SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex
Succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode of action is based on blocking the activity of succinate dehydrogenase (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH is involved in...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-10-01
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| Series: | Environment International |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412023004920 |
| _version_ | 1797659932303032320 |
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| author | Carolina Duarte Hospital Arnaud Tête Kloé Debizet Jules Imler Céline Tomkiewicz-Raulet Etienne B. Blanc Robert Barouki Xavier Coumoul Sylvie Bortoli |
| author_facet | Carolina Duarte Hospital Arnaud Tête Kloé Debizet Jules Imler Céline Tomkiewicz-Raulet Etienne B. Blanc Robert Barouki Xavier Coumoul Sylvie Bortoli |
| author_sort | Carolina Duarte Hospital |
| collection | DOAJ |
| description | Succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode of action is based on blocking the activity of succinate dehydrogenase (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH is involved in two interconnected metabolic processes for energy production: the transfer of electrons in the mitochondrial respiratory chain and the oxidation of succinate to fumarate in the Krebs cycle. In humans, inherited SDH deficiencies may cause major pathologies including encephalopathies and cancers. The cellular and molecular mechanisms related to such genetic inactivation have been well described in neuroendocrine tumors, in which it induces an oxidative stress, a pseudohypoxic phenotype, a metabolic, epigenetic and transcriptomic remodeling, and alterations in the migration and invasion capacities of cancer cells, in connection with the accumulation of succinate, an oncometabolite, substrate of the SDH. We will discuss recent studies reporting toxic effects of SDHi in non-target organisms and their implications for risk assessment of pesticides. Recent data show that the SDH structure is highly conserved during evolution and that SDHi can inhibit SDH activity in mitochondria of non-target species, including humans. These observations suggest that SDHi are not specific inhibitors of fungal SDH. We hypothesize that SDHi could have toxic effects in other species, including humans. Moreover, the analysis of regulatory assessment reports shows that most SDHi induce tumors in animals without evidence of genotoxicity. Thus, these substances could have a non-genotoxic mechanism of carcinogenicity that still needs to be fully characterized and that could be related to SDH inhibition. The use of pesticides targeting mitochondrial enzymes encoded by tumor suppressor genes raises questions on the risk assessment framework of mitotoxic pesticides. The issue of SDHi fungicides is therefore a textbook case that highlights the urgent need for changes in regulatory assessment. |
| first_indexed | 2024-03-11T18:23:21Z |
| format | Article |
| id | doaj.art-b1abd25c45944828ace5a5182fbb0bda |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-03-11T18:23:21Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-b1abd25c45944828ace5a5182fbb0bda2023-10-15T04:36:30ZengElsevierEnvironment International0160-41202023-10-01180108219SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complexCarolina Duarte Hospital0Arnaud Tête1Kloé Debizet2Jules Imler3Céline Tomkiewicz-Raulet4Etienne B. Blanc5Robert Barouki6Xavier Coumoul7Sylvie Bortoli8Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisUniversité Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisUniversité Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisUniversité Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisUniversité Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisUniversité Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisUniversité Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisCorresponding authors.; Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisCorresponding authors.; Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 ParisSuccinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode of action is based on blocking the activity of succinate dehydrogenase (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH is involved in two interconnected metabolic processes for energy production: the transfer of electrons in the mitochondrial respiratory chain and the oxidation of succinate to fumarate in the Krebs cycle. In humans, inherited SDH deficiencies may cause major pathologies including encephalopathies and cancers. The cellular and molecular mechanisms related to such genetic inactivation have been well described in neuroendocrine tumors, in which it induces an oxidative stress, a pseudohypoxic phenotype, a metabolic, epigenetic and transcriptomic remodeling, and alterations in the migration and invasion capacities of cancer cells, in connection with the accumulation of succinate, an oncometabolite, substrate of the SDH. We will discuss recent studies reporting toxic effects of SDHi in non-target organisms and their implications for risk assessment of pesticides. Recent data show that the SDH structure is highly conserved during evolution and that SDHi can inhibit SDH activity in mitochondria of non-target species, including humans. These observations suggest that SDHi are not specific inhibitors of fungal SDH. We hypothesize that SDHi could have toxic effects in other species, including humans. Moreover, the analysis of regulatory assessment reports shows that most SDHi induce tumors in animals without evidence of genotoxicity. Thus, these substances could have a non-genotoxic mechanism of carcinogenicity that still needs to be fully characterized and that could be related to SDH inhibition. The use of pesticides targeting mitochondrial enzymes encoded by tumor suppressor genes raises questions on the risk assessment framework of mitotoxic pesticides. The issue of SDHi fungicides is therefore a textbook case that highlights the urgent need for changes in regulatory assessment.http://www.sciencedirect.com/science/article/pii/S0160412023004920PesticidesMitochondriaCancerOncometaboliteMitotoxicity |
| spellingShingle | Carolina Duarte Hospital Arnaud Tête Kloé Debizet Jules Imler Céline Tomkiewicz-Raulet Etienne B. Blanc Robert Barouki Xavier Coumoul Sylvie Bortoli SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex Environment International Pesticides Mitochondria Cancer Oncometabolite Mitotoxicity |
| title | SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex |
| title_full | SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex |
| title_fullStr | SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex |
| title_full_unstemmed | SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex |
| title_short | SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex |
| title_sort | sdhi fungicides an example of mitotoxic pesticides targeting the succinate dehydrogenase complex |
| topic | Pesticides Mitochondria Cancer Oncometabolite Mitotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S0160412023004920 |
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