Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver

Huan Liu,Jing Fang,Xun Wang,Ling Zhao,Hongrui Guo,Junliang Deng,Hengmin Cui,Zhicai Zuo,Yinglun Li,Zhijie Jian

doi:10.1155/2020/1359164

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.

Highlights

Copper (Cu) is an essential trace element involved in the normal physiological processes of animals [1]
The results showed that the mRNA expression levels of these antioxidant enzymes were decreased in the three Cu treatment groups at different degrees, which are consistent with the reduction of their activities
We found that excess Cu exposure increased the mRNA and protein expression levels of tumor necrosis factor receptor-1 (TNF-R1), Fas-associated death domain (FADD), TNFR-associated death domain (TRADD), and caspase-8, which represent the important members in the death receptor signaling pathway

Summary

Introduction

Copper (Cu) is an essential trace element involved in the normal physiological processes of animals [1]. Despite its necessity for various metabolic processes and enzyme activities [2], chronic overexposure to Cu may produce some detrimental effects on our body. Occupational exposure to Cu can result in Cu toxicity among industrial workers [3]. The metabolism of Cu is mainly regulated by the liver, where it can be released into the circulatory system or excreted via the bile [1]. During chronic Cu toxicity, Cu is gradually accumulated in the liver without producing any obvious signs or symptoms. When the hepatic Cu storage capacity is exceeded, it may result in hepatocellular lesions, and the liberation of Cu from the liver into the blood stream triggers hemolysis, jaundice, and renal insufficiency [4]

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