Nanotechnology has witnessed a revolution in our current era and has penetrating into consumer industries, biomedical and electronic fields, and environmental treatments, due to the chemical-physical properties of nanoparticles, especially metal ones, and the advantage of large surface area to volume. Thus, the growing consumption of these minutes has increased the exposure of living organisms to potential risks associated with their toxicity, especially vital organs as liver. The present review summarizes the potential hepatotoxicity in vivo (rat model) of experimentally exposed metal nanoparticles or their oxides. Most of the literature indicates that the induced hepatotoxicity is due to oxidative stress, cytotoxicity, and disturbance of liver function depending on the concentrations and method of exposure to these nanoparticles. Therefore, the toxic potential must be taken into account and the damage that may be caused to other vital organs in the body must be constantly evaluated in order to reach safe use of these nanoparticles.

Nanoparticles (NPs) are engineered materials with a size range of 1-100 nm [1]. These particles have been exploited with unparalleled merit in various biotechnology and medical applications [2,3] due to their small size and larger surface area to volume ratio [4], in addition to their unique physical, chemical and electrical properties [5]. NPs are used in many consumer products, as paints and ceramics [6], as well as in cosmetics, which has become popular in the current era [7], in addition to being recruited as a new delivery system for drugs [8], biosensors [9], and cancer treatment [10]. The growing application of MNPs has led to an increasing release of these materials into the environment, threatening human life and other living organisms. Therefore, its potential toxicity to environmental health has received more attention [11]. It is worth noting that NPs are considered more toxic to the living body compared to large particles of the same chemical substance [12]. In this regard, many experimental studies have been conducted to evaluate the toxicity related to NPs, with the aim of reaching the safe use of these particles [13-15]. MNPs can penetrate the body in possible ways, such as inhalation, orally, or through the skin, and accumulate in vital organs of the body [16], including the liver, kidneys, heart, lungs, and brain, in addition to the spleen and digestive system, via the blood or lymphatic system [16-18]. These particles can also easily cross cell membranes and cause cytotoxicity [19]. Many recent experimental nanoparticle toxicology studies have confirmed that MNPs accumulate in higher quantities in liver than in rest of body, inducing structural and functional damage to hepatocytes [20-22]. From the above, this article aims to review the hepatotoxicity induced by metal nanoparticles or their oxides in vivo, especially the rat model.

Silver Nanoparticles

Silver nanoparticles (AgNPs) remain distinct among MNPs to date due to their many commercial uses [23], as more than 300 tons of these nanoparticles are manufactured annually and are recruited in biomedical applications, household appliances and food product storage [24]. They are characterized by their antimicrobial, optical, electrical and catalytic properties [25,26]. In a study conducted by Yousef et al. (2022), they administered intraperitoneal injections of AgNPs as spherical forms with sizes ranging from (7.7 - 28.4 nm) to adult male rats (low dose, 1 mg/kg, and high dose, 2 mg/kg), daily for 30 days. They found that AgNPs caused significant damage to liver tissue, characterized by elevated levels of liver function indicators, oxidative stress, and inflammatory markers TNF-α and IL-6, with a significant decrease in total protein, total albumin, and antioxidants in hepatic tissue. This was accompanied by marked histopathological changes through the destruction of normal hepatic architecture, with a decrease in the numbers of normal liver cells versus an increase in necrotic liver cells and inflammatory cells, leading to hepatotoxicity [27]. Parang and Moghadamnia (2018) in their experiment on adult male Wistar rats injected with silver nanoparticles intraperitoneally with doses of 25 and 100 mg/kg for 14 days respectively observed enhanced serum levels of hepatic enzymes and increased liver tissue necrosis as well [28]. Shehata et al. (2022) confirmed that Ag-NPs (50 nm) have hepatotoxic and nephrotoxic effects in Sprague-Dawley rats via various mechanisms including oxidative stress, inflammation, and apoptosis [29]. In another experimental study by Ramadhan and Ghareeb (2021), male rats were treated with 50 μl/kg/day of AgNPs for 28 continuous days. The toxic effect of silver nanoparticles (AgNPs) on liver function parameters was confirmed [30].

