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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 5-13

Cadmium-induced hematological, renal, and hepatic toxicity: The amelioration by spirulina platensis


1 Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Forensic Medicine and Clinical Toxicology, College of Medicine, Jouf University, Aljouf, Saudi Arabia
2 Department of Pathology, College of Medicine, Jouf University, Aljouf, Saudi Arabia
3 Department of Biochemistry, Faculty of Medicine, Benha University, Benha, Egypt
4 Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Alazhar University, Cairo, Egypt
5 Department Biochemistry, Faculty of Medicine, Benghazi University, Benghazi, Libya

Date of Web Publication25-May-2018

Correspondence Address:
Mahrous Abdelbasset Ibrahim
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Suez Canal University, Ismailia 41522

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjfms.sjfms_7_17

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  Abstract 


Background: spirulina platensis (SP) is known as a valuable additional food and therapeutic agent. Objective: We investigate the protective effect of SP on cadmium (Cd)-induced hematological, renal and hepatic toxicity in rats. Materials and Methods: The rats were divided into four groups. Group 1: received saline orally. Group 2: treated with SP orally for 28 days. Groups 3: treated with CdCl2for 28 days. Group 4: treated with CdCl2and SP for 28 days. Renal and hepatic damages were evaluated by investigating the renal and hepatic functions, oxidative markers, and histopathological changes. Results: There was a statistically significant (P ≤ 0.05) increase in Cd concentration in the liver and kidneys of G3 and a significant decrease with the administration of SP in G4. In rat hepatic and renal tissues, superoxide dismutase and catalase were significantly reduced while malondialdehyde (MDA) was significantly increased and significant decrease in RBC count, hemoglobin concentration, and hematocrit in Group 3 when compared to G1 and G2 (P ≤ 0.05), with improvements of these parameters in G4 when compared to G3. A significant increase was observed in plasma MDA level in Group 3 compared to control group and SP-treated group, and it was significantly decreased in G4 compared to G3. Conclusion: It can be concise that accumulation of Cd in liver and kidneys of rats is associated with remarkable alterations enzymatic activities of the antioxidant system. Our data suggested that lipid peroxidation was associated with Cd toxicity in both liver and kidney tissues. The oxidative damage in kidney and liver of rats induced by Cd is protected by SP.

Keywords: Antioxidant enzymes, cadmium, hematological, hepatic, histological, renal, Spirulina platensis


How to cite this article:
Ibrahim MA, Almaeen AH, El Moneim MA, Tammam HG, Khalifa AM, Nasibe M N. Cadmium-induced hematological, renal, and hepatic toxicity: The amelioration by spirulina platensis. Saudi J Forensic Med Sci 2018;1:5-13

How to cite this URL:
Ibrahim MA, Almaeen AH, El Moneim MA, Tammam HG, Khalifa AM, Nasibe M N. Cadmium-induced hematological, renal, and hepatic toxicity: The amelioration by spirulina platensis. Saudi J Forensic Med Sci [serial online] 2018 [cited 2018 Nov 21];1:5-13. Available from: http://www.sjfms.org/text.asp?2018/1/1/5/233186




  Introduction Top


Cadmium (Cd) is considered a nonessential heavy metal that is dangerous to human being as well as brings danger to growth and development of aquatic organisms.[1],[2] Cd is an exceptionally harmful metal, and furthermore broadly disseminated poisonous ecological and modern toxins which are greatly recognized in nourishment, soil, water, and air.[3] Cd is released to the aquatic environment from agricultural, industrial, and urban sewage discharged into a river or the sea and natural sources, such as rocks and soils. In this way, individual can be exposed to Cd by food utilization, drinking water, and accidental intake of soil sullied by Cd.[4]

The liver was believed to be the most generous tissue for recognizing oxidative stress. The exogenous chemicals were detoxified and metabolized by the liver as it is considered the fundamental organ for that.[5] It was well known from the previous researches that the liver is the largest and the first repository of heavy metals in the body followed by the renal tissue.[6],[7]

Cd poisonous in the previous researches has been nearly connected with oxidative stress and zinc homeostasis in mammalian cells. The main idea behind this correlation are to be present in the preventive effect frequently conveyed by zinc against the malicious outcomes of Cd exposure, as previously restated [8],[9],[10] and in the propinquity between the two metals in the chemical structure.

