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Ameliorative Effect of Zinc and Vitamin E on Cadmium-Induced Brain Tissues Oxidative Stress

1Mfem CC, 2Seriki SA and 3Oyama SE

1. Department of Physiology, University of Calabar, Calabar, Nigeria 2. Department of Physiology, Edo State University, Uzairue, Nigeria

3. Department of Family Medicine, University of Alberta, Canada

ABSTRACT

BACKGROUND/AIM:Cadmium chloride (CdCl2) is a heavy metal of cadmium halide in the form of colourless crystals, soluble in water, methanol and ethanol. It constitutes environmental pollution due to its widespread use in industry throughout the world.

It is in the group of metals that are believed to have no established biological functions and are therefore considered as non-essential metals, yet they find their way into the body system and sometimes alter the course of some processes of the body system. The current study investigates the effect of cadmium chloride on oxidative stress level, and also the effect of zinc and vitamin E on the oxidative stress levels of cadmium chloride- exposed CD1 mice. METHOD: A total number of 24 adult mice were used for the study. They were randomly assigned into four groups (n=6). Group A animals served as control. Group B animals were exposed to CdCl2 (20 mg/kg body weight, each). Group C animals were exposed to CdCl2 (20 mg/kg body weight, each) and also treated with zinc at 10mg/kg/day, while Group D animals were also exposed to CdCl2 (20 mg/kg body weight, each) and treated with Vit E at 10mg/kg day. The experiment lasted for 21 days after which brain tissues form all 24 mice were harvested and oxidative stress biomarkers such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and malondialdehyde (MDA) were assayed. RESULTS: SOD concentration was significantly lower (p>0.5) in the CdCl2 treated group compared to control.

There was significant increase (p<0.05) in SOD in both CdCl2 + Zn and CdCl2+ Vit E groups compared to CdCl2 treated group.. There was a significant decrease (p<0.05) in mean catalase concentration in CdCl2 treated group compared to control. The catalase concentration in CdCl2 + Zn and CdCl2 + Vit E treated groups were significantly higher (p<0.05) compared to CdCl2

group. GPx concentration was significantly lower (p<0.05) in CdCl2compared to control. The GPx concentration in both CdCl2 + Zn and CdCl2+ vit E treated groups were significantly higher (p<0.05) compared to CdCl2. Malondialdehyde concentration in CdCl2 treated group was significantly higher (p<0.05) compared to control group. Its concentration in CdCl2 + Zinc and CdCl2 + Vit E treated groups were significantly lower (p<0.05) compared to the CdCl2 induced oxidative stress effect. CONCLUSION:Cadmium chlorideinduces oxidative stress. But zinc and vitamin E which are non-enzymatic antioxidants reverse this effect, thus attention needs to be paid to the level of exposure to cadmium containing compound. Also, zinc and vitamin E are anti-oxidants that ameliorate this oxidative stress effect where it occurs.

Keywords: Oxidative stress,malondialdehyde,superoxide dismutase,catalase, glutathione peroxidase

Corresponding Author:Seriki [email protected];+2348036041121

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INTRODUCTION

Cadmium (Cd) is a notorious environmental pollutant with numerous adverse health effects [1].

It is a toxic metal found in the earth crust naturally at an abundance of 0.1-0.5 part per million (ppm) [2]. It has a half-life of 30years in human [3].

Increasing evidence demonstrated that environmental exposure to cadmium is associated with male infertility and the poor semen quality in human [4]. It has a profound effect on sex organ weight which is the primary indicator of possible alteration in androgen status. Many studies indicate that cadmium induces oxidative stress which causes damage in many species of animals, including mice, hanisteals, rabbits, guinea pigs and dogs [5].

Cadmium, a non-essential element, enters human and animals bodies via different industrial products, environmental pollution and different contaminated foods. When cadmium enters the body, it reaches the liver within the first 6 hours and binds to metallothionein, which is a protein with a low molecular weight (6000-10,000Da) , and which is rich in cystein[6].

Oxidative stress is a general term used to describe a process of tissue damage caused by reactive O2 species. It is often defined as an imbalance in favour of the oxidant and in disfavour of the antioxidants, potentially leading to cellular damage [7]. It is said to be harmful because oxygen free radicals attack biological molecules such as lipids, proteins and DNA damage. Oxidative stress also has a harmful role in physiologic adaptation and in the regulation of intracellular signal transduction. Hence, many bio-markers of oxidative stress have been proposed which include superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) etc[8].

Antioxidants are the molecules that have the ability to counterbalance the effects of oxidants before these attacks the cells. There are highly complex antioxidant systems (enzymatic and non- enzymatic) in the mice cells, working in collaboration in other to protect the body against free radicals’ damage, other antioxidants include Vitamin E and Zinc ion (Zn2+).

Zinc, an antioxidant as well as a trace element essential for living organisms plays an important role in DNA replication, transcription and protein synthesis, influence cell division and differentiation while vitamin E is an essential micro nutrient for mammals that functions as lipid- soluble antioxidant. They both counterbalance the toxic effect of cadmium chloride [8].

Zn not only ameliorates different metals’ toxic levels but also improve plant growth attributes by inhibiting heavy metals uptake in plant parts. Heavy metals induced oxidative stress and decline plant growth, biomass, chlorophyll contents, photosynthetic traits and many metabolic functions.

Zn combats heavy metals toxicity by generating antioxidant defence system against oxidative damage and improved plant growth parameters by alleviating metals toxicity in different plants [9].

