Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver

Abstract

Copper (Cu) is an essential trace element involved in the normal physiological processes of animals. However, excessive exposure to Cu can produce numerous detrimental impacts. The aim of this study was to investigate the effects of Cu on oxidative stress and apoptosis as well as their relationship in the mouse liver. Four-week-old ICR mice (n=240) were randomly assigned to different Cu (Cu2+-CuSO4) treatment groups (0, 4, 8, and 16 mg/kg) for periods of 21 and 42 days. The high doses of Cu exposure could induce oxidative stress, by increasing the levels of reactive oxygen species (ROS) and protein carbonyls (PC) and decreasing the activities of antisuperoxide anion (ASA) and antihydroxyl radical (AHR) and content of glutathione (GSH), as well as activities and mRNA expression levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Moreover, high doses of Cu exposure induced hepatic apoptosis via the mitochondrial apoptotic pathway, as characterized by the depolarization of mitochondrial membrane potential (MMP); significantly increased mRNA and protein expression levels of cytosolic cytochrome (Cyt c), apoptosis-inducing factor (AIF), endonuclease G (Endo G), apoptosis protease-activating factor-1 (Apaf-1), cleaved caspase-9, cleaved caspase-3, cleaved PARP, Bcl-2 antagonist killer (Bak), Bcl-2-associated X protein (Bax), and Bcl-2-interacting mediator of cell death (Bim); and decreased mRNA and protein expression levels of B-cell lymphoma-2 (Bcl-2) and Bcl-extra-large (Bcl-xL). Furthermore, the activation of the tumor necrosis factor receptor-1 (TNF-R1) signaling pathway was involved in Cu-induced apoptosis, as characterized by the significantly increased mRNA and protein expression levels of TNF-R1, Fas-associated death domain (FADD), TNFR-associated death domain (TRADD), and cleaved caspase-8. These results indicated that exposure to excess Cu could cause oxidative stress triggered by ROS overproduction and diminished antioxidant function, which in turn promoted hepatic apoptosis via mitochondrial apoptosis and that the TNF-R1 signaling pathway was also involved in the Cu-induced apoptosis.

<p>MAGOH/MAGOHB Inhibits the Tumorigenesis of Gastric Cancer via Inactivation of b-RAF/MEK/ERK Signaling</p>

“…19 Additionally, cleaved PARP can also be upregulated during the cell apoptosis. 20,21 Our finding was consistent with these studies, suggesting that knockdown of MAGOH or double knockdown of MAGOH and MAGOHB induced the apoptosis of gastric cancer cells via upregulation of cleaved caspase 3 and cleaved PARP. Cyclin B1, CDK1 and p27 Kip1 were key mediators in cell cycle distribution.…”

“…Cells were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 100 μg/mL streptomycin and penicillin at 37°C in 5% CO 2 . The use of cells was approved by the Ethics Committee of Zhejiang University School of Medicine (20,190,711).…”

“…All participants have signed written informed consent. This study was in line with the Helsinki Declaration and has been approved by the Ethics Committee of Zhejiang University School of Medicine (20,190,405). The clinical information of patients was presented in supplementary information.…”

Molecular Mechanisms Underlying Protective Role of Quercetin on Copper Sulfate-Induced Nephrotoxicity in Mice

“…Cu overdose could disturb this balance and induce the production of excessive ROS, which leads to lipid, protein and DNA damage ( 39 ). Previous studies demonstrated that CuSO 4 or copper chloride (CuCl 2 ) exposure can induce the production of excessive ROS in HEK293 cells, mouse liver cells or neuronal cells ( 23 , 40 , 41 ). Mitochondria are not only the major producer of cellular ROS but also a target ( 42 ).…”

Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper

“…As revealed in previous studies, various death pathways have been triggered upon copper exposure, depending on the copper concentration used, treatment period and the cellular or animal model under study. Copper overload may result in caspase-dependent and caspase-independent programmed cell death, autophagy and necrosis [ 19 , 42 , 43 ]. In some studies, exposure to excess copper initiated a classical apoptotic pathway and the activation of executioner caspase-3 [ 43 ].…”