Cd has numerous toxic impacts on abundant body tissues of both animals and human.[11] Nephrotoxicity is caused by accumulated Cd foremost in the kidney. Circulated Cd in the blood is found in two forms, the first as free ion and the second bound to carriers, such as albumin, metallothioniens (MTs), and glutathione. The cellular production of reactive oxygen species (ROS) and apoptosis occur when the free form of Cd is taken up into the renal cells.[12] The renal proximal tubules are the primarily affected portions in the Cd-induced nephrotoxicity leads to glycosuria, proteinuria, and aminoaciduria. Previous studies demonstrated that Cd accumulated fundamentally in the S1 and S2 segments of renal proximal tubules,[13] which have a mutual relationship well with its nephrotoxicity that was mostly targeted to the premier portion of the proximal tubule.

Various studies reported the protective effect of zinc,[14] selenium,[15] diallyl tetrasulfide,[16] and quercetin [17] against Cd toxicity as antioxidants agents.

Blood or urine Cd concentrations provide a better index of excessive exposure in industrial situations or following acute poisoning, whereas organ tissue (lung, liver, and kidney) Cd concentrations may be useful in fatalities resulting from either acute or chronic poisoning. Cd concentrations in healthy persons without excessive Cd exposure are generally <1 μg/L in either blood or urine.[18],[19]

Spirulina platensis (SP), a cyanobacterial blue-green algae, predominantly grows as microscopic and multicellular filaments.[20] SP was used for long times as a dietary supplement due to its beneficial effect. At present, SP is widely sold on by considerable companies as a dietary supplement.[21] It was reported in previous studies that SP acts as a protective agent in many oxidative stress injuries induced by toxins because of its direct effect on ROS. The antioxidant prospect of SP was referred to tocopherol, β-carotene, phycocyanin, γ-linolenic acid, and phenolic compounds. An important enzyme superoxide dismutase (SOD) presents in SP and outcompetes indirectly damaging reactions of superoxide by delaying the rate of cellular oxygen radical generations.[22]

The experimental demonstration of the protective activities of SP against Cd-induced hepatic and nephrotoxicity is lacking. This study aimed to investigate postulated protective effect of oral administration of SP on Cd-induced hematological, renal and hepatic toxicity in male albino rats.


  Materials and Methods Top


Chemicals

Cd in the form of CdCl2 was purchased from (Sigma-Aldrich, St. Louis, MO, USA). SP tablets were purchased from the local pharmacy at Sakaka city, Al Jouf, KSA. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine kits were purchased from Biovision, USA. Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) assay kits were purchased from Biodiagnostic, Egypt. The other chemicals were purchased from Sigma Aldrich (St. Louis, Mo. USA).

Animals and experimental design

All experiments were performed with male albino (Wistar) rats, weighing 191.25 ± 8.39 g at the beginning of the experiment. Animals were housed and fed with pellet chow and tap water ad libitum. After 1 week of adaptation in a room with controlled temperature (24°C ± 2°C) and lighting (12-h light: 12-h dark), the rats were divided into four groups consisting each of eight animals. Both the Cd-exposed groups received of Cd as CdCl2, which was administered by gavage.

  • Group 1 (Control): Received 2 ml physiological saline orally, used as a vehicle, once in a day, for 28 days continuously
  • Group 2 (SP): Was treated once a day with 1000 mg SP/kg bw/day orally for 28 days
  • Groups 3 (CdCl2): Was treated with 1.8 mg Cd Cl2/kg bw/day (which corresponded to 1/50 LD50), dissolved in saline once a day for 28 days. An average oral lethal dose (LD50) value for CdCl2 in rat was reported as 88 mg Cd/kg/bw [23]
  • Group 4 (CdCl2+ SP): Animals were orally pretreated with SP (1000 mg/kg b.w), 90 min before a dose of 1.8 mg CdCl2/kg bw/day once for 28 days.


