Potential Impact of Cobalt Nanoparticles on Human Health

Co-NPs serve as efficient contrast agents for MRI among other biomedical use; however, the study observed significant neural damage in both hippocampus and cortex of the temporal lobe in Wistar rats when exposed to Co-NPs and Co2+ in 96-123 nM doses suggesting potential neurological risk in humans. Co2+ accumulated to a greater extent in brain and blood compared to Co-NPs, whereas Co-NPs amount was higher in the liver [41]. Experimental data indicate that Co-NPs can induce endothelial inflammatory responses not only via oxidative stress but also through various pathways. Internalization of Co-NPs by cells occurred rapidly and upregulation of adhesion molecules (ICAM-1, VCAM-1, E-selectin) at mRNA and protein levels takes place and subsequently releases monocyte chemoattractant protein-1 (MCP-1) and interleukin 8 (IL-8) in human aorta (HAECs) and HUVECs. In addition, Co-NPs induced time- and concentration-dependent metabolic impairment and oxidative stress compared with titanium oxide nanoparticles [38]. Mechanistically Co-NPs increase malondialdehyde and caspase-9 protein level leading to lipid peroxidation and apoptosis in PC12 cells [41]. Co2+ showed an association with enhanced weight gain in animals [41].

Tungsten carbide (WC) shows less toxicity to the cells; however, when attached with Co-NPs (WC-Co-NPs) its toxicity is enhanced almost similar to cobalt ions (Co2+) in human keratinocytes (HaCaT). Gene expression analysis showed that WC exerted very little effects on the transcriptomic level after 3 and 72h of exposure, whereas WC-Co-NPs caused significant transcriptional changes that were similar to Co2+. Gene set enrichment analyses revealed that the differentially expressed genes were related to hypoxia response, carbohydrate metabolism, endocrine pathways, cell adhesion, and targets of several transcription factors (e.g., SOX2, YY1) [10]. Cobalt ferrite nanoparticles (Co-Fe-NPs) have great advantages compared to other contestants because of its physicochemical and magnetic properties with ease of synthesis resulting in extensive use in biomedical fields. Human body can be exposed to Co-Fe-NPs easily by ingestion, inhalation, adsorption, etc. which might induce oxidative stress, cytotoxicity, genotoxicity, inflammation, apoptosis, and developmental, metabolic, and hormonal abnormalities [37]. Research has shown the putative role of the hypoxia-inducible factor (HIF) pathway in the mechanism of Co-NPs toxicity (Figure 15.1) in human macrophage models using the U937 cell line, human alveolar macrophages, and monocyte-derived macrophages. Co-NPs induced HIF-la stabilization which can be prevented by the addition of either ascorbic acid (100 mM) or glutathione (1 mM) suggesting the involvement of ROS-independent pathway in Co-NPs-induced cytotoxicity. Additionally, ascorbic acid causes the downregulation of IL-lb showing a possible link between HIF and the inflammatory response to Co-NPs [19].

Human lymphocytes play a foremost role in the immune system. Studies revealed that the Co,04- NPs are more toxic to human lymphocytes when compared with other metal-oxide NPs (Fe203, Si02, and AljO, NPs). The Co304-NPs treatment causes reduction in cell viability and induces cell membrane damage in a dose-dependent manner. Further, Co304-NPs shown to deplete catalase, glutathione, and superoxide dismutase resulting in ROS-mediated oxidative stress. Chromosomal aberration was detected when exposed to Co304-NPs and Fe203-NPs at lOOmg/mL concentration. The oxidative stress leads to DNA damage and chromosomal aberrations in human lymphocytes [39]. Cobalt Nanoparticles Are Toxic to Cells and Tissues

In vitro studies showed that Co-NPs exposure can cause toxicity within 2-24h of exposure in Balb/ЗТЗ cells. The study observed nuclear and DNA damage by micronucleus test and comet assay; however, Co-NPs at <1 mM concentration did not show any detectable toxicity. By using radiolabeled compounds (60Co-nano and 57 Co2+), the authors also compared cobalt ions (cobalt chloride, CoCl2) with Co-NPs and observed higher cytotoxicity and cellular uptake of Co-NPs [16]. A superparamagnetic zinc-cobalt ferrite nanoparticle (SFN) has been developed for early cancer diagnostics and targeted therapy. However, toxicity and biological evaluation showed that acute exposure (4h) of SFN (100 pg/mL) decreases the viability of healthy HUVECs. The study also observed toxic effects in lungs, liver, and kidney tissues of New Zealand rabbits. Therefore, these NPs are not suitable for biomedical applications and should classify as toxic despite their interesting magnetic properties [42]. Cobalt Nanoparticles Largely Mediates Oxidative Damage

