Melatonin counteracts cobalt nanoparticle-induced cytotoxicity and genotoxicity by deactivating reactive oxygen species-dependent mechanisms in the NRK cell line

Abstract

Cobalt nanoparticles (CoNPs) released from metal-on-metal implants have caused considerable concern. Oxidative stress is associated with the mechanism underlying cobalt-induced cytotoxicity and genotoxicity. The indolamine melatonin exhibits protective effects against damage induced by metals. The present study investigated the in vitro effects of melatonin on the cytotoxicity and genotoxicity induced by CoNPs. CoNPs (20–50 nm in diameter) were employed in the present study. NRK rat kidney cells were exposed to various concentrations of CoNPs for different durations. The results of the current study demonstrated that CoNPs significantly increased reactive oxygen species (ROS) production and reduced cell viability, as determined by dichlorofluorescein diacetate, and Cell Counting Kit-8 and lactate dehydrogenase leakage assays, respectively. Furthermore, western blot analysis demonstrated that CoNPs led to an increase in the ratio of Bcl-2-associated X/Bcl-2, and the expression of cleaved caspase-3 was upregulated, which indicated increased apoptosis levels. Genotoxicity was detected by a comet assay, which revealed a significant induction in DNA damage, as determined by increases in the tail DNA % and olive tail moment. Phosphorylated-histone H2AX foci analyses by immunofluorescence also demonstrated that CoNPs induced DNA-double strand breaks. However, cellular treatment with melatonin reduced the effects of CoNPs on NRK cells by reducing the production of ROS. The results of the present study demonstrated that CoNPs induced cytotoxicity and genotoxicity by increasing oxidative stress, and melatonin may have pharmacological potential in protecting against the damaging effects of CoNPs following total hip arthroplasty.

Alpha lipoic acid antagonizes cytotoxicity of cobalt nanoparticles by inhibiting ferroptosis-like cell death

“…According to different signaling pathways and molecular mechanisms, the current detoxification drugs for CoNPs toxicity in vitro or in vivo are following categories: (1) Antioxidants such as nitrogen-acetylcysteine (NAC) [50], L-ascorbic acid (LAA) [46], melatonin [58], alpha-tocopher [48], etc. (2) Antagonists, such as zinc [59,60]; (3) Chelating agents, such as EDTA [20,21] and dimercaptopropanol sulfonic acid sodium [22]; (4) Endoplasmic reticulum stress inhibitor, such as sodium 4-phenylbutyrate [36,37].…”

Melatonin: A Versatile Protector against Oxidative DNA Damage

“…This metal can cause DNA-protein cross-linking and disruption of the DNA repair system. In addition, it has been proposed that OS may be involved in the Co-induced cytotoxicity and genotoxicity [ 247 ]. In the same work, it was found that melatonin lowers tail DNA % and olive tail moment in rat kidney cells exposed to Co nanoparticles.…”

A paradox: Fe2+-containing agents decreased ROS and apoptosis induced by CoNPs in vascular endothelial cells by inhibiting HIF-1α

“…The toxic effects of CoNPs have earlier been reported in liver, kidney, and brain but few studies have investigated the influence of CoNPs on blood vessels [1][2][3][4]. After…”

“…Cobalt-chromium (CoCr) alloy casting implants have been extensively used in total hip arthroplasties, especially in younger and more active patients. Compared with early metal-on-polyethylene bearing implants, CoCr metal-on-metal (MOM) resurfacing implants improve wear characteristics, thereby reducing wear-induced Downloaded from http://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20203456/900510/bsr-2020-3456.pdf by guest on 28 December 2020 osteolysis, the main cause of loosening and dislocation of prostheses [1,2]. However, numerous studies have demonstrated that CoCr implants release a large amount of very small wear particles and metal ions [1,2].…”

“…Once the diameter of CoCr materials reaches the nanoscale, the nature of their biological effects changes [2]. Nano-sized Co particles can get incorporated into the periprosthetic tissue or enter the bloodstream and then reach organs such as heart, liver, kidney, and brain [1][2][3][4] and the toxicity of CoNPs has been observed in fibroblasts, U937 cells, peripheral blood mononuclear cells, and alveolar macrophages [5][6][7]. The deposition of CoNPs in tissues may trigger oxidative stress and inflammatory reactions, which could potentially lead to tissue necrosis and organ dysfunction [1][2][3][4].…”