Differential Effects of Paraquat, Rotenone, and MPTP on Cellular Bioenergetics of Undifferentiated and Differentiated Human Neuroblastoma Cells

Elmorsy, Ekramy; Al-Ghafari, Ayat; Al Doghaither, Huda; Hashish, Sara; Salama, Mohamed; Mudyanselage, Anusha W.; James, Lipta; Carter, Wayne G.

Abstract

Paraquat (PQ), rotenone (RO), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are neurotoxicants that can damage human health. Exposure to these neurotoxicants has been linked to neurodegeneration, particularly Parkinson’s disease. However, their mechanisms of action have not been fully elucidated, nor has the relative vulnerability of neuronal subtypes to their exposures. To address this, the current study investigated the cytotoxic effects of PQ, RO, and MPTP and their relative effects on cellular bioenergetics and oxidative stress on undifferentiated human neuroblastoma (SH-SY5Y) cells and those differentiated to dopaminergic (DA) or cholinergic (CH) phenotypes. The tested neurotoxicants were all cytotoxic to the three cell phenotypes that correlated with both concentration and exposure duration. At half-maximal effective concentrations (EC50s), there were significant reductions in cellular ATP levels and reduced activity of the mitochondrial complexes I and III, with a parallel increase in lactate production. PQ at 10 µM significantly decreased ATP production and mitochondrial complex III activity only in DA cells. RO was the most potent inhibitor of mitochondrial complex 1 and did not inhibit mitochondrial complex III even at concentrations that induced a 50% loss of cell viability. MPTP was the most potent toxicant in undifferentiated cells. All neurotoxicants significantly increased reactive oxygen species, lipid peroxidation, and nuclear expression of Nrf2, with a corresponding inhibition of the antioxidant enzymes catalase and superoxide dismutase. At a 10 µM exposure to PQ or RO, oxidative stress biomarkers were significant in DA cells. Collectively, this study underscores the importance of mitochondrial dysfunction and oxidative stress in PQ, RO, and MPTP-induced cytotoxicity and that neuronal phenotypes display differential vulnerability to these neurotoxicants.

• Journal Article Type: Article
• Acceptance Date: Dec 12, 2023
• Online Publication Date: Dec 14, 2023
• Publication Date: 2023-12
• Deposit Date: Dec 15, 2023
• Publicly Available Date: Dec 15, 2023
• Journal: Brain Sciences
• Electronic ISSN: 2076-3425
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 12
• Article Number: 1717
• DOI: https://doi.org/10.3390/brainsci13121717
• Keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); mitochondrial damage; neurotoxi- city; oxidative stress; paraquat; pesticides; rotenone
• Public URL: https://nottingham-repository.worktribe.com/output/28432846
• Additional Information: Received: 17 October 2023 Revised: 7 December 2023 Accepted: 12 December 2023; Academic Editor: Sadaf Jahan Copyright: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). brain sciences Article 5 Institute of Global Health and Human Ecology, The American University in Cairo (AUC), Cairo 11385, Egypt