SDHi pesticides: mitochondrial disruptors with carcinogenic potential?

Sylvie Bortoli is a researcher in mechanistic toxicology at the HEALTHFEX laboratory - INSERM UMRS 1124 at Paris Cité University, headed by Xavier Coumoul. As part of the METATOX team, she coordinates several projects aimed at characterising the impact of dietary exposure to environmental contaminants on human health. She is particularly interested in the mechanisms of toxicity that alter mitochondrial function and metabolic homeostasis in relation to tumour progression. She participated in the INSERM collective expertise ‘Pesticides and Health’ for the chapter on SDHi fungicides and is a member of the ‘Cancer and Environment’ steering committee of the National League Against Cancer and the scientific council of the French Nutrition Society.

Presentation summary: Fungicides belonging to the succinate dehydrogenase inhibitor (SDHi) family are widely used to limit the proliferation of fungi responsible for reducing agricultural yields, and their presence in foodstuffs leads to chronic exposure among the population. SDHIs work by inhibiting succinate dehydrogenase (SDH), a highly conserved mitochondrial enzyme complex that plays a major role in maintaining energy homeostasis. The genes encoding SDH are tumour suppressor genes, and their genetic inactivation is associated with a predisposition to the development of certain cancers in humans. The mechanisms involved in the acquisition of the cancer phenotype and tumour aggressiveness include the accumulation of an oncometabolite (succinate), the establishment of pseudohypoxia, metabolic and epigenetic remodelling, oxidative stress and an increase in cell migration and invasion capabilities.

The lack of specificity of SDHIs with respect to fungal SDH raises the question of their potential toxicity to non-target organisms, including humans. Regulatory assessment reports indicate that most SDHIs induce tumours in animals, with no evidence of genotoxicity. Thus, for these substances, the mechanisms of carcinogenicity are not yet clearly established.

What do we know today about the consequences of exposure to SDHi pesticides on human health? Is the chemical inactivation of SDH by SDHIs likely to reproduce certain molecular and cellular mechanisms involved in the development of tumours in subjects with genetic SDH deficiency? Can we identify populations that are particularly sensitive to exposure to SDHIs?
This presentation will discuss the issues surrounding these pesticides that are toxic to mitochondria, the limitations of regulatory assessments, and our recent work exploring the mechanisms of SDHi toxicity.