The oral route was chosen in our study to deliver Cd and SP as it had been reported previously that the animals and human were mainly exposed to Cd through this route. The doses of CdCl2, SP, and the period of treatment were selected on the basis of previous studies.[23],[24]

At the end of treatment, control and treated groups were fasted overnight before being sacrificed by cervical dislocation under pentobarbital sodium (35 mg/kg, IP) anesthesia and the blood samples were collected before scarification. To eschew any conceivable diurnal variations in the level of antioxidant enzymes, all the rats were sacrificed between 8:00 and 10:00 am. Moreover, the anesthetic procedures and handling of animals complied with the ethical guidelines of the Jouf University's Ethical Committee, and the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978).

Sample preparation

Blood was collected into evacuated tubes containing EDTA solution as anticoagulant. After centrifugation (1600 ×g) for 10 min, the supernatant plasma was carefully removed to avoid contamination with platelets, and the samples were stored at −20°C for further utilization. Ice-cold saline buffer (20 mM Tris–HCl, 0.14M NaCl buffer, pH 7.4) was used to rinse the kidney and liver after their removal and weighting, and then a Potter–Elvehjem homogenizer was used to homogenize them in the same minced solution. LPO assay was done immediately using the homogenate tissue and plasma, and homogenate aliquots were kept for further biochemical analysis.

Cadmium concentration in the hepatic and renal tissues

Cd concentration was determined by the inductively coupled plasma mass spectrometry method according to the manufacturer's recommendation. 0.08 lg Cd/L was considered the detection limit.

Biochemical and hematological assays

Hematological profile

Samples of fresh blood were obtained from all the study groups from the orbital plexus of the eyes of rats and were used to assess red blood cells (RBCs) counts, the hemoglobin (Hb) concentration (Hb g/dl), and hematocrit (Hct) value utilizing the electronic blood counter.

Biochemical assays

Reitman and Frankel [25] method was used for assaying ALT and AST. Trinder [26] method was used for assaying creatinine and urea levels utilizing the commercial diagnostic kits.

Determination of the activity of oxidative and antioxidant markers

The method of Aebi [27] was used to determine the hepatic and renal CAT activity in tissue homogenates. Hepatic and renal homogenate activity of SOD was estimated according to Spitz and Oberley [28] technique. According to the method of Ohkawa et al.[29] and Yagi,[30],[31] thiobarbituric acid reactive substances measurement is used to estimate the LPO, and they was expressed in terms of MDA content.

Histopathological examination of liver and kidney

For microscopic evaluation, liver and kidneys were fixed in 10% formalin for 24 h, and standard dehydration in ascending series of ethanol (70%, 80%, 95%, and 100%). Tissue samples were then cleared in xylene and embedding in paraffin-wax. Sections (5 μm) were cut in a microtome and stained with hematoxylin and eosin. The sections were then viewed and photographed.

Statistical analysis

The data are presented as mean ± standard deviation value. Number of animals per group was stated in the table or figure legends. One-way analysis of variance followed by Student–Newman–Keuls test was used to analyze mean differences between experimental groups for each parameter separately after ascertaining the homogeneity of variance between treatment groups by Bartlett's test. Values of P ≤ 0.05 were considered of statistical significance.


