Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen Species
Hexachloronaphthalene (PCN67) is one of the most toxic among polychlorinated naphthalenes. Despite the known high bioaccumulation and persistence of PCN67 in the environment, it is still unclear to what extent exposure to these substances may interfere with normal neuronal physiology and lead to neu...
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doaj-04693644eddb46d2a6962453ef199a7c2020-11-25T03:02:47ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942020-01-01202010.1155/2020/24792342479234Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen SpeciesMalwina Lisek0Joanna Stragierowicz1Feng Guo2Philipp P. Prosseda3Magdalena Wiktorska4Bozena Ferenc5Anna Kilanowicz6Ludmila Zylinska7Tomasz Boczek8Department of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, PolandDepartment of Toxicology, Medical University of Lodz, 90151 Lodz, PolandDepartment of Pharmaceutical Toxicology, China Medical University, Shenyang 110122, ChinaDepartment of Patho Biochemistry, Goethe Universitätsklinikum, 60590 Frankfurt am Main, GermanyDepartment of Molecular Cell Mechanisms, Medical University of Lodz, 92215 Lodz, PolandDepartment of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, PolandDepartment of Toxicology, Medical University of Lodz, 90151 Lodz, PolandDepartment of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, PolandDepartment of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, PolandHexachloronaphthalene (PCN67) is one of the most toxic among polychlorinated naphthalenes. Despite the known high bioaccumulation and persistence of PCN67 in the environment, it is still unclear to what extent exposure to these substances may interfere with normal neuronal physiology and lead to neurotoxicity. Therefore, the primary goal of this study was to assess the effect of PCN67 in neuronal in vitro models. Neuronal death was assessed upon PCN67 treatment using differentiated PC12 cells and primary hippocampal neurons. At 72 h postexposure, cell viability assays showed an IC50 value of 0.35 μg/ml and dose-dependent damage of neurites and concomitant downregulation of neurofilaments L and M. Moreover, we found that younger primary neurons (DIV4) were much more sensitive to PCN67 toxicity than mature cultures (DIV14). Our comprehensive analysis indicated that the application of PCN67 at the IC50 concentration caused necrosis, which was reflected by an increase in LDH release, HMGB1 protein export to the cytosol, nuclear swelling, and loss of homeostatic control of energy balance. The blockage of mitochondrial calcium uniporter partially rescued the cell viability, loss of mitochondrial membrane potential (ΔΨm), and the overproduction of reactive oxygen species, suggesting that the underlying mechanism of neurotoxicity involved mitochondrial calcium accumulation. Increased lipid peroxidation as a consequence of oxidative stress was additionally seen for 0.1 μg/ml of PCN67, while this concentration did not affect ΔΨm and plasma membrane permeability. Our results show for the first time that neuronal mitochondria act as a target for PCN67 and indicate that exposure to this drug may result in neuron loss via mitochondrial-dependent mechanisms.http://dx.doi.org/10.1155/2020/2479234 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Malwina Lisek Joanna Stragierowicz Feng Guo Philipp P. Prosseda Magdalena Wiktorska Bozena Ferenc Anna Kilanowicz Ludmila Zylinska Tomasz Boczek |
spellingShingle |
Malwina Lisek Joanna Stragierowicz Feng Guo Philipp P. Prosseda Magdalena Wiktorska Bozena Ferenc Anna Kilanowicz Ludmila Zylinska Tomasz Boczek Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen Species Oxidative Medicine and Cellular Longevity |
author_facet |
Malwina Lisek Joanna Stragierowicz Feng Guo Philipp P. Prosseda Magdalena Wiktorska Bozena Ferenc Anna Kilanowicz Ludmila Zylinska Tomasz Boczek |
author_sort |
Malwina Lisek |
title |
Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen Species |
title_short |
Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen Species |
title_full |
Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen Species |
title_fullStr |
Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen Species |
title_full_unstemmed |
Hexachloronaphthalene Induces Mitochondrial-Dependent Neurotoxicity via a Mechanism of Enhanced Production of Reactive Oxygen Species |
title_sort |
hexachloronaphthalene induces mitochondrial-dependent neurotoxicity via a mechanism of enhanced production of reactive oxygen species |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2020-01-01 |
description |
Hexachloronaphthalene (PCN67) is one of the most toxic among polychlorinated naphthalenes. Despite the known high bioaccumulation and persistence of PCN67 in the environment, it is still unclear to what extent exposure to these substances may interfere with normal neuronal physiology and lead to neurotoxicity. Therefore, the primary goal of this study was to assess the effect of PCN67 in neuronal in vitro models. Neuronal death was assessed upon PCN67 treatment using differentiated PC12 cells and primary hippocampal neurons. At 72 h postexposure, cell viability assays showed an IC50 value of 0.35 μg/ml and dose-dependent damage of neurites and concomitant downregulation of neurofilaments L and M. Moreover, we found that younger primary neurons (DIV4) were much more sensitive to PCN67 toxicity than mature cultures (DIV14). Our comprehensive analysis indicated that the application of PCN67 at the IC50 concentration caused necrosis, which was reflected by an increase in LDH release, HMGB1 protein export to the cytosol, nuclear swelling, and loss of homeostatic control of energy balance. The blockage of mitochondrial calcium uniporter partially rescued the cell viability, loss of mitochondrial membrane potential (ΔΨm), and the overproduction of reactive oxygen species, suggesting that the underlying mechanism of neurotoxicity involved mitochondrial calcium accumulation. Increased lipid peroxidation as a consequence of oxidative stress was additionally seen for 0.1 μg/ml of PCN67, while this concentration did not affect ΔΨm and plasma membrane permeability. Our results show for the first time that neuronal mitochondria act as a target for PCN67 and indicate that exposure to this drug may result in neuron loss via mitochondrial-dependent mechanisms. |
url |
http://dx.doi.org/10.1155/2020/2479234 |
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