Environmental Engineering Reference
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basis [28]. The mechanisms of nanocopper-induced nephrotoxicity were studied by analyzing renal gene expression profiles
phenotypically anchored to conventional toxicological outcomes. male Wistar rats were given nanocopper (50, 100, 200 mg/kg)
and microcopper (200 mg/kg) at different doses for 5 days. Nanocopper induced widespread renal proximal tubule necrosis in
rat kidneys with increased levels of blood urea nitrogen and creatinine. Whole-genome transcriptome profiling of rat kidneys
revealed significant alterations in the expression of many genes involved in valine, leucine, and isoleucine degradation,
complement and coagulation cascades, oxidative phosphorylation, cell cycle, mitogen-activated protein kinase signaling
pathway, and glutathione metabolism. Systems used in nanotoxicology studies have proved to provide valuable insight and
toxicogenomic approaches are presenting an unprecedented amount of mechanistic information on molecular responses to
nanocopper, thus helping hazard identification and risk assessment [29].
To understand the impact of airborne nanoparticles on the respiratory system, airway epithelial (HEp-2) cells were exposed
to increasing doses of silicon oxide (Sio 2 ), ferric oxide (Fe 2 o 3 ), and copper oxide (cuo) nanoparticles, the leading metal oxides
found in ambient air surrounding factories. cuo induced the greatest amount of cytotoxicity in a dose-dependent manner, while
even high doses (400 µg/cm 2 ) of Sio 2 and Fe 2 o 3 were nontoxic to HEp-2 cells. Although all metal oxide nanoparticles were able
to generate RoS in HEp-2 cells, cuo could overcome the cellular antioxidant defenses (e.g., catalase and glutathione reductase).
A significant increase in the level of eight-isoprostanes and in the ratio of gSSg to total glutathione in cells exposed to cuo
suggested that RoS generated by cuo induced oxidative stress in HEp-2 cells. cotreatment of cells with cuo and the antioxi-
dant resveratrol increased cell viability, suggesting that oxidative stress may be the cause of the cytotoxic effect of cuo. These
studies demonstrated that there is a high degree of variability in the cytotoxic effects of metal oxides and that this variability is
not due to the solubility of the transition metal but due to the sustained oxidative stress possibly due to redox cycling [30]. cuo
had already been reported to be highly cytotoxic; however, carbon-coated copper nanoparticles are much less cytotoxic and
more tolerated. measuring the two materials' intra- and extracellular solubility in model buffers explained this difference on the
basis of altered copper release when supplying copper metal or the corresponding oxide particles to the cells. These observa-
tions are in line with a Trojan horse-type mechanism and illustrate the dominating influence of physicochemical parameters on
the cytotoxicity of a given metal [35].
31.4
mEcHanism of cytotoxicity and gEnotoxictiy of nanoparticlEs
Nanoparticles can gain access to the human body through ingestion, injection, transdermal delivery, and inhalation. Further,
they can translocate to secondary organs [36]. Airborne nanoparticles enter through the respiratory system. Endocytosis of
nanoparticles through alveolar epithelial cells plays an important role in its translocation to other organs. Nanoparticles are able
to translocate from the lung to the liver, spleen, heart, and other organs [37]. if the inhaled nanoparticles are able to gain entry
into other organs via the olfactory bulb, it could cause potential hazard as they would have direct access to the central nervous
system [38]. Nanoparticles can enter the body via the skin through injection during drug delivery and imaging studies or by
application of cosmetics and antimicrobials for wound healing. Nanoparticles injected into the skin can elicit photocatalytic
activity in the dermal layers, causing the formation of free radicals in skin cells, damaging DNA, and disrupting normal cell
functions and cell viability [39]. Nanoparticles administered in the dermis can migrate to regional lymph nodes, potentially via
skin macrophages and langerhans cells, raising potential concern for immunomodulation [40]. Nanoparticles used in food
packaging and processing and as additives can be ingested. Following ingestion, translocation of particles into and across the
gastrointestinal mucosa can occur but uptake via gut and translocation is probably size-dependent. Further, nanoparticles can
also enter the bloodstream via gastrointestinal assimilation [41].
The biological effects of nanoparticles are due to both its physical and chemical mechanisms of action [42]. The production
of RoS, dissolution and release of toxic ions, disturbance of electron/ion cell membrane transport activity, oxidative damage
through catalysis, lipid peroxidation, and surfactant properties are considered to be chemical mechanisms. The generation of
RoS is implied to be the main underlying chemical process in nanotoxicology leading to secondary processes that cause cell
damage and eventually cell death. RoS are also involved in inflammatory processes. Free radical formation also has direct
impact on cell integrity. The physical mechanisms known to cause biological effects are due to the nanoparticle size and surface
properties. They involve membrane damage and disruption of membrane activity, and effect transport processes, protein con-
formation/folding, and protein aggregation/fibrillation [43].
The biological response to nanoparticles is a result of the various processes occurring as a result of the chemical and physical
interactions in the cell. These cellular responses can occur before or after internalization of particles, or as a response to the
uptake mechanism itself (Fig. 31.1). membrane stability can be affected by nanoparticles either directly (e.g., physical damage)
or indirectly (e.g., oxidation) and can lead to cell death. The cell membranes are able to control intracellular homeostasis
through selective permeability and transport mechanisms, and this makes them a vulnerable target for possible damaging
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