Titanium pharmaceutical preparations. Despite the wide use of

Titanium dioxide nanoparticles (TiO2NPs) are the most commonly used as one of the top five nanoparticles inclusion in many commercial products, nanomedicine, agriculture, paints electronics, cosmetics and pharmaceutical preparations. Despite the wide use of TiO2 nanoparticles in various industries and extant theories about its harmful effects, few studies in vivo were conducted on the toxicity of these nanoparticles until now, the present study was carried out to study histological effects of titanium dioxide nanoparticles on kidney of male rats that injected intraperitoneal of TiO2 nanoparticles in an attempt to understand the toxicity effect of their therapeutic and diagnostic use. To investigate TiO2NPs effect on the renal tissue, a total of 40 healthy male Wistar albino rats (Rattus norvegicus) were exposed to TiO2NPs (126, 252, 378 mg/kg b.w.

) for 24 and 48 h. In comparison with control rats. Exposure to TiO2NPs doses has marked histopathological alterations like an infiltration of inflammatory cells, congestion, necrosis and vacuolated hydropic degeneration, glomerular congestion and dilation of congested blood vessel in the cortex of NPs treated rats.

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From the present study it could be concluded that TiO2NPs are capable of inducing kidney damage and further biochemical, immunohistochemical, and ultra-structural studies are needed.Keywords: TiO2 nanoparticles; Rats; Kidney tissue; Histopathology, Degeneration, Nanotoxicity.?1.

IntroductionThe term “Nano-science” refers to the study of existing principles and properties on the nanometer scale at the level of atoms and molecules (1). Nanoparticles (NPs) are particles with the size of 1–100 nm (2-3). According to a recent statistical studies, the number of NPs products available in the world market has crossed the 1000 mark (21). This is due to NPs characteristics that make them suitable for biological, commercial and medical applications of NPs (e.g. chemical, physical, mechanical, optical, magnetic, and biological) (22; 23).

Nanotechnology has become one of the very important new approaches for many applications in recent years. However, no or very little data was available about its toxicity on non-target organisms (4). Nanotechnology is the newest technology & applied highly with potential applications in industrial and biomedical products (2,5-7).

Due to its low production cost, very high refractive index, photostability in solution general non-toxicity and anticorrosive properties, titanium dioxide nanoparticles (TiO2NPs) are the most used, in industry, nanomedicine (therapy, pharmaceuticals including drug delivery system), engineering, agriculture, personal care products (including cosmetics, sunscreens, and toothpaste), electronics, basic sciences, biotechnology and cosmetics, clothes, paints, and covers, contrast agent of imaging, foodstuffs (food resources, food dressing, food packaging care, whitening of food, food preservation additives, food colorants), varnishes, paper, lacquer, rubber, glassware, roofing granules, rubber tire manufacturing, and in the production of electronic components, dental impressions, printing ink, welding rod coatings, floor coverings, catalysts, coated fabrics, textiles, TiO2 has been coated with other materials (e.g., silica,alumina) for commercial applications and environmental decontamination systems, other consumer products used by people everywhere, etc.

(1-2, 13-14, 17-20). four million tons TiO2 (70%) of total production volume of pigments in the world (8-11). Total produced is about 3,000 tons TiO2NPs per year in the world in different fields of commercial application like plastics (6%), paints (14%), and other applications (e.g., cement) (12%) The recently studies predicted that most of the currently produced TiO2 will be converted into TiO2NPs by the end of year 2026 (8-13). Due to the growing number of applications, there are much attention and increasing risk exposure to NPs’ toxicology, which in both medically and environmentally (2).

In vivo studies of nanotoxicity have not established on biological systems and remains superficial ; incomplete in experimental animals until now (2, 14-15). Toxicity of NPs to biological, ecological systems has recently emerged as an important field of research (16). The effects of nanoparticles need to be investigated in order to provide a scientific evidence for a safe utilization of nanotechnologies (2). Nephrotoxicity ; Hepatotoxicity are basic biosafety and markers evaluation for harmful compounds, drugs, as well as NPs.

In recent years use of nanotechnology ; metal oxide nanoparticles have experienced a growing trend in their use in a wide range of industrial applications. Titanium dioxide (TiO2), is a noncombustible, white, crystalline, solid, odorless powder TiO2 is insoluble in water, hydrochloric acid, nitric acid, or alcohol, and it is soluble in hot concentrated sulfuric acid, hydrogen fluoride, or alkali (18). TiO2 has several naturally mineral forms, which have the same chemical formula and different crystalline structure. Common TiO2 polymorphs include rutile and anatase (18). TiO2NPs have different sizes, shapes, chemistry and crystalline structures (24). Titanium dioxide nanoparticles (TiO2) produced abundantly and used widely in several fields in our daily life, solar cells, air sanitizers and applications to control microorganism’s growth, anticorrosive and photocatalytic properties, because of special characterizations such as surface functionalization and size and their higher stability (25). TiO2 have several industrial applications and can be used in several catalytic reactions, contaminated water purification from hazardous and industrial products (26), and in nanocrystalline solar cells as a photoactive material (27-28).

