الفهرس 
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Abstract
Titanium dioxide (TiO2) was considered as a safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO2 nanoparticles, with numerous novel and useful properties, are increasingly used. Therefore, increased human exposure can be expected.
Sub-Chronic exposure to Tio2NPs have been shown to induce oxidative stress and lipid peroxidation. For this reason, it shows species and organ toxicity such as liver and testis.
The present study was conducted to evaluate Sub-chronic toxic effects of TiO2NP on liver and testes of adult male Wistar rats and the possible protective role of beta carotene for 60 days.
It was conducted on 90 sexually mature male Wistar rats divided into nine groups, ten rats each. group I was considered as negative control group, group II received saline, group III received beta carotene in a dose of 10 mg/kg body weight / day , The TiO2 NPs treated groups (IV, V, VI) received TiO2 NPs in a dose of ( 30, 50 , 70 mg/kg body weight/day) respectively, the protected groups (VII, VIII, IX) received (10 mg/kg) body weight beta carotene one hour before TiO2 (30, 50, 70 mg/kg) body weight respectively.
After 30 days from the start of the experiment, blood samples in living rats were taken by intracardiac blood sampling from six rats each group to analyze SGOT, SGPT and serum testosterone hormonal levels to detect early abnormalities.
At the end of the study: blood samples were taken from cervical blood vessels to measure (SGOT, SGPT) and total serum testosterone hormonal assay and rats were sacrificed by cutthroat and dissected to obtain liver and testes.
Part from the liver and one testis were obtained for tissue homogenization for oxidative stress (MDA and SOD) measurement and the rest of liver tissue and other testis was used for histopathological examination.
In the present study, it has been found that after 30 days Tio2NPs treated groups (V, VI) had significantly higher mean values of GOT enzyme levels as compared to the control groups (I, II). Also, there was highly statistically significant decrease in mean values of GOT enzyme level after 30 days in the protected groups as compared to the treated groups (V, VI).
There were significantly higher mean values of GOT enzyme level in the treated groups (V, VI) after 60 days as compared to the control groups.
While there were non-significant mean values in GPT enzyme levels after 30 days in treated groups and the protected groups as compared to control groups but had significantly higher mean values of GPT enzyme levels after 60 days in treated groups as compared to the mean values of GPT in control groups.
Also, it was found that the treated groups had significantly lower mean values of SOD-L and had significantly higher mean values of MDA-L as compared to the control groups.
Histological changes were detected especially in higher dose TiO2NPs groups in the form of numerous vacuolated hepatocytes, congestion in the portal vein and central vein, dilated congested sinusoids, numerous degenerated hepatocytes, periportal inflammatory cell infiltration and some apoptotic cells are seen as compared to the control groups. Histological observations were improved in the protected groups by BC.
The present study revealed increase in the mean values of serum testosterone hormonal level of the treated groups and also the protected groups as compared to control groups after 30 days of the study, while there was non-significant change in mean values of serum testosterone hormonal level of the treated groups and the protected groups as compared to the control groups.
Paired t-test showed no significant differences between the control groups, the BC treated group (III) and the treated groups (IV, VI) after 60 days as compared to the same groups after 30 days.
While, it had been noticed that after 30 days there were primary stimulation in Leydig cells reflected on primary increase in serum testosterone hormonal level after 30 days in Tio2 treated groups and also in the protected groups, then secondary non-significant decline in some groups (IV, VI) and significant in the groups (V, VII, VIII, IX) in serum testosterone levels after 60 days which explained as there were primary stimulation Leydig cells in the treated groups after 30 days and then destruction of Leydig cells reflected on slow decline in serum testosterone levels happened by oxidative stress after 60 days. This was evidenced by two events the histopathological examination and oxidative stress markers SOD and MDA tissue levels measured in testicular tissues.
This study was supported by the higher significant decrease in the Tio2 treated groups (IV,V,VI) in SOD-T enzyme level which is explained with depletion of dismutase enzyme ( 200.2± 25, 205.82± 45, 198.7± 16) respectively as compared to the control groups, and also the higher significant increase in the treated groups (IV,V, VI) in MDA-T the marker of lipid peroxidation (8.17 ± 2, 10.47± 0.252, 14.57± 0.603) as compared to the control groups.
The histopathological results revealed that the treated groups had irregularity in the basement membrane with detached parts, disorganization of germ cells and germ cell degeneration. Leydig cell showed pyknotic dense nuclei, congestion of interstitial blood capillaries, interstitial hemorrhage and exudation, while the BC protected groups showed that most of seminiferous tubules retained organization of basement membrane with their lumen filled with sperms, some germ cells became more organized, decreased interstitial hemorrhage and blood capillaries decreased congestion. Leydig cells became normal with vesicular nuclei.
Conclusion
• The present study concluded that sub-chronic oral exposure to TiO2 NPs have toxic effects on liver and testis functionally and pathologically and these effects were attributed to oxidative stress in both tissues.
• Titanium dioxide nanoparticles have a dose dependent toxicity (higher doses have more toxic action).
• Administration of beta carotene resulted in protection to larger extent of hepatic and testicular biochemical parameters and preservation of their architecture.
• The duration of exposure to TiO2NPs affect the toxic manifestations.