Effect of the Fungicides - Succinate dehydrogenase Inhibitors On Neurodevelopment – FUSION

Succinate dehydrogenase inhibitors (SDHi) are fungicides that have been used for the past decade on a wide variety of crops to control the proliferation of pathogenic fungal that may impair crop yields. The mode of action of SDHi is based on the inhibition of succinate dehydrogenase (SDH), a mitochondrial enzyme that plays a crucial role in cellular respiration and energy metabolism. A recent work has shown that the catalytic site of SDH (SDHi binding site) exhibits a high degree of evolutionary conservation, and that SDHi inhibit SDH in the mitochondria of several non-target species, including humans. These observations suggest that SDHi are not specific to the fungal SDH and may have adverse effects on non-target organisms. Despite the observation of severe neurological defects related to genetic alteration of SDH in humans, the impact of its chemical inactivation by SDHi on neurodevelopment has been little studied. To fill this gap, this project proposes to use different in vivo and in vitro models in order to 1) to study the effects of SDHi exposure on neurodevelopment in zebrafish, xenopus, C. elegans and mice in vivo using biochemical, behavioral and imaging approaches; 2) to characterize the cellular and molecular mechanisms disrupted by chronic exposures to SDHi in human 2D neuronal cell line SH-SY5Y, human 3D neural stem cell models representing different neurodevelopmental stages, murine neurospheres, and zebrafish embryos using targeted and non-targeted approaches; 3) to identify species-overarching biomarkers of effects common to the studied non-target organisms and 4) based on in vivo and in vitro studies, to develop an adverse outcome pathway (AOP) network useful for regulatory toxicology, by identifying key cellular and molecular events linking an exposure to SDHi during development and the occurrence of behavioral, motor and cognitive alterations.