  Results Top


Effects of treatments on body weight gain, liver, kidney weights, and cadmium concentration in liver and kidneys

No fatal outcomes in rats occurred during the study period. In our study, the rats body, liver, and kidney weights subjected to various remediations are presented in [Table 1]. In Group 3 (Cd-treated rats), the findings depicted obviously significant diminution (P ≤ 0.05) in rats' body weight as compared to Group 1 (the control group) and SP-treated group (Group 2). Furthermore, a significant elevation of the liver weight in Cd-treated group and a significant decrease in kidney weights were noticed (P ≤ 0.05) when compared to both G1 and G2. However, Cd + SP administration, the gain in body weight restored and became significantly higher (P ≤ 0.05) than in Cd-exposed group, with decreased hepatic weight and increased kidney weights (P ≤ 0.05). [Table 1] also showed Cd concentration in the control and experimental rats. There is significant (P ≤ 0.05) increase in Cd concentration in the liver and kidneys of Cd-treated rats. All these changes induced by Cd intoxication were significantly (P ≤ 0.05) decreased on preadministration of SP.
Table 1: Effects of cadmium and Spirulina platensis, and their combination, on body weight gain, liver and kidney weights of rat's groups, and cadmium concentration after 4 weeks of treatment

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Effect on hematological parameters

The finding in our study depicted that there was a nonsignificant difference (P > 0.05) in the total count neither of RBCs nor in the Hb concentration and Hct rate in both the control and SP (G1and G2) groups. However, Cd administration gives rise to a significant decrease in RBC count, Hb concentration, and Hct in Cd-exposed group (G3) compared to control group (G1) (P ≤ 0.05) [Table 2]. Treatment of rats with SP combined with Cd administration (G4) restores the level of the total number of RBCs into their normal values and increases the Hb content and Hct level with significant increase when compared to the Cd-treated group (G3) (P ≤ 0.05), but these still significantly decreased when compared to the control and SP groups (G1 and G2).
Table 2: Effects of cadmium and Spirulina platensis, and their combination, on hematological parameters (red blood cells, hemoglobin, and hematocrit) of rat's groups after 4 weeks of treatment

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Effect of treatment on serum alanine aminotransferase, aspartate aminotransferase, urea, and creatinine

ALT and AST levels showed no significant difference between the control (G1) and SP-treated groups (G2) (P > 0.05) as shown in [Figure 1]a and [Figure 1]b. However, ALT and AST levels were significantly increased in Cd-treated group (G3) when compared to G1 and G2 (P ≤ 0.05). ALT and AST levels were significantly diminished in rats that exposed to SP combined with Cd (G4) when compared to G3 (P ≤ 0.05). Renal deterioration was found as a highly significant increase in plasma urea and creatinine in G3 as compared with G1 and G2 (P ≤ 0.05) as shown in [Figure 1]c and [Figure 1]d. However, the treatment with SP combined with Cd (G4) showed highly significant decrease in both plasma urea and creatinine in G4 when compared with G3 (P ≤ 0.05).
Figure 1: Effects of cadmium, Spirulina platensis, and their combination on the hepatic and renal parameters in the blood of the Wistar rats. Each value represents the mean and standard deviation of 8 rats per group. (a) Alanine aminotransferase, (b) aspartate aminotransferase, (c) blood urea, (d) serum creatinine. aCompared to the control (G1) group. bCompared to the Spirulina platensis (G2) group. cCompared to the Cadmium (G3) group. a,b,cP ≤ 0.05

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Evaluation of hepatic and renal oxidative stress parameters after cadmium treatment in different groups

Hepatic and renal CAT and SOD in rat showed no significant difference between control group (G1) and SP-treated group (G2) (P > 0.05) as shown in [Table 3]. However, SOD and CAT levels were significantly decreased in Cd-treated group (G3) when compared to G1 and G2 (P ≤ 0.05). Interestingly, SOD and CAT levels were significantly increased in rat liver and kidney in G4 (SP combined with Cd) when compared to G3 (P ≤ 0.05), but they were significantly decreased when compared to control group (G1) and SP-treated group (G2) (P ≤ 0.05).
Table 3: Effects of cadmium and Spirulina platensis, and their combination, on antioxidant enzymes activities (superoxide dismutase and catalase) in liver and kidney of rats groups after 4 weeks of treatment

