Glutathione in Chlorpyrifos-and Chlorpyrifos-Oxon-Induced Toxicity: a Comparative Study Focused on Non-cholinergic Toxic

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Glutathione in Chlorpyrifos-and Chlorpyrifos-Oxon-Induced Toxicity: a Comparative Study Focused on Non-cholinergic Toxicity in HT22 Cells Aline Aita Naime 1 & Mark William Lopes 1,2 & Dirleise Colle 3 & Alcir Luiz Dafré 1 & Cristina Suñol 4 & João Batista Teixeira da Rocha 5 & Michael Aschner 6 & Rodrigo Bainy Leal 1 & Marcelo Farina 1 Received: 31 March 2020 / Revised: 30 June 2020 / Accepted: 3 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Chlorpyrifos (CPF) is a neurotoxic organophosphorus (OP) insecticide widely used for agricultural purposes. CPF-mediated neurotoxicity is mainly associated with its anticholinesterase activity, which may lead to a cholinergic syndrome. CPF metabolism generates chlorpyrifos-oxon (CPF-O), which possesses higher anticholinesterase activity and, consequently, plays a major role in the cholinergic syndrome observed after CPF poisoning. Recent lines of evidence have also reported non-cholinergic endpoints of CPF- and CPF-O-induced neurotoxicities, but comparisons on the non-cholinergic toxic properties of CPF and CPFO are lacking. In this study, we compared the non-cholinergic toxicities displayed by CPF and CPF-O in cultured neuronal cells, with a particular emphasis on their pro-oxidant properties. Using immortalized cells derived from mouse hippocampus (HT22 line, which does present detectable acetylcholinesterase activity), we observed that CPF-O was 5-fold more potent in decreasing cell viability compared with CPF. Atropine, a muscarinic acetylcholine receptor antagonist, protected against acetylcholine (ACh)-induced toxicity but failed to prevent the CPF- and CPF-O-induced cytotoxicities in HT22 cells. CPF or CPF-O exposures significantly decreased the levels of the antioxidant glutathione (GSH); this event preceded the significant decrease in cell viability. Pretreatment with N-acetylcysteine (NAC, a GSH precursor) protected against the cytotoxicity induced by both CPF and CPF-O. The present study indicates that GSH depletion is a non-cholinergic event involved in CPF and CPF-O toxicities. The study also shows that in addition of being a more potent AChE inhibitor, CPF-O is also a more potent pro-oxidant molecule when compared with CPF, highlighting the role of CPF metabolism (bioactivation to CPF-O) in the ensuing non-cholinergic toxicity.

Highlights • Chlorpyrifos and chlorpyrifos-oxon caused toxicity in HT22 cells. • Chlorpyrifos-oxon is more toxic to HT22 cells when compared with chlorpyrifos. • Atropine does not prevent such toxicity. • Chlorpyrifos and chlorpyrifos-oxon caused glutathione depletion. • N-acetylcysteine prevented chlorpyrifos- and chlorpyrifos-oxoninduced toxicity. * Aline Aita Naime [email protected] * Marcelo Farina [email protected] 1

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Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC 88040900, Brazil Area of Biological Sciences, Medical and Health, Centro Universitário para o Desenvolvimento do Alto Vale do It