Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysis
Di(2-ethylhexyl) phthalate (DEHP) is a widespread ubiquitous phthalate environmental contaminant. The male reproductive toxicity (MRT) from exposure to DEHP and its main metabolite, mono(2-ethylhexyl) phthalate (MEHP), has been well documented. Fully elucidating its toxic mechanism and discovering e...
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325000764 |
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| author | Huan Gao Xue Zhang Ziqi Liu Xiaoge Yang Yajie Li Mengxing Cui Han Wang Xiaoyu Chen Weiying Zhang Zhihan Liu Yongjiang Yu Liping Chen Daochuan Li Yongmei Xiao Wen Chen Qing Wang |
| author_facet | Huan Gao Xue Zhang Ziqi Liu Xiaoge Yang Yajie Li Mengxing Cui Han Wang Xiaoyu Chen Weiying Zhang Zhihan Liu Yongjiang Yu Liping Chen Daochuan Li Yongmei Xiao Wen Chen Qing Wang |
| author_sort | Huan Gao |
| collection | DOAJ |
| description | Di(2-ethylhexyl) phthalate (DEHP) is a widespread ubiquitous phthalate environmental contaminant. The male reproductive toxicity (MRT) from exposure to DEHP and its main metabolite, mono(2-ethylhexyl) phthalate (MEHP), has been well documented. Fully elucidating its toxic mechanism and discovering effective antagonists are desirable means to reduce the health risks of DEHP. In this study, 552 genes related to MRT induced by DEHP/MEHP were screened out from the Comparative Toxicogenomics Database (CTD) and DisGeNET database. Next, we developed a global adverse outcome pathway (AOP) network based on the existed AOP-wiki. After functional enrichment analyses and mapping to the global AOP network, we found that the increased ROS level, cell cycle arrest, and increased apoptosis are key events (KEs) involved in DEHP-mediated MRT, which was validated in TM3 Leydig cell model. Among them, cellular apoptosis is the core KE in DEHP-induced MRT via network topological analysis. Eventually, we developed a novel in silico antagonist screening platform (http://43.136.69.224:3838/wlab/) based on drug-target gene set enrichment analysis (dtGSEA version 2.0). Several potential candidates that mitigate DEHP-mediated cellular apoptosis have been screened out, including quercetin, taurine, methionine, and phloridzin. Further experimental results demonstrated that phloridzin provided the most effective protection against MEHP-induced apoptosis in TM3 cells probably through the p53 and MAPK signaling pathways. Molecular docking and molecular dynamics simulations suggest that STAT3 and RUNX1 may be important targets for phloridzin to antagonize MEHP-induced MRT. Our study provides a new approach to discover the antagonists for the toxicity of environmental contaminants based on AOP network and dtGSEA methods. |
| format | Article |
| id | doaj-art-c2322ba326c04ea6981ddff736b17f82 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-c2322ba326c04ea6981ddff736b17f822025-02-12T05:30:09ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01290117740Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysisHuan Gao0Xue Zhang1Ziqi Liu2Xiaoge Yang3Yajie Li4Mengxing Cui5Han Wang6Xiaoyu Chen7Weiying Zhang8Zhihan Liu9Yongjiang Yu10Liping Chen11Daochuan Li12Yongmei Xiao13Wen Chen14Qing Wang15Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaCorrespondence to: Department of Toxicology, School of Public Health, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, China.; Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, ChinaDi(2-ethylhexyl) phthalate (DEHP) is a widespread ubiquitous phthalate environmental contaminant. The male reproductive toxicity (MRT) from exposure to DEHP and its main metabolite, mono(2-ethylhexyl) phthalate (MEHP), has been well documented. Fully elucidating its toxic mechanism and discovering effective antagonists are desirable means to reduce the health risks of DEHP. In this study, 552 genes related to MRT induced by DEHP/MEHP were screened out from the Comparative Toxicogenomics Database (CTD) and DisGeNET database. Next, we developed a global adverse outcome pathway (AOP) network based on the existed AOP-wiki. After functional enrichment analyses and mapping to the global AOP network, we found that the increased ROS level, cell cycle arrest, and increased apoptosis are key events (KEs) involved in DEHP-mediated MRT, which was validated in TM3 Leydig cell model. Among them, cellular apoptosis is the core KE in DEHP-induced MRT via network topological analysis. Eventually, we developed a novel in silico antagonist screening platform (http://43.136.69.224:3838/wlab/) based on drug-target gene set enrichment analysis (dtGSEA version 2.0). Several potential candidates that mitigate DEHP-mediated cellular apoptosis have been screened out, including quercetin, taurine, methionine, and phloridzin. Further experimental results demonstrated that phloridzin provided the most effective protection against MEHP-induced apoptosis in TM3 cells probably through the p53 and MAPK signaling pathways. Molecular docking and molecular dynamics simulations suggest that STAT3 and RUNX1 may be important targets for phloridzin to antagonize MEHP-induced MRT. Our study provides a new approach to discover the antagonists for the toxicity of environmental contaminants based on AOP network and dtGSEA methods.http://www.sciencedirect.com/science/article/pii/S0147651325000764AOPDEHPMEHPMale reproductive toxicityAntagonistsDtGSEA |
| spellingShingle | Huan Gao Xue Zhang Ziqi Liu Xiaoge Yang Yajie Li Mengxing Cui Han Wang Xiaoyu Chen Weiying Zhang Zhihan Liu Yongjiang Yu Liping Chen Daochuan Li Yongmei Xiao Wen Chen Qing Wang Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysis Ecotoxicology and Environmental Safety AOP DEHP MEHP Male reproductive toxicity Antagonists DtGSEA |
| title | Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysis |
| title_full | Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysis |
| title_fullStr | Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysis |
| title_full_unstemmed | Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysis |
| title_short | Discovery of phloridzin as a new antagonist for Di(2-ethylhexyl) phthalate-induced male reproductive toxicity based on the adverse outcome pathway network and drug-target gene set enrichment analysis |
| title_sort | discovery of phloridzin as a new antagonist for di 2 ethylhexyl phthalate induced male reproductive toxicity based on the adverse outcome pathway network and drug target gene set enrichment analysis |
| topic | AOP DEHP MEHP Male reproductive toxicity Antagonists DtGSEA |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325000764 |
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