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The data showed that the plasma MDA level in Cd-treated group (G3) is significantly increased compared to both the control group G1 and SP-treated group G2 (P ≤ 0.05), and it was significantly decreased in G4 (SP combined with Cd) compared to G3 (Cd-treated group). Our findings showed that both the hepatic and renal tissue MDA levels were significantly increased in Cd-treated group G3 in rat compared to control group G1 and SP-treated group (G2) (P ≤ 0.05). This value was significantly decreased in G4 (SP combined with Cd) compared to G3 (Cd-treated group), but it was still significantly increased when compared to control group (G1) and SP-treated group (G2) (P ≤ 0.05) [Table 4].
Table 4: Effects of cadmium and Spirulina platensis, and their combination, on malondialdehyde concentration in the plasma, liver, and kidney of rats groups after 4 weeks of treatment

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Histopathological examination

Cd-induced hepatic and renal damage was demonstrated through histopathological investigations. This severe hepatic damage after Cd exposure included the existence of outspread hepatocytes degeneration, necrosis, inflammation, cytoplasmic vacuolization, and various cellular debris within the central liver vein [Figure 2]c when compared with control and SP-treated rats [Figure 2]a and [Figure 2]b, respectively]. However, the combination groups of Cd-spirulina showed prominent recovery in the form of the liver histoarchitecture such as the reduced cytoplasmic vacuolization, the normal sinusoidal spaces, and the lamellar pattern of hepatocytes was restored to almost normal [Figure 2]d.
Figure 2: Effect of spirulina coadministered with cadmium on histological damage in the liver. (a) Control and (b) Spirulina platensis group showed normal histoarchitecture of the liver (c) cadmium group showed extensive degeneration of hepatocytes with necrosis, inflammation, the presence of cellular debris within a central vein, and cytological vacuolization (d) cadmium + Spirulina platensis group showed prominent recovery in the form of reduced cytoplasmic vacuolization, the normal sinusoidal spaces, and the lamellar pattern of hepatocytes was restored to almost normal (H and E, 400Ũ)

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Transverse sections of the kidney in control and SP alone-treated rats showed normal glomeruli and renal tubules [Figure 3]a and [Figure 3]b, respectively]. Whereas, Cd intoxicated rats showed cellular glomeruli, congestion cortex, and outer medulla such as tubular brush border loss, interstitial edema, and necrosis of epithelium [Figure 3]c. On the other hand, concomitant treatment with SP exhibited minimal histological changes in kidney limited only to tubular cells [Figure 3]d.
Figure 3: Effect of spirulina coadministered with cadmium on histological damage in the kidney. (a) Control and (b) Spirulina platensis-treated groups showed normal glomeruli and renal tubules (c) cadmium-treated group showed cellular glomeruli, congestion cortex and outer medulla such as tubular brush border loss, interstitial edema, and necrosis of epithelium (d) cadmium + Spirulina platensis-treated group exhibited minimal histological changes in kidney limited only to tubular cells (H and E, 400Ũ)

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  Discussion Top


Recently, due to the properties of the heavy metals that are to a great degree hurtful to people and wildlife, numerous toxicological researches have been carried out to assess their effects. Many researchers had depicted in their studies the different types of toxicity that conveyed by the heavy metals under various endpoints.[32],[33]

Stajn et al.[34] had reported that Cd is an exceptionally poisonous metal that is extremely harmful to people because its accumulation in tissues causing metabolic, histological, and pathological changes. Oxidative damage induced by Cd caused by disturbing the prooxidant-antioxidant balance in the tissues. They also announced that Cd-induced oxidative stress damage by disturbing the adjustments of the prooxidant-antioxidant in the cells

It has been noticed previously that damage of the system of cellular antioxidant and antioxidant enzymes inhibition occurs with Cd exposure. Previous researches depicted that the oxidative stress seems to have a major role in the kidneys, liver, bone, brain, ovaries, and testes toxicities induced by Cd. However, to the best of our knowledge, no studies address the ameliorative effect of SP in Cd-induced oxidative stress in liver and kidney, so we aimed in this study to assess the potential protective effects of SP against Cd-induced hepatic and renal toxicities in rats.[17]