Gold Nanoparticles

Gold nanoparticles (AuNPs) have gained immense importance due to their catalytic, electronic, fluorescence and biological potential [31,32]. These nanoparticles applied widely in biomedical felid as diagnosis many diseases, drug delivery, and cancers medications [33]. There are many studies that have proven negative functional and even structural changes induced by these nanoparticles in various vital organs including liver at high concentrations[34-36]. In a study by Abdelhalim et al. (2018), they found that administering a dose of 50 μl of 10 nm gold nanoparticles intraperitoneally for 7 days resulted in inflammatory liver damage through an increase in the serum levels of alkaline phosphatase, total protein, alanine aminotransferase, total bilirubin, besides malondialdehyde in hepatic tissue and low glutathione levels in adult rats [37]. In a study by Jarrar et al. (2022), they found that exposing healthy male Wistar Albino rats to 20 injections of 10 nm gold nanoparticles at a daily dose of 2 mg/kg induced hepatic changes including hepatocyte degeneration, cytoplasmic vacuolization, and nuclear modifications with sinusoidal expansion [38]. In another previous study, adult male rats received gold NPs at a dose of 1100 µg/kg orally for 42 days, and the rats showed a significant increase (P<0>

Zinc oxide Nanoparticles

They are metal oxide nanoparticles (ZnONPs) with wide uses in industry, biomedicine, and cosmetics [40]. These particles have unique antibacterial and antitumor properties, high catalytic as well as high photochemical activities [41]. However, there are reports indicating their potential toxicity to the living body, such as hepatotoxicity, nephrotoxicity, and neurotoxicity [42-44]. Aboulhoda et al. (2020), confirmed in their experiment on rats that exposure to zinc oxide NPs led to histological and functional liver changes. This hepatotoxicity was due to oxidative stress-induced apoptosis coupled with induction of JNK/p38MAPK and STAT-3 signaling [45]. A previous experiment was conducted to estimate pathological effects of ZnONPs on liver by dosing adult rats with 50 mg/kg of ZnONPs for 28 days. The results confirmed a significant increase in the activity of serum liver enzymes resulting from liver dysfunction [46]. In a study by Sakr and Steenkamp (2021), albino male rats were exposed to zinc oxide nanoparticles (200 mg/kg) for 30 days. They noted that sub-chronic exposure caused toxicity, oxidative stress, and hereditary disorders in the liver and thyroid gland [47]. On the other hand, it has been demonstrated by Hosseini et al (2020) have proven that zinc oxide nanoparticles at high doses for 30 days twice a week have toxic effects on liver and pancreas, as they recorded tissue destruction and cellular changes in adult female rats [48]. According to the results of rat model experiment by Ramadan et al., liver cells could exhibit genotoxicity and cytotoxicity after being exposed to zinc oxide NPs with sizes of 30 nm for ten weeks [49].  

Copper oxide nanoparticles

Copper oxide nanoparticles (CuONPs) are widely employed in many industrial applications, electronics and environmental treatments, as well as an antibacterial and antifungal agent due to their distinct elastic and electrochemical properties [50,51]. The seriousness of its environmental pollution has received special attention from many environmental scientists [52-55]. There are many literatures that have confirmed that CuONPs in vivo provoke the generation of reactive oxygen species, oxidative stress, and cytotoxicity and hepatotoxicity [56-58]. In a recent study by Haroun et al. (2023), they concluded that treatment of rats orally with CuONPs (20-30 nm) at 100 mg/kg for continuous 8 weeks led to bioaccumulation of copper in the liver and damage through increased serum ALT activity, decreased hepatic arginase activity, and serum total protein content along with increased oxidative stress (lipid peroxidation), inflammation, and apoptosis. It also resulted in severe DNA fragmentation as assessed by the comet assay and significant pathological changes in liver architecture [59]. In a study by Ghonimi and colleagues (2022), they injected healthy mature rats intraperitoneally with CuONPs at different doses for 9 consecutive days. They observed that increasing the dose of these NPs induced hepatotoxicity through severe necrosis of hepatocytes with complete disruption of hepatic rays and loss of hepatic structures [60].

It is necessary to make the use of nanoparticles and their release to the environment as well as living organisms as safe as possible and thus reduce their potential toxicity to the living body. Also pay attention to applying sustainable standards in various fields regarding the environment to ensure the regulation of pollution and the prevention of toxins harmful to public health.