Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation
Phthalates, as a class of known endocrine disruptors, have been controversial because of their potential carcinogenicity and toxicity. Diisononyl cyclohexane-1,2-dicarboxylate (DINCH) is considered to be less toxic and more prone to environmental degradation, and is widely used as a substitute for p...
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Elsevier
2025-07-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325006414 |
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| author | Jingxin Xin Changxu Zhou Ying Wang Huiqi Chen Keling Yin Ling Gao Shanshan Shao |
| author_facet | Jingxin Xin Changxu Zhou Ying Wang Huiqi Chen Keling Yin Ling Gao Shanshan Shao |
| author_sort | Jingxin Xin |
| collection | DOAJ |
| description | Phthalates, as a class of known endocrine disruptors, have been controversial because of their potential carcinogenicity and toxicity. Diisononyl cyclohexane-1,2-dicarboxylate (DINCH) is considered to be less toxic and more prone to environmental degradation, and is widely used as a substitute for phthalate. With the increasing use of DINCH in consumer products and industrial materials, the frequency of its detection in the air and human urine has also increased, which has aroused concern about its potential toxicity in food safety. Despite the increasing popularity of DINCH, toxicological studies on this topic are still limited. This study first predicted the hepatotoxicity and carcinogenicity of DINCH via the ADMETlab 3.0 platform. Next, the potential hepatotoxic genes associated with DINCH were collected through multiple databases, and a gene network was constructed. Through proteinprotein interaction, GO enrichment and KEGG pathway analyses, we elucidated the primary mechanism by which DINCH may induce hepatotoxicity. The expression of the selected key genes in related diseases was subsequently validated via the liver cancer database of TCGA and the NASH dataset of GEO. In addition, molecular docking technology and dynamics simulation were used to simulate the interaction and binding ability between DINCH and the core target. Cell experiments verified that DINCH increases hepatotoxicity primarily by upregulating TNF, TP53, and PPARG. In summary, this study elucidates the potential biological mechanisms of DINCH-induced hepatotoxicity, providing new scientific insights for the prevention and management of related toxicities. |
| format | Article |
| id | doaj-art-abf07e9b63bc4ebc8493c8ac300da5e3 |
| institution | DOAJ |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-abf07e9b63bc4ebc8493c8ac300da5e32025-08-20T03:07:51ZengElsevierEcotoxicology and Environmental Safety0147-65132025-07-0129911830510.1016/j.ecoenv.2025.118305Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validationJingxin Xin0Changxu Zhou1Ying Wang2Huiqi Chen3Keling Yin4Ling Gao5Shanshan Shao6Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, ChinaDepartment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, ChinaDepartment of Endocrinology, Shandong Provincial Hospital, Shandong University, Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, ChinaDepartment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, ChinaDepartment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, ChinaDepartment of Endocrinology, Shandong Provincial Hospital, Shandong University, Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong 250021, China; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, ChinaDepartment of Endocrinology, Shandong Provincial Hospital, Shandong University, Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong 250021, China; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; Corresponding author at: Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong 250021, China.Phthalates, as a class of known endocrine disruptors, have been controversial because of their potential carcinogenicity and toxicity. Diisononyl cyclohexane-1,2-dicarboxylate (DINCH) is considered to be less toxic and more prone to environmental degradation, and is widely used as a substitute for phthalate. With the increasing use of DINCH in consumer products and industrial materials, the frequency of its detection in the air and human urine has also increased, which has aroused concern about its potential toxicity in food safety. Despite the increasing popularity of DINCH, toxicological studies on this topic are still limited. This study first predicted the hepatotoxicity and carcinogenicity of DINCH via the ADMETlab 3.0 platform. Next, the potential hepatotoxic genes associated with DINCH were collected through multiple databases, and a gene network was constructed. Through proteinprotein interaction, GO enrichment and KEGG pathway analyses, we elucidated the primary mechanism by which DINCH may induce hepatotoxicity. The expression of the selected key genes in related diseases was subsequently validated via the liver cancer database of TCGA and the NASH dataset of GEO. In addition, molecular docking technology and dynamics simulation were used to simulate the interaction and binding ability between DINCH and the core target. Cell experiments verified that DINCH increases hepatotoxicity primarily by upregulating TNF, TP53, and PPARG. In summary, this study elucidates the potential biological mechanisms of DINCH-induced hepatotoxicity, providing new scientific insights for the prevention and management of related toxicities.http://www.sciencedirect.com/science/article/pii/S0147651325006414DINCHHepatotoxicityNetwork toxicologyMolecular dockingExperimental validation |
| spellingShingle | Jingxin Xin Changxu Zhou Ying Wang Huiqi Chen Keling Yin Ling Gao Shanshan Shao Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation Ecotoxicology and Environmental Safety DINCH Hepatotoxicity Network toxicology Molecular docking Experimental validation |
| title | Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation |
| title_full | Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation |
| title_fullStr | Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation |
| title_full_unstemmed | Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation |
| title_short | Unraveling DINCH – Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation |
| title_sort | unraveling dinch induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation |
| topic | DINCH Hepatotoxicity Network toxicology Molecular docking Experimental validation |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325006414 |
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