In our study, the decreased weight gain of rats observed was in agreement with some previously studies.[35] It was noticed weight gain reduction in our experiment, which can be explained by the effects of Cd toxicities on proteins and lipids catabolism. Erdogan et al.[36] demonstrated the increase in proteins and lipids catabolism associated with Cd toxicity. The reduction of weight gain can be due to the decrease in food intake, as weight gain relies on accessibility of food materials and might be the catabolic effect of Cd. The findings from our study showed a significantly increased liver weight in Cd-treated group, thus, the selective Cd accumulation in liver might have been induced by the oral ingestion of Cd chloride. These findings in our study were inconsistent with Karmakar and Chatterjee.[37] In contrast to our finding, Tzirogiannis et al.[38] were reported that the reduction of liver weights in rats or mice could be resulted from Cd toxicities under various experimental situations.

Höfer et al.[39] have reported significant accumulation of Cd in many organs as intestines, kidneys, and livers. They [39] also assumed that the mechanism of accumulation is the same in these organs with induction of MTs. It was depicted by the same researchers [39] that expression of MTs in the small intestine, kidneys, and livers can be regulated by estrogens. Klaassen et al.[40] were reported that the existence of metallothioneins in Cd toxicity might explain the uterus susceptibility to the oxidative stress. Klaassen et al. mentioned also that metallothioneins protein has a crucial role in defending against Cd toxicity and in protecting against ROS induced by Cd intake out of scavenging of the free radical or sequestration of Cd.

Serum AST and ALT were considerably elevated in Cd-induced toxicity group (G3) in comparison to the control group (G1), G2 and G4 indicating liver injury. These results were in agreement with Brzóska et al.[41] and Injac and Strukelj [42] who reported that Cd-treated rats induce significantly increased in ALT, AST serum levels when compared with the control group. The higher activities of these liver enzymes as recorded in the present study could be related to the liver damage resulting in release and leakage out of these enzymes from the liver cytosol into the bloodstream which gives an indication on the toxic effect of this metal on the liver. These results were confirmed by significant increase (P ≤ 0.05) in CD concentration in liver rats in G3 compared to other groups.

Administration of SP at the dose of 1000 mg/kg body weight with Cd in G4 significantly lowered (P ≤ 0.05) the elevation of AST and ALT plasma enzymes in relation to the Cd-treated group. This decrease of AST and ALT plasma enzymes in G4 is attributed to a significant improvement of liver function and also revealed the therapeutic activity of the SP against well-known hepatotoxicity produced by Cd. This result was in agreement with Gaurav et al.[43] These results were confirmed by concomitant significant decrease (P ≤ 0.05) in CD concentration in liver rats in G4 compared to G3.

Our results showed a significant increase in plasma urea and creatinine in Cd-treated group (G3) compared with G1, G2, and G4. Kidneys are vulnerable to damage due to perfusion and the elevated condensation of excreted compositions in the cells of the renal tubule. The renal dysfunction observed in this study may be due to exposure of kidney to Cd during the normal process of excretion and is therefore a target organ for Cd toxicity. These results were confirmed by a significant increase in CD concentration in kidney rats in G3 compared to other groups.

Administration of SP at the dose of 1000 mg/kg body weight with Cd in G4 significantly lowered the elevation of plasma creatinine and urea induced by Cd in G3. Hence, the oral intake of SP had preserved kidney function parameters from Cd-induced toxicities. These results were confirmed by concomitant significant decrease in CD concentration in liver rats in G4 compared to G3.

Our findings also are in line with the results of Mitra et al.[44] which confirmed the higher accumulation of Cd in liver and kidneys.

In a study of Karadeniz et al.,[45] SP at dose of 1000 mg/kg produced significant renal protective activity by decreasing plasma urea, while increasing reduced glutathione (GSH), glutathione peroxidase (GPx), and SOD levels indicating the therapeutic activity of SP against gentamicin sulfate-induced nephrotoxicity and ROS production. Samuel et al.[46] had confirmed the induction of oxidative stress in many body organs as pancreas, lungs, liver, kidneys, ovaries, and testicles after intoxication by Cd administration. They had also depicted that these effects might be depend on several factors as the Cd dose, the administration route, and the exposure time of Cd.

