There are many ways in which NP can be ingested in the gastrointestinal tract. The absorption of particles of different sizes through the gastrointestinal tract can also end up in various toxic effects . Although NP may contact the respiratory organs, however, other organs such as the gastrointestinal tract should be considered because NP can enter the gastrointestinal tract in many ways and indirectly through the mucosa or directly via the oral route. There are few reports on the toxicological study of the gastrointestinal tract of nanomaterials. In a study in which only a few mice exhibited spectral symptoms, all mice treated with nano-copper clearly showed symptoms of food channel dysfunction, loss of appetite, diarrhea and vomiting.
Furthermore, it can promote phagocytosis in the gastrointestinal mucosa and produce immune responses mediated by antigens .
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Consistency can be directly linked to the route of exposure and the physico-chemical properties of the nanosustancia for example, type, size, structure, surface modification, crystalline phase. The oral route is a relatively simple toxicological process compared to the pulmonary routine . This chemical process undoubtedly causes an ionic copper overload in vivo.
Because the ultrafine NPs of copper nanoparticles are highly active in the biological system when they are in the stomach. Nano-particles cause the accumulation of copper highly alkaloscentes heavy substances and excessive copper ions concludes with metabolic alkalosis and copper overload .
ATSDR - Toxicological Profile: Copper
When nano-copper reacts to the acidic substance in the stomach, many proton ions are consumed. Metabolic alkalosis, such as poisoned copper ions, ends with a higher mortality than microcirculation in the same dose . In one study, the appearance of the stomach of mice exposed to nano-copper swelled and presented a cyan color. The result of nano-copper suggests that it may remain in the stomach longer, in other words, the lasting interaction with the acidic juice can cause the persistent production of heavy metal ions in vivo.
With regard to nano-copper particles, both metabolic alkalosis and copper overload contribute to its severe toxicity. Unlike this, micro-copper does not stagnate in the stomach and the ionization rate is much lower than that of NPs. After the particles have been pushed into the small intestine, the ionization reaction is prohibited due to the primary condition and finally it is expelled as faeces. For direct ingestion of copper ions, the temporary glomerulonephritis and the alimentary canal disturbance occur in experimental animals. These toxicological responses can be partially corrected within 72 hours .
In the first carcinogenicity and genotoxicity studies of copper-soluble copper compounds, such as copper sulfate, they were genotoxic, with functions including induction of chromosomal aberrations and micronuclei Leghorn white chickens and chromosomal aberrations in Swiss mice [47, 48]. Copper NPs have been shown to be extremely reactive in a simulated intracorporeal environment . This was demonstrated by a study in which NP nm dependent degradation caused dose of isolated DNA molecules to generate singlet oxygen 1O 2 in and HeLa  cells.
NP copper and its compounds caused a variety of effects, including oxidative stress, cytotoxicity, neurotoxicity, DNA damage and DNA lesions in a variety of cell lines . DNA damage has been documented as a result of oxidative stress, controlled by elevated 8-isoprostane levels and the percentage of glutathione disulfide GSSG total glutathione in respiratory epithelial cells in the human airway Hep High oxidative stress can cause damage to DNA, which in turn has the potential to be carcinogenic [26, 49].
In another study on A cells, copper oxide NPs were the most potent with respect to cytotoxicity and DNA damage . The size, surface chemistry, surface area, morphology and reactivity of particles in the soluble particle are key factors that must be clarified to accurately assess the toxicity of NPs. Nano-copper material appears to be toxic not only for DRG neurons but also for glial cells.
This could be due to differences in the properties of copper and NP pure copper NPs and could also be due to the nature of cells in different studies and the duration of exposure to NP . These NPs of copper oxide within neurons would inhibit mitochondrial dehydrogenases and cause ROS generation. Several studies have demonstrated cytotoxicity resulting from the primary induction of lipid peroxidation of a mitochondrial membrane of a metal that can lead to the breakdown of electron transport, the decoupling of oxidative phosphorylation and decreased mitochondrial membrane potential [54, 55].
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Copper can also induce oxidative stress by reducing glutathione levels in neurons. Copper NPs enter the cell, so they can attack mitochondria and cause an increase in oxidative stress . Prabhu, B. However, exposure to NP of copper size 40 nm, 60 nm and 80 nm had toxic results in DRG neurons, 40 nm copper NP and 60 nm size had a higher toxic result of 80 nm particles nm. Therefore, the toxic effect seems to depend on concentration and size. The mechanism that correlates the toxicological effects followed with the exposure of DRG neurons to copper NPs may be oxidative stress .
Unresolved inflammation can cause aberrations and DNA abnormalities that may be mutagenic. Wistar male rats used to study the mechanisms of hepatotoxicity induced by copper NP with the identification of hepatic gene expression profiles that were phenotypically correlated with conventional toxicological outcomes . Copper NPs have also been shown to be neuropathological and neurotoxic.