In vitro and in vivo studies showed toxicological harmful effects of Co-Fe-NPs on diverse organs and systems through the generation of ROS [37]. In vitro experiment in PCI2 cells with Co-NPs showed downregulation of antioxidant response gene NRF2 along with reduced cell viability and increased apoptotic cell death [41]. In human macrophage cells (U937 cell line, human alveolar macrophages, and monocyte-derived macrophages), Co-NPs (5-20mg/mL) induced enhanced cytotoxicity and elevated ROS, compared to cobalt ions (CoCl2, up to 350 nM) [19]. Studies showed that bare cobalt oxide nanoparticles (CoO-NPs) provoked a significant amount of ROS in a dose- dependent manner within 24 h of exposure in primary human lymphocytes leading to cell death. To induce apoptotic cell death, the elevated ROS causes the elevation of TNF-a which, in turn, activates caspase-8, phosphorylate P38 mitogen-activated protein kinase (МАРК) followed by activation of caspase-3 (Figure 15.1). CoO-NPs can induce toxicity in vitro at 5 pg/mL (for24h culture) and in vivo at 200 pg/kg body weight (for 15days). These findings suggested that bare CoO-NPs is toxic and fatal for human health [5]. Cobalt Nanoparticles Able to Penetrate Damage Skins

Co304-NPs are usually used in industry and in biomedicine, and skin absorption of these NPs is a deep concern. The workers and users can be exposed to Co,04-NPs via powders or solutions. Studies demonstrated that Co,04-NPs cannot penetrate Franz diffusion intact skin cells but able to penetrate when a damaged skin protocol is used. A long-term exposure to Co,04-NPs (1,000 mg/L) induces cell damage and necrosis in cultured keratinocytes. The findings showed that a long-term exposure (7days) can induce a dose-dependent cell viability reduction (effective concentration-50 (EC50) values: 1.3 x Ю"4 M; MTT essay; 3.7 x 105 M, AlamarBlue® assay) that seems to be associated to necrotic events (EC50 value: 1.3 x 104 M, PI assay). It is recommended that study workers, and atopic subjects should use personal protective equipment to avoid contamination of the skin with Co,04-NPs [40]. Genetic Background Can Affect Cobalt Nanoparticle Toxicity

Genetic background plays a role in Co-NPs toxicity. A study was also performed with long-term exposures of 12 weeks to sub-toxic doses (0.05mg/mL) of Co-NPs to assess the oxidative DNA damage. Oggl deleted mouse embryonic fibroblast (MEF) failed to remove the 8-OH-dG lesions from DNA. Consequently, MEF accumulates ROS, cellular transformation, increases in metallo- proteinases (MMPs), and anchorage-independent growth suggested potential cancer risk associated with Oggl genetic background. The study observed increase in expressions of antioxidant genes (Figure 15.1), Gstpl, Sod2, Hoi, and Keapl in Oggl deleted MEF, which can be mediated by the activation of nuclear factor erythroid-2-related factor-2 (Nrf2). The conditioned media from MEF Oggl deleted cells promote the growth of HeLa cells. This further confirms that MEF Oggl deleted cells are prone to acquire oncogenic characteristics [13]. Modification of Cobalt Nanoparticles Surface to Overcome Toxicity

It has been shown in earlier studies that bare Co-NPs cause significant toxicity in diverse types of human cells as well as in animals. Surface coating of Co-NPs can reduce the toxicity. A study was conducted to coat cobalt ferrite nanoparticle (CoFe204-NPs) core with negatively charged polyacrylic acid (sodium salt) (PAA) and positively charged polyethylenimine (PEI). The effect of coated NPs on primary human myoblasts (MYO) and B16 mouse melanoma cell lines revealed that negatively charged PAA-coated NPs did not induce cytotoxicity, ROS, and did not activate the transcription factor NF-kB even at high concentrations (lOOmg/mL) for 24h. On the contrary, positively charged PEI NPs caused a dose-dependent necrotic cell death with the elevation of ROS at low concentrations (>4mg/mL). Besides, PEI NPs-induced NF-kB activation 15-30 min after incubation in MYO cells might be through activation of TLR4 receptors. Thus Co-NPs toxicity can be reduced by the modification of surface coating materials [43].

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