The present study demonstrated that Cdin vivo may induce LPO as well as oxidative stress in the rat liver and kidney cells. This result was confirmed by a significantly reduction in the CAT and SOD activities in G3 compared to G1 and G2, but in Cd-treated group with SP (G4), the CAT and SOD were significantly elevated in relation to G3. H2O2 detoxification is the responsibility of CAT and SOD plays an important role in protecting tissues against oxygen free radicals. SOD is one of the metalloenzymes that plays a critical antioxidant role and constitutes the primary defense mechanism against superoxide radical in the aerobic organism.[47] The oxidative stress in the liver and kidneys which have been observed in our study can be inferred from the changes in activities of these enzymes.

The current study indicated that oral intake of SP with high dose of 1000 mg/kg considerably elevated the CAT and SOD activities in G4 in relation to G3. Hence, the administration of SP significantly increased these enzymatic activities to be near the normal level. The significant lowered CAT and SOD in G3 indicate higher Cd concentrations in the kidney and liver which may inhibit both antioxidative enzymes. In a previous research, Samuel et al.[46] reported that Cd-induced toxicity in the rat ovary resulted in strong inhibition of both SOD and CAT activities.

Wang et al.[48] in their previous research reported that the antioxidant defense mechanisms in the liver, kidneys, and testis could be induced and stimulated by low concentrations of Cd, while these antioxidant defense mechanisms were inhibited in higher concentrations of Cd as occurred with SOD and CAT enzymes. Nagaraj et al.[49] also reported that the production of free radicals and decreased GSH levels significantly increased oxidative stress.

The toxic mechanisms of the Cd on the body organs are operating in several directions. However, the main mechanism is the induction of oxidative stress. It was supposed that there is a correlation between the histological and oxidative statuses induced by CdCl2. Cd might disorganize the balance between the oxidative and the antioxidative mechanisms and did not stimulate the direct production of free radicals. Cd induces the indirect progression of oxidative stress through certain pathways as undermining of the mechanisms of the antioxidative protection, alterations of the electron transport chain in mitochondria, and ions of some metals segregation such as copper (Cu) and iron (Fe) from the proteins in the cells, which are potent to stimulate the production of ROS in a direct way.[50]

The decrease in SOD activity and its change to be inactive enzymes induced by Cd toxicity was explained by the replacement of Zn by Cd. Jurczuk et al.[51] had reported in their research that iron insufficiency may be the cause of the abatement in CAT activity in the rats' livers in Cd toxicity, and in light of the fact that CAT enzyme has Fe ions in his active sites, and the fact that Cd toxicity diminishes the liver concentrations of iron (Fe), therefore, the diminished Fe levels might result in a reduction in the CAT enzyme activity. This is one of the mechanisms of effects on CAT enzyme activity induced by Cd exposure. But in our study, we did not estimate iron concentration in liver tissue following Cd administration. Dröge [52] had depicted in a previous study that H2O2 is a key element in the ROS metabolism. It was also mentioned by Dröge (2002) that the hindrance of antioxidative status as in CAT enzyme might be presumably associated with the increment in H2O2 and superoxide radicals.

MDA was formed by the degradation of polyunsaturated lipids by ROS. The resultant compound is considered as a reactive aldehyde and it belongs to the many species of reactive electrophile that form covalent protein adducts referred to as advanced lipoxidation end products and cause toxic stress in cells. The researchers were used this aldehyde product as a biomarker to assess the oxidative stress level in the body. It was formerly shown that LPO in many tissues was induced by Cd toxicity as happens in the ovaries, uterus, kidneys, and liver.[46]

In the present study, there were significant increases in MDA in plasma, liver, and kidney tissues in G3 related to G1, G2, and G4. The same results in G4 compared to G1 and G2.

The observed decrease in CAT and SOD activity in our study may be responsible for increase in H2O2 production in the liver and kidney of Cd-treated group (G3), this leads to the observed increased in MDA concentration.

