Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells
Succinate dehydrogenase inhibitors (SDHi) are fungicides used worldwide to control the proliferation of fungi in crops. They act by blocking the activity of succinate dehydrogenase (SDH), a universal enzyme involved in mitochondrial functions and metabolism. While SDH-encoding genes are tumour suppr...
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| Format: | Article |
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Elsevier
2025-05-01
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| Series: | Environment International |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412025002545 |
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| author | Carolina Duarte Hospital Arnaud Tête Kloé Debizet Clémence Rives Jules Imler Sofiane Safi-Stibler Lara Gales Floriant Bellvert Julien Dairou Auriane Hagimont Agnès Burel Dominique Lagadic-Gossmann Robert Barouki Jerry W. Shay Jean Bastin Sophie Mouillet-Richard Anthony Lemarié Fatima Djouadi Sandrine Ellero-Simatos Xavier Coumoul Judith Favier Sylvie Bortoli |
| author_facet | Carolina Duarte Hospital Arnaud Tête Kloé Debizet Clémence Rives Jules Imler Sofiane Safi-Stibler Lara Gales Floriant Bellvert Julien Dairou Auriane Hagimont Agnès Burel Dominique Lagadic-Gossmann Robert Barouki Jerry W. Shay Jean Bastin Sophie Mouillet-Richard Anthony Lemarié Fatima Djouadi Sandrine Ellero-Simatos Xavier Coumoul Judith Favier Sylvie Bortoli |
| author_sort | Carolina Duarte Hospital |
| collection | DOAJ |
| description | Succinate dehydrogenase inhibitors (SDHi) are fungicides used worldwide to control the proliferation of fungi in crops. They act by blocking the activity of succinate dehydrogenase (SDH), a universal enzyme involved in mitochondrial functions and metabolism. While SDH-encoding genes are tumour suppressors, which loss-of-function mutations predispose to different types of rare tumors in humans, the consequences of chemical inactivation of SDH by SDHi remain largely unknown, particularly regarding their carcinogenic potential. Here, we investigated the metabolic and cellular impact of SDHi on human non-cancer and transformed colon cells. We show that SDHi inhibit SDH activity and increase the level of succinate, known to act as an oncometabolite in SDH-deficient cancers. SDHi exposure also induces a Warburg-like metabolic reprogramming typical of cancer cells, associated with transcriptomic and morphological changes promoting cell migration and invasion. These effects are enhanced in transformed colon cells carrying mutations in colorectal cancer (CRC) driver genes. These findings provide the first evidence that SDHi-mediated chemical inactivation of SDH mimics some metabolic and phenotypic features previously described in human tumors with SDH genetic deficiencies. Given that loss of SDH expression in CRC patients correlates with a poor prognosis, these patients could represent a population sensitive to SDHi exposure. Therefore, it would be wise to include them in biomonitoring programs. Finally, our work highlights the need to improve regulatory assessment procedures to take better account of SDHi mode of action, by developing relevant tests to cover the multiple key events linked to SDH inactivation and assess the resulting mitochondrial toxicity. |
| format | Article |
| id | doaj-art-ec3cc09f973449eeafb6360d8e8903af |
| institution | Kabale University |
| issn | 0160-4120 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj-art-ec3cc09f973449eeafb6360d8e8903af2025-08-20T03:52:47ZengElsevierEnvironment International0160-41202025-05-0119910950310.1016/j.envint.2025.109503Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cellsCarolina Duarte Hospital0Arnaud Tête1Kloé Debizet2Clémence Rives3Jules Imler4Sofiane Safi-Stibler5Lara Gales6Floriant Bellvert7Julien Dairou8Auriane Hagimont9Agnès Burel10Dominique Lagadic-Gossmann11Robert Barouki12Jerry W. Shay13Jean Bastin14Sophie Mouillet-Richard15Anthony Lemarié16Fatima Djouadi17Sandrine Ellero-Simatos18Xavier Coumoul19Judith Favier20Sylvie Bortoli21Université Paris Cité, Inserm, HealthFex, F75006 Paris, FranceUniversité Paris Cité, Inserm, HealthFex, F75006 Paris, FranceUniversité Paris Cité, Inserm, HealthFex, F75006 Paris, FranceToxalim (Research Centre in Food Toxicology), INRAe, ENVT, INP-Purpan, UPS, Université de Toulouse 31300 Toulouse, FranceUniversité Paris Cité, Inserm, HealthFex, F75006 Paris, FranceUniversité Paris Cité, PARCC INSERM UMR970, Equipe