Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomics
The increasing environmental detection of antidepressants such as amitriptyline (AT) has raised toxicological concerns, yet its long-term safety profile remains poorly characterized. We applied an integrative strategy combining phenome-wide association studies (PheWAS), Mendelian randomization (MR),...
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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/S0147651325009327 |
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| author | Jiachen Liu Zihan Li Zebin Deng Yinhuai Wang Fei Deng |
| author_facet | Jiachen Liu Zihan Li Zebin Deng Yinhuai Wang Fei Deng |
| author_sort | Jiachen Liu |
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| description | The increasing environmental detection of antidepressants such as amitriptyline (AT) has raised toxicological concerns, yet its long-term safety profile remains poorly characterized. We applied an integrative strategy combining phenome-wide association studies (PheWAS), Mendelian randomization (MR), network toxicology, and molecular docking to systematically evaluate potential adverse effects of AT. PheWAS analyses were performed across 784 phenotypes using UK Biobank and FinnGen (R10). Among these, loss-of-function mutations in AT targets SLC6A2 and SLC6A4 showed significant associations after multiple-testing correction with pancreatic cancer and erythematous conditions, respectively. Complementary MR analyses using GTEx v8 tissue-specific cis-expression quantitative trait loci (eQTLs) and multiple autoimmune and inflammatory genome-wide association study (GWAS) datasets demonstrated that elevated expression of SLC6A2 and SLC6A4 conferred protective effects against systemic lupus erythematosus, psoriasis, rosacea, and erythema nodosum across tissues, supporting the causal relevance of these pathways. Network toxicology based on protein-protein interactions (STRING v11.5, Cytoscape v3.10.1) and functional enrichment (ClusterProfiler v4.10.0) highlighted immunoinflammatory, neuroendocrine, and ion channel regulatory mechanisms potentially involved in AT-induced toxicity. Finally, molecular docking simulations (AutoDock Vina v1.2.7, AlphaFold structures) provided structural evidence for AT interactions with key targets including TRPV1. Collectively, these findings suggest that pharmacological inhibition or environmental accumulation of AT may contribute to inflammatory skin reactions and pancreatic tumorigenesis through multiple converging molecular pathways. |
| format | Article |
| id | doaj-art-d4f368a27f164aa9b2c7f03c422747f4 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-d4f368a27f164aa9b2c7f03c422747f42025-08-20T03:41:17ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130211858710.1016/j.ecoenv.2025.118587Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomicsJiachen Liu0Zihan Li1Zebin Deng2Yinhuai Wang3Fei Deng4Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; The Center of Systems Biology and Data science, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Xiangya Hospital, Central South University, Changsha, Hunan, ChinaXiangya School of medicine, Central South University, Changsha, Hunan, ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Correspondence to: Department of Urology, the Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China.The increasing environmental detection of antidepressants such as amitriptyline (AT) has raised toxicological concerns, yet its long-term safety profile remains poorly characterized. We applied an integrative strategy combining phenome-wide association studies (PheWAS), Mendelian randomization (MR), network toxicology, and molecular docking to systematically evaluate potential adverse effects of AT. PheWAS analyses were performed across 784 phenotypes using UK Biobank and FinnGen (R10). Among these, loss-of-function mutations in AT targets SLC6A2 and SLC6A4 showed significant associations after multiple-testing correction with pancreatic cancer and erythematous conditions, respectively. Complementary MR analyses using GTEx v8 tissue-specific cis-expression quantitative trait loci (eQTLs) and multiple autoimmune and inflammatory genome-wide association study (GWAS) datasets demonstrated that elevated expression of SLC6A2 and SLC6A4 conferred protective effects against systemic lupus erythematosus, psoriasis, rosacea, and erythema nodosum across tissues, supporting the causal relevance of these pathways. Network toxicology based on protein-protein interactions (STRING v11.5, Cytoscape v3.10.1) and functional enrichment (ClusterProfiler v4.10.0) highlighted immunoinflammatory, neuroendocrine, and ion channel regulatory mechanisms potentially involved in AT-induced toxicity. Finally, molecular docking simulations (AutoDock Vina v1.2.7, AlphaFold structures) provided structural evidence for AT interactions with key targets including TRPV1. Collectively, these findings suggest that pharmacological inhibition or environmental accumulation of AT may contribute to inflammatory skin reactions and pancreatic tumorigenesis through multiple converging molecular pathways.http://www.sciencedirect.com/science/article/pii/S0147651325009327AmitriptylinePheWASNetwork toxicologyMendelian randomizationAntidepressant |
| spellingShingle | Jiachen Liu Zihan Li Zebin Deng Yinhuai Wang Fei Deng Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomics Ecotoxicology and Environmental Safety Amitriptyline PheWAS Network toxicology Mendelian randomization Antidepressant |
| title | Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomics |
| title_full | Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomics |
| title_fullStr | Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomics |
| title_full_unstemmed | Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomics |
| title_short | Investigation of potential toxicity associated with long-term amitriptyline exposure: Evidence from genomics |
| title_sort | investigation of potential toxicity associated with long term amitriptyline exposure evidence from genomics |
| topic | Amitriptyline PheWAS Network toxicology Mendelian randomization Antidepressant |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325009327 |
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