Our finding in this study revealed that significant increase in the mean level of LPO with a reduction in antioxidant defense systems that protect tissues against oxidative damage through a decrease in activity of SOD and CAT levels in CdCl2-treated group (G3), and there was significant decrease of LPO values in Cd + Spirulina-treated group (G4) when compared with CdCl2-treated group (G3). Hence, in our study, the rats treated with Spirulina revealed improvement in oxidants/antioxidant mechanism.

Our results were in agreement with Karadeniz et al.,[53] who found that pretreatment with SP might play a role in reducing the toxic effect of Cd and its antioxidant properties mediate such a protective effect, indicated by the lowering MDA and NO as well as increase of GSH and SOD levels in the liver tissue. They also stated that addition of SP with Doxorubicin increases in serum SOD content compared to Doxorubicin only. These results run parallel to Belay,[22] who stated that SP has direct effect on ROS.

El-Maraghy et al., 2001 reported that the leakage of cellular components occurred likely as a result to LPO of biomembranes, which explain the high level and the increase in the plasma ALT and AST in Cd intoxicated rats activities.[54]

Furthermore, as Cd-induced toxicity in the Cd-treated group has functional impairments as a result of tissue damage, a significant elevation in the hepatic markers as a result of elevation in hepatic peroxides level. Our finding in this study demonstrated that SP-treated group in G4 significantly decreases the production of lipid peroxides, the embodiment that an LPO reduction and cellular damage protect against Cd-induced oxidative damage in the hepatic tissue. Accordingly, ALT and AST parameters were also improved.

The role of SP in decreasing the oxidative stress may be due to the presence of its several active components. These active components in SP may provoke the activity of free-radical scavenging enzyme systems and provides protection against Cd-induced tissues damages. The metalloprotective role of SP may be related to the presence of β-carotene, Vitamin E and Vitamin C, and selenium with the high phytopigments (carotenoids, chlorophyll, and phycocyanin) in SP.[55]

β-carotene is known to act as a powerful quencher of singlet oxygen and a scavenger of free radicals. Similarly, Vitamin E in SP prevents LPO induced by Cd and maintains ascorbic acid levels and intracellular thiols in damaged tissues by inhibiting the formation of free radical and oxidative damage. Selenium component in SP induces selenium-containing enzymes as GPx, protein or compound such as selenoglutathione, selenocysteine, and selenodimethylselenide which are known to modulate the toxic effects of heavy metals.[55]

The C-phycocyanin has a powerful antioxidant property and scavenging free radicals like superoxide and hydroxyl radicals. The significant protection by C-phycocyanin is due to the radical-scavenging activity and its inhibitory effect on LPO chain reaction.[56]

Therefore, the biochemical disturbances appear to be associated with the Cd-induced damage demonstrated histologically in the liver and kidneys. This damage included the existence of cytoplasmic vacuolization and various cellular debris within the central liver vein. Brzóska et al.[41] reported in their study the histological damage in the liver induced by Cd exposure in the form of the dilated central vein, necrosis of the hepatocyte, enlarged nuclei, and overall cellular hypertrophy. These findings are in agreement with our study. In accordance with the present findings, the previous studies [56],[57] showed that exposure to Cd-induced cellular glomeruli and congestion cortex as our experimental findings. On the other hand, it was determined in our research that SP treatment improved the toxic effects of CdCl2 on liver and kidney histology when given together with CdCl2.


  Conclusion Top


Accumulation of Cd in liver and kidneys of rats is associated with histopathological damage, LPO, and decreased RBCs count. We have additionally demonstrated that SP stimulates the antioxidants systems which defended against the harmful effect of oxidative stress induced by Cd toxicity in the rats' kidneys and liver with improvement in the hematological parameters. The LPO induced by Cd toxicity in the kidneys and liver might also have a vital factor in cancer induction. More researches in the future on molecular levels will permit elucidation of this component.

Acknowledgments

The authors are greatly thankful to the pathology department for facilitating the working of the research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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