labellisée par la Ligue Contre le Cancer Paris, FranceMetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, 31077 Toulouse, FranceMetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, 31077 Toulouse, FranceUniversité Paris Cité, CNRS, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, F-75006 Paris, FranceCRCT, Université de Toulouse, Inserm, CNRS, Université Toulouse III–Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, RADOPT team, Toulouse, FranceUniv Rennes, CNRS, INSERM, BIOSIT – UAR 3480, US_S 018, Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000 Rennes, FranceUniversité Paris Cité, Inserm, HealthFex, F75006 Paris, FranceDepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USACentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, FranceCRCT, Université de Toulouse, Inserm, CNRS, Université Toulouse III–Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, RADOPT team, Toulouse, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, FranceToxalim (Research Centre in Food Toxicology), INRAe, ENVT, INP-Purpan, UPS, Université de Toulouse 31300 Toulouse, FranceUniversité Paris Cité, Inserm, HealthFex, F75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, FranceUniversité Paris Cité, Inserm, HealthFex, F75006 Paris, France; Corresponding author.Succinate dehydrogenase inhibitors (SDHi) are fungicides used worldwide to control the proliferation of fungi in crops. They act by blocking the activity of succinate dehydrogenase (SDH), a universal enzyme involved in mitochondrial functions and metabolism. While SDH-encoding genes are tumour suppressors, which loss-of-function mutations predispose to different types of rare tumors in humans, the consequences of chemical inactivation of SDH by SDHi remain largely unknown, particularly regarding their carcinogenic potential. Here, we investigated the metabolic and cellular impact of SDHi on human non-cancer and transformed colon cells. We show that SDHi inhibit SDH activity and increase the level of succinate, known to act as an oncometabolite in SDH-deficient cancers. SDHi exposure also induces a Warburg-like metabolic reprogramming typical of cancer cells, associated with transcriptomic and morphological changes promoting cell migration and invasion. These effects are enhanced in transformed colon cells carrying mutations in colorectal cancer (CRC) driver genes. These findings provide the first evidence that SDHi-mediated chemical inactivation of SDH mimics some metabolic and phenotypic features previously described in human tumors with SDH genetic deficiencies. Given that loss of SDH expression in CRC patients correlates with a poor prognosis, these patients could represent a population sensitive to SDHi exposure. Therefore, it would be wise to include them in biomonitoring programs. Finally, our work highlights the need to improve regulatory assessment procedures to take better account of SDHi mode of action, by developing relevant tests to cover the multiple key events linked to SDH inactivation and assess the resulting mitochondrial toxicity.http://www.sciencedirect.com/science/article/pii/S0160412025002545PesticidesMitochondriaMetabolic reprogrammingCancerOncometabolite |
| spellingShingle | Carolina Duarte Hospital Arnaud Tête Kloé Debizet Clémence Rives Jules Imler Sofiane Safi-Stibler Lara Gales Floriant Bellvert Julien Dairou Auriane Hagimont Agnès Burel Dominique Lagadic-Gossmann Robert Barouki Jerry W. Shay Jean Bastin Sophie Mouillet-Richard Anthony Lemarié Fatima Djouadi Sandrine Ellero-Simatos Xavier Coumoul Judith Favier Sylvie Bortoli Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells Environment International Pesticides Mitochondria Metabolic reprogramming Cancer Oncometabolite |
| title | Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells |
| title_full | Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells |
| title_fullStr | Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells |
| title_full_unstemmed | Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells |
| title_short | Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells |
| title_sort | triggering tumorigenic signaling succinate dehydrogenase inhibitor sdhi fungicides induce oncometabolite accumulation and metabolic shift in human colon cells |
| topic | Pesticides Mitochondria Metabolic reprogramming Cancer Oncometabolite |
| url | http://www.sciencedirect.com/science/article/pii/S0160412025002545 |
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