Regarding Nano medicine applications, TiO2NPs are being used in diseases diagnosis and advanced imaging and nanotherapeutics like photodynamic therapy, antimicrobial drugs and skin care products (10; 27-28). TiO2-based photocatalysis has attracted extensive interest because of its great advantages in the complete mineralization of organic pollutants in waste water and air (29). As a popular photocatalyst, TiO2 has been widely used in paint production, cosmetics, ceramic production, photocalysts production, sunscreen creams, water and sewage and many other industries because of its unique properties, such as optical-electronic properties, low-cost and chemical stability (6). Nanoparticles-based sunscreen creams that are colorless and reflect UV rays more benefit than other creams (6). According to recent data there is many evidences about toxicity of TiO2 for human health and environment due to its unique physicochemical properties such as small size, increase in surface per mass, chemical composition, surface structure, form and accumulation, and high reactivity (6). Furthermore, several researchers have revealed the toxic impacts of TiO2NPs on various organs (30-32). The exposure of TiO2NPs could be absorbed through inhalation, oral ingestion, intravenous injection and dermal penetration into the body, and distributed in the important organs such as lymph nodes, brain, lung, liver and kidney (33-36). In vivo, it was observed that ultrafine anatase TiO2 particles produced increases in broncheo-alveolar lavage inflammatory indicators, cell proliferation, and histopathology (37).

Characteristics of TiO2 nanoparticles can be modified by several methods to improve their performance, these NPs are highly & rapidly distributed in organs and tissues after injection and are highly absorbed by the cells (6). Due to their small size, TiO2NPs have the potential to cross biological barriers “blood– brain barriers and blood placenta barriers” to reach different organs and tissues (38-39). Several studies mentioned to accumulate TiO2NPs in several organs of experimental animals such as the liver, kidneys, spleen, lymph node, lungs, and heart, because of TiO2NPs could not be cleared from the liver and kidney within 15 days after administration (35; 40-42).

Free radical generation and oxidative stress be induced DNA damage and apoptosis (20, 43-44). Recently, the International Agency for Research in Cancer (IARC) has classified TiO2 as possibly carcinogenic (group 2B) to human beings (1). Earlier studies refereed to the TiO2 was retained in different organs like liver, spleen, kidney, and lung tissues, after oral administration in mice indicating uptake by the gastrointestinal tract and systemic transport to the other tissues, hepatic injury and kidney damage was also observed in female mice treated with TiO2NPs, the liver injury included hydropic degeneration around the central vein and spotty necrosis of hepatocytes; renal damage included protein-filled liquid in the renal tubule and swelling of the renal glomerulus (18). (45) Chang et al.,2013 reviewed all the available studies (347 in total) either human or animal and the experimental exposure conditions concerning TiO2-NPs toxicity to the human body, clearly stated and highlighted the presence of nano-TiO2 in various important organs, such as liver, kidney, spleen and brain (42) reviewed many studies on the possible genotoxicity induced by exposure to TiO2NPs.

The testicular tissue of mice treated with TiO2NPs showed histological effects like sever congestion, disturbance diameters of seminiferous tubules, sever edema between seminiferous tubules, vacuolation and necrosis in the germinal epithelium (46), significant reduction in sperm density and motility; increased sperm morphological abnormalities and germ cell apoptosis, testosterone, LH and FSH levels associated with histological changes in the testes (47).(2) Yang et al.,2017 reviewed the current histopathological studies of NPs toxicity to the human body in different systems, including the hepatic and renal, gastrointestinal, pulmonary, cardiovascular, nervous, and immune systems and discussed specific functional examinations studies in each system and related injury mechanisms. Also in vivo studies of nanoparticles have not established a unified system until now (2).

Experimental studies, additional data and information are needed to evaluate the safety and health issues of working with fine and ultrafine TiO2 (18). In the past decades, much attention has been drawn to NPs’ toxicology both medically and environmentally and assessment of nanoparticles toxicity prior to clinical and biological applications. Therefore, in the present study an attempt was designed to investigate the toxicity of TiO2NPs on kidney tissues of male rats.