However, apart from the induction of other types of pathology, none of these studies reported carcinogenesis. In general, changes in apoptosis, gene expression, oxidative stress and persistent inflammation were the main effects of copper-based NPs that may predispose to carcinogenicity. Pathological examinations and morphological changes indicate that the kidney and liver are two important target organs for copper NP through the oral route. In one study of all mice exposed to NP, these four biochemical indices were significantly higher than the control. The anomaly of BUN and Cr is particularly obvious .
Increased triglycerides in serum, liver and renal tissues could be considered an important sensitive index reflecting lipidosis caused by nano-copper. To date, it is unclear whether nano-copper can enter the bloodstream through the entire gastrointestinal lining . The increase in the pH of the blood causes a compensation: a the respiratory compensation is naturally caused by several minutes.
Unlike micro-copper, nano-copper could cause a high level of serum copper SC , an index of acute toxicosis. More importantly, nano-copper has a low elimination frequency in vivo, which can worsen heavy metal toxicosis. It maintains a high level of SC in the nano group even at 72 hours, suggesting that mice carry high persistent copper concentrations in the blood, possibly eventually ending up in a fatal copper overload [7, 61]. Bcl-2 proteins are regulatory upstream of the mitochondrial membrane.
From immunoblotting, it was observed that pro apoptotic Bax regulated protein increased nano-copper and anti-apoptotic Bcl-2 protein reduce mitochondrial membrane potential. Apoptotic cell death causes oxidative stress directly related to mitochondrial dysfunction. Alteration of mitochondrial membrane potential, cytochrome c release in the cytosol and possibly activation of caspase 3 are biomarkers related to cell death induced by oxidative stress via dependent mitochondrial pathway.
The influence of Bcl-2 family proteins in mitochondria regulates mitochondrial dependent cell death . Immunoblot analysis showed that nano-copper poisoning leads to high levels of cytosolic cytochrome c, Apaf 1 caspase 9 and caspase 3 cleaved.
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New research has shown that nano-copper exposure significantly increases the cellular level of Fas protein , caspase 8 protein and tBid protein . The increase in the ROS level induces a cascade of pathways that in turn activate the transcription of several genes; those genes change the regulatory pathways of cell survival and eventually lead to apoptosis. Apoptosis could be mediated by dependent and independent mitochondrial pathways. Tests suggest that the variation of mitochondrial membrane potential can alter the cells involved in apoptotic death through cascades sensitive to oxidative stress signaling via mitochondrial dependent .
When decreasing the expression of Bcl-2 proteins and the Bax protein expression is improved, there will be a decrease in mitochondrial membrane potential due to rupture of the mitochondrial membrane Fig.
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This phenomenon helps to release cytochrome c from the mitochondria to the cytosol. When this happens, a cascade reaction involves the binding of cytochrome c with Apaf1, with consequent activation of the active caspase-9, creating an apoptosomal complex that triggers the activation of caspase-3 . The extrinsic pathway is triggered by a committed death receptor Fas, TNF, etc. When copper intake exceeds the tolerable limit, it exerts toxic effects that lead to cell death. The increase in the production of reactive oxygen species ROS and reactive nitrogen species RNS plays an important role in copper-induced organic dysfunction.
All NP copper concentrations cause toxicity and alterations in the histopathology of the liver and pulmonary tissues of rats. The increase in oxidative stress is a fundamental mechanism in the damage of podocytes caused by nano-copper. Nano-copper can pass from the lumen of the intestinal tract through aggregations of intestinal lymphatic tissue Peyer patches PP containing M cells. The liver and kidneys are two target organs for exposure to NP of copper via the oral route. Compared to micro-copper, nano-copper could obviously induce more levels of serum copper SC , a marker of acute toxicosis.
New research has shown that nano-copper exposure significantly increases the cellular level of Fas protein , caspase 8 protein and tBid protein. It will be important to continue the interpretation of laboratory data in the clinical context of the patient to use molecular and emerging technologies. At the same time, a growing understanding of the mechanisms that drive the toxicity of this NP will improve the classification, prognosis and treatment of patients with NP copper toxicity.
The authors declare that there are no conflicts of interest regarding the publication of this manuscript. Acute toxicological effects of copper nanoparticles in vivo. Toxicology Letters. Colvin VL. The potential environmental impact of engineered nanomaterials. Nature Biotechnology.
Copper oxide nanoparticle toxicity profiling using untargeted metabolomics
Nanotechnology: convergence with modern biology and medicine. Current Opinion in Biotechnology.
Physiological effects of nanoparticles on fish: A comparison of nanometals versus metal ions. Environment International. Environmental copper: its dynamics and human exposure issues. Tribology Letters. Ultrahigh reactivity provokes nanotoxicity: Explanation of oral toxicity of nano-copper particles. Eating or drinking too much copper can cause vomiting, diarrhea, stomach cramps, nausea, liver damage, and kidney disease.