Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris.
Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris.
Environ Int. 2023 Oct;180:108219. doi: 10.1016/j.envint.2023.108219. Epub 2023 Sep 19.
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.
琥珀酸脱氢酶抑制剂（SDHi）是一种用于控制作物中致病真菌增殖的杀菌剂。其作用机制基于阻断琥珀酸脱氢酶（SDH）的活性，SDH 是所有具有线粒体的物种表达的一种普遍酶。SDH 参与两个相互关联的代谢过程：用于能量产生的电子在线粒体呼吸链中的转移和琥珀酸在线粒体三羧酸循环中氧化为富马酸。在人类中，遗传性 SDH 缺乏可能导致包括脑病和癌症在内的主要病理。与这种遗传失活相关的细胞和分子机制已在神经内分泌肿瘤中得到很好的描述，其中它诱导氧化应激、假性缺氧表型、代谢、表观遗传和转录组重编程以及癌细胞迁移和侵袭能力的改变，与琥珀酸盐（一种致癌代谢物，SDH 的底物）的积累有关。我们将讨论最近的研究报告，这些研究报告报道了 SDHi 在非靶标生物中的毒性作用及其对农药风险评估的影响。最近的数据表明，SDH 结构在进化过程中高度保守，SDHi 可以抑制非靶标物种（包括人类）线粒体中的 SDH 活性。这些观察结果表明，SDHi 不是真菌 SDH 的特异性抑制剂。我们假设 SDHi 可能对其他物种（包括人类）具有毒性作用。此外，对监管评估报告的分析表明，大多数 SDHi 在没有遗传毒性证据的情况下在动物中诱导肿瘤。因此，这些物质可能具有尚未完全表征的非遗传毒性致癌机制，可能与 SDH 抑制有关。靶向肿瘤抑制基因编码的线粒体酶的农药的使用引发了对线粒体毒性农药风险评估框架的质疑。因此，SDHi 杀菌剂问题是一个典型案例，突出了监管评估需要进行变革的紧迫性。
