si-fan Lu Yu-feng Gu Yanhong Ma Chao-hua Luo Yi Liu Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis Ecotoxicology and Environmental Safety Network toxicology Mendelian randomization Molecular dynamics AZU1/CTSD protein Bisphenol S Depression |
| title | Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis |
| title_full | Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis |
| title_fullStr | Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis |
| title_full_unstemmed | Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis |
| title_short | Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis |
| title_sort | plastic additive bisphenol s induces depression by promoting azu1 ctsd proteins to mediate plasma related proteins and metabolites a comprehensive multi omics analysis |
| topic | Network toxicology Mendelian randomization Molecular dynamics AZU1/CTSD protein Bisphenol S Depression |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325010620 |
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