Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure
Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that can interfere with the endocrine system and cause liver damage. However, the molecular mechanism of DEHP-induced liver injury is unclear. This study aimed to investigate the effects of DEHP on liver function and its relationship wit...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324001787 |
| _version_ | 1797300344080826368 |
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| author | Peng Xu Yang-ni Su Chen Ling Jing Wang Wang Zhang |
| author_facet | Peng Xu Yang-ni Su Chen Ling Jing Wang Wang Zhang |
| author_sort | Peng Xu |
| collection | DOAJ |
| description | Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that can interfere with the endocrine system and cause liver damage. However, the molecular mechanism of DEHP-induced liver injury is unclear. This study aimed to investigate the effects of DEHP on liver function and its relationship with thioredoxin-interacting protein (TXNIP) and mitochondrial oxidative stress pathway. We used C57BL/6 J mice and THLE-2 liver cells as in vivo and in vitro models, respectively, and treated them with different doses of DEHP, and measured the relevant biochemical indicators and molecular markers. We found that DEHP significantly increased the expression of TXNIP and NLRP3, while decreasing the expression of mitochondrial functional proteins, such as PGC-1α, TFAM, NRF1, NDUHA9, SDHA, MFN1. This resulted in mitochondrial dysfunction, manifested by reduced ATP generation, increased inflammatory factor release, elevated liver enzyme indicators, decreased mitochondrial membrane potential and increased oxidative stress. We further demonstrated that TXNIP upregulation activated NF-κB and MAPK signaling pathways, such as NF-κB, IκB, TAB2, TRAF6, ERK1, JNK, p38 MAPK, MEK1, which exacerbated oxidative stress and inflammation, leading to liver damage. Additionally, we found that treatment with the antioxidant MitoQ partially alleviated DEHP-induced liver toxicity, while silencing TXNIP more effectively restored mitochondrial function. Our study supports the hypothesis that DEHP induces mitochondrial oxidative stress through the TXNIP signaling pathway, resulting in liver dysfunction in mice, and suggests possible links between endocrine-disrupting chemicals and human diseases. |
| first_indexed | 2024-03-07T23:06:52Z |
| format | Article |
| id | doaj.art-39cf59a79af94f9dafdabf52cf04766a |
| institution | Directory Open Access Journal |
| issn | 0147-6513 |
| language | English |
| last_indexed | 2024-03-07T23:06:52Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj.art-39cf59a79af94f9dafdabf52cf04766a2024-02-22T04:51:40ZengElsevierEcotoxicology and Environmental Safety0147-65132024-03-01272116103Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failurePeng Xu0Yang-ni Su1Chen Ling2Jing Wang3Wang Zhang4Department of Pharmacy, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University, Hefei 230022, ChinaDepartment of Pharmacy, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University, Hefei 230022, ChinaDepartment of Pharmacy, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University, Hefei 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Pharmacy, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University, Hefei 230022, ChinaDepartment of Pharmacy, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University, Hefei 230022, China; Corresponding author.Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that can interfere with the endocrine system and cause liver damage. However, the molecular mechanism of DEHP-induced liver injury is unclear. This study aimed to investigate the effects of DEHP on liver function and its relationship with thioredoxin-interacting protein (TXNIP) and mitochondrial oxidative stress pathway. We used C57BL/6 J mice and THLE-2 liver cells as in vivo and in vitro models, respectively, and treated them with different doses of DEHP, and measured the relevant biochemical indicators and molecular markers. We found that DEHP significantly increased the expression of TXNIP and NLRP3, while decreasing the expression of mitochondrial functional proteins, such as PGC-1α, TFAM, NRF1, NDUHA9, SDHA, MFN1. This resulted in mitochondrial dysfunction, manifested by reduced ATP generation, increased inflammatory factor release, elevated liver enzyme indicators, decreased mitochondrial membrane potential and increased oxidative stress. We further demonstrated that TXNIP upregulation activated NF-κB and MAPK signaling pathways, such as NF-κB, IκB, TAB2, TRAF6, ERK1, JNK, p38 MAPK, MEK1, which exacerbated oxidative stress and inflammation, leading to liver damage. Additionally, we found that treatment with the antioxidant MitoQ partially alleviated DEHP-induced liver toxicity, while silencing TXNIP more effectively restored mitochondrial function. Our study supports the hypothesis that DEHP induces mitochondrial oxidative stress through the TXNIP signaling pathway, resulting in liver dysfunction in mice, and suggests possible links between endocrine-disrupting chemicals and human diseases.http://www.sciencedirect.com/science/article/pii/S0147651324001787DEHPTXNIPNLRP3MitochondriaOxidative stressLiver failure |
| spellingShingle | Peng Xu Yang-ni Su Chen Ling Jing Wang Wang Zhang Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure Ecotoxicology and Environmental Safety DEHP TXNIP NLRP3 Mitochondria Oxidative stress Liver failure |
| title | Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure |
| title_full | Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure |
| title_fullStr | Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure |
| title_full_unstemmed | Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure |
| title_short | Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure |
| title_sort | mitochondrial dysfunction mediated by thioredoxin interacting protein a crucial determinant in di 2 ethylhexyl phthalate induced liver failure |
| topic | DEHP TXNIP NLRP3 Mitochondria Oxidative stress Liver failure |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324001787 |
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