الفهرس 
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Abstract
Metals such as zinc (Zn), copper (Cu) and chromium (Cr) are required for various physiological and biochemical functions in the body. Inadequate intake of these metals may results in deficiency diseases or syndromes but in high doses they may cause acute or chronic toxicities.
The present study was designed to evaluate the toxicity of high doses of these three some heavy metals (zinc, copper and chromium) and their effects on oxidative stress, inflammation, some organs function (spleen, brain, liver and kidney), immune response, cell damage and mitochondrial dysfunction in adult male rats, for two different durations (4 and 8 weeks)
Ninety six adult male albino rats (Sprague-Dawely) strains weighing (160 ±10) g were divided into 8 groups 12 rats each. G1 (C1): served as healthy control while G2 (Zn1), G3 (Cu1) and G4 (Cr1) were received (500, 200 or 0.8 mg / kg b. wt /day) of zinc, copper and chromium, respectively for 4 weeks. G5 (C2) served as healthy control, G6 (Zn2), G7 (Cu2) and G8 (Cr2) were received the same of zinc, copper and chromium doses for 8 weeks.
The following parameters were measured;
• Behavior signs
• Survival rate
• Body weight, food intake, FER and relative organs weights in all experimental rats were recorded.
• Liver and kidney function tests: serum ALT, AST, ALT, ALP, γ-GT, total protein, albumin, globulin, albumin /globulin ratio and bilirubin level, urea , creatinine and uric acid Levels.
• Complete blood picture, blood smear and leishman staining for examination of Howell-jolly bodies and morphology of the blood cells and differential counts.
• Serum SOD, blood GSH, TAC, CAT, MDA and NO.
• Tested heavy metals concentration in spleen and brain tissues.
• Brain functions in serum dopamine, serotonin, nor epinephrine and γ-amino butyric acid level.
• Serum TNF-α, IL-6, IL-1, CRP EMAP-II and MPO activity.
• Serum IgG and IgM.
• Cell damage markers; DNA fragmentation %, PCG level in spleen and brain and serum LDH activity.
• IDH and CCO activities in spleen and brain tissues
• Histopathological examination of spleen and brain tissue.
The result of our study can be summarized as follows:
Effect of Zinc, Copper and chromium on Behavior Signs during the Experiment
In zinc intoxicated groups there were no abnormal toxicity signs were recorded; however the behavioral changes were observed in copper intoxicated animals which exhibited behaviors like jumping and leaping movements in cages and their hair turned yellow. The behavioral changes in chromium intoxicated groups were recorded adipsia (lack of drinking), hypokinesia (reduced locomotor activity) and restlessness.
Effect of Zinc, Copper and chromium Exposure on Survival of Rats
There were no death recorded in Zn1 while there were one rat died after 49 days in Zn2.In copper intoxicated groups there were one rat died in Cu1 after 17 days and one rat died in Cu2 after 42 days. Finally for chromium intoxicated group there were one rat died after 10 days in Cr1 and one rat died after 35 days in Cr2.
Food intake, body weight change, feed efficiency ratio and relative organs weight in experimental groups
Toxicity induced by higher doses of zinc, copper and chromium, caused a marked reduction in food intake accompanied by a marked reduction in body weight and FER in all intoxicated group compared to control groups. Moreover, there was marked decrease in relative organs (kidney, liver, spleen and brain) weights. The toxic effect of three tested metals administration was time dependent and the higher toxicity effect was confirmed for chromium followed by copper and the lowest effect for zinc.
Liver Function Tests in serum
Our study indicated that high doses of three tested metals induced hepatotoxicity causing degeneration of hepatocytes which cause massive increase in the level of liver enzymes as serum ALT, AST, ALP and γ-GT activities in intoxicated groups when compared with a healthy control groups; as liver is the main organ for protein synthesis; in a time-dependent manner the serum contents of albumin, globulin, and total protein decreased significantly after overexposure to zinc, copper and chromium salts causing liver dysfunction.
Kidney Function Tests
The present study demonstrated that tested metals, altered the serum concentrations of markers that assess the renal functions in the experimental rats; the results indicated that there were a statistically significant increment in the levels of serum creatinine, urea and uric acid concentration as compared with their corresponding control groups. This indicated that this salts can induce nephrotoxicity.
Complete Blood Picture
Toxicity was induced microcytic hypochromic anemia characterized by a significant reduction in RBC’s, Hb and blood indices in all intoxicated rats as compared with healthy control groups. Our results indicated that Howell-Jolly bodies appear in peripheral blood smears in intoxicated groups that reflect the harmful effect of metals accumulation in spleen tissues. There were leukocytosis with relative lymphocytosis and neutropenia in all intoxicated rats. Finally there were a significant reduction in platelets count in all intoxicated groups as compared with control groups.
Antioxidant Biomarkers and Oxidative Stress Status
The present study illustrated that toxicity induced disturbance in total antioxidant status which reflected by a marked increase in lipid peroxidation that can be reflected by increasing serum MDA, No levels and OSI index and marked decrease in TAC level and antioxidant enzymes including SOD, CAT activities and GSH level which inferred by the reduction in their activities in all intoxicated groups as compared with control groups.
Tested Heavy Metals Concentration in Spleen and Brain Tissues
Our results showed that there was a severe accumulation in zinc, copper and chromium concentration in spleen and brain tissues in all intoxicated groups in comparison to healthy groups. It was confirmed that the accumulation of these tested metals in spleen and brain tissues were proportional to the exposure duration.
Biochemical Evaluation of Brain Function in Serum
The results clearly indicated that zinc acetate dihydrate, copper sulfate and potassium dichromate pentahydrate had significantly altered the levels of dopamine, serotonin, norepinephrine, and γ-Amino Butyric Acid in all intoxicated rats. Maximum alteration was noticed in chromium intoxicated groups followed by copper intoxicated groups then zinc intoxicated groups.
Inflammatory Biomarkers in Serum
There was aggressive cellular inflammatory response to Zn, Cu and Cr excessive exposure in the form of zinc acetate dihydrate, copper sulfate and potassium dichromate pentahydrate elevated levels of TNF-α, IL-6, IL-1β, CRP, EMAP-II and MPO.
Serum Immune Response
As a result of histopathology spleen depletion there was a significant decline in antibody titers in zinc, copper and chromium intoxicated groups in comparison to control groups.
Cell Damage Markers
It was proved that zinc acetate dihydrate, copper sulfate pentahydrate and potassium dichromate induced cell damage in spleen and brain which was confirmed by elevated protein carbonyl group and DNA fragmentation levels in all intoxicated rats. Also from the results, it was clear that there was a statistically significant increase in LDH level in all intoxicated rats in comparison to control groups.
Cytosolic and Mitochondrial Dysfunction in Spleen and Brain Tissues
The present study indicated a significant reduction in IDH activity in spleen and brain of all intoxicated rats which reflect cytosolic dysfunction, while there was significant elevation of CCO activity in spleen and brain which reflect a sever state of mitochondrial injury in all intoxicated rats in comparison to control groups.
Histopathological Examination of Spleen and Brain Tissues.
Microscopic examination for spleen and brain tissues showed that daily administration of Zn, Cu and Cr doses caused an impairment in these tissues .Moreover tested groups for 8 weeks were more affected than tested group for 4 weeks.