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Toxicité cellulaire d’un herbicide organophosphoré, le glufosinate d’ammonium, et de son principal métabolite : Induction d’un stress oxydatif et modifications des voies de différenciation sur un modèle murin in vitro de culture primaire de cellules souches neurales

Abstract : The glufosinate-ammonium (GLA) is an organophosphorus herbicide commonly used in agriculture. Many cases of intentional ingestions have highlighted its neurotoxicity. However, its effects on neurodevelopment are not well studied. Indeed, the brain is an important target of GLA due to its structural homology with glutamate, the main excitatory neurotransmitter of the central nervous system. Our previous data are shown that a perinatal exposure to low doses of GLA induces disturbances in neurogenesis and in neuroblasts migration from the subventricular zone to the olfactory bulbs. These changes are associated with the development of autism spectrum disorders in the offspring. My thesis is in the continuity of his work and addresses the cellular and molecular aspects involved in early exposure to GLA. Since we are continuously exposed to pesticides, but also to their metabolites, I studied in parallel the effects of the main metabolite of GLA, the 4 methylphosphinyl-2-oxo-butanoic acid (PPO).The first work of my thesis was to develop an in vitro protocol for the primary culture of neural stem cells from the subventricular zone of mice, for the analysis of the neurotoxic effects of GLA and PPO. The results of the first study of my thesis showed an induction of related oxidative stress involving the glutamatergic system, and associated with a disruption of calcium homeostasis. Since neural stem cells are sensitive to the effects of oxidative stress, in a second study, I studied the impact of these effects on the cellular differentiation mechanisms of neural stem cells. My results indicated a significant effect of exposure to GLA and PPO on the formation and maintenance of the subventricular neurogenic niche in vitro. GLA and PPO interfere with the formation of ependyma and induce a disruption in the neuroglial differentiation of neural stem cells, without influencing their growth or proliferation capacity.All these data highlight on the interest of studying the cellular and molecular mechanisms linked to the neurotoxicity of the active substances of pesticides, the metabolites of these same pesticides, but also the mixtures of active substances and metabolites to which we are continuously exposed in our environment.
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https://tel.archives-ouvertes.fr/tel-02103247
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Submitted on : Thursday, April 18, 2019 - 11:15:20 AM
Last modification on : Friday, August 21, 2020 - 3:20:27 AM

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Justyne Feat. Toxicité cellulaire d’un herbicide organophosphoré, le glufosinate d’ammonium, et de son principal métabolite : Induction d’un stress oxydatif et modifications des voies de différenciation sur un modèle murin in vitro de culture primaire de cellules souches neurales. Sciences agricoles. Université d'Orléans, 2018. Français. ⟨NNT : 2018ORLE2035⟩. ⟨tel-02103247⟩

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