During the Cd exposure it has been reported that lipid peroxidation is prevented by Vit-E [10].Vit-E inhibits the peroxidation of membrane lipids by hunting lipid peroxyl radicals, and this process converts it into a tocopheroxyl radical. In fact, tocopherylquinone may act as a potent an antioxidant through its reduction to hydro-quinone[11].

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Additionally, [12] reported that the protective role of Vit-E against the toxicity of oxidants may be due to the quenching of hydroxyl radicals. Therefore, this report addresses the oxidative stress marker enzymes that constitute an important part of antioxidant defense mechanisms in cellular systems and also examines whether the combination of Ca, Zn and/or Vit-E can reverse Cd- induced renal oxidative damage in rats using oxidative marker enzymes as oxidative defense biomarkers

Hence, this study seeks to investigate the ameliorative effect of Zinc and vitamin E on cadmium induced oxidative stress.

MATERIALS AND METHOD

The materials used in this experiment includes; laboratory coat, plastic cages (4), saw dust, distilled water, water troughs, feeding troughs, rodent chow (Growers mesh), marker, tissue paper, methylated spirit, sample bottles, plastics basin, masking tape, disinfectant (dettol), chloroform chamber, syringe, hand gloves, cotton wood.

Reagents include; phosphate buffer solution, MDA lysis buffer (25ml), phosphotunstic acid solution (12.5ml), BHT (1ml), thiobarbiluric acid, MDA standard (4.17m), 100μL, glacial acetic acid, glutathione peroxidase assay buffer, NADPH (hypophilized), glutathione reductase, cumenehydroperioxide, gluthathione peroxidase positive control (lyophilized) catalase assay buffer (25ml), OxiRed probe (in DMSO) (200μL), HRP, 1 vial, H2O2 (3%, 0.88m), 25μL, stop solution, 1ml, catalase positive control, 2μL.

Experimental animals

The mice used in this study were albino mice. These animals were kept in the faculty of basic medical sciences animals’ house University of Calabar, Calabar, Nigeria.

The mice were twenty four (24) in number and were within the ages of 3-4 weeks with body weight between 19-25g. The animals were kept in plastic cages with soft iron netting roof.

Bedding made of saw dust were provided for the animals in other to keep them warm and give them a sense of homeliness (acclimatization) for seven days before the commencement of the actual experiments.

Animal exposure

Mice used for the present study were exposed to CdCl2 sample (20 mg/kg body weight, each).

Animals were housed at a constant temperature (28 ± 2◦C) and relative humidity 60 ± 10% with a 12-h light/dark cycle. Standard mice chow and water were made available ad libitum. All protocols for animal care and use were approved by the Animal Ethical Clearance Committee, University of Calabar (No. 011/2019-2020).

Experimental design

Twenty four (24) mice weighing between 19g and 25g were randomly assigned into four (4) groups (n=6) (shown in table 1),

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Group A was the control group while group B, C and D were test groups.

Group A: control group fed only with chow and water

Group B: Test group freely fed with rodent chow and CdCl2 solution only ad libitum.

Group C: test group freely fed with rodent chow CdCl2 solution ad libitum and exposed to Zn+2 via oral administration at a dose of 10mg/kg/day.

Group D: Test group freely fed with rodent chow, CdCl2 solution ad libitum and exposed to vitamin E via oral administration at a dose of 10mg/kg/day.

The treatment lasted for a period of 21 days (3 weeks). Their feed and water were hygienically changed on daily basis while the beddings were changed at an interval of 3 days throughout the treatment period.

At the end of 21 days, brain samples were harvested dissolved in normal saline, homogenized and centrifuged. The homogenate was then used for assay of enzymatic oxidative stress markers such as lipid peroxidation (LPx), glutathione peroxidase (GPx), catalase activities (CAT) and superoxide dismutase (SOD).

Table 1: Grouping of experimental animals

GROUP NUMBER TREATMENT

A: Control group 6 Normal mice chow and water solution

B: Test group 6 Normal mice chow, cadmium solution

C: Test group 6 Normal mice chow, cadmium solution and Zinc2+

D: Test group 6 Normal mice chow, cadmium and libitum and Vitamin E

Assessment of oxidative stress markers

The brain levels of malondialdehyde (MDA) and glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) served as markers of oxidative stress, and were assessed as follows;

1. Estimation of tissue malondialdehyde (MDA) level Principle

Lipid peroxidation forms malondialdehyde (MDA) and 4- hydroxynonenal (4-HNE), as natural by-products. MDA reacts with thiobabituric acid (TBA) to generate the MDA-TBA adduct. The MDA-TBA adduct can be easily quantified colorimetrically at 532nm.

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Reagent composition

MDA lysis buffer (25ml), phosphotungstic acid solution (12.5ml), BHT (l ml), Thiobarbituric acid, MDA standard (4.17m), l00𝜇L, glacial acetic acid

Procedure

lml of brain tissue was homogenized on ice in 300µL of the MDA lysis buffer, and then centrifuged at 13,600xg for l0min. 200µL from homogenized sample was placed into a microcentrifuge tube. 0, 2,4,6,8,10µL of the 2mmol MDA standard\as added into separate microcentrifuge tubes and the final volume adjusted to 200µL with distilled water to generate 0,4,8,12,16 and 20nmol standard per well. 600µL to TBA solution was added into each vial containing standard and sample, and incubated at 65°C for 60 minutes. It was then cooled to room temperature in ice bath for 40 minute and 200pL (from each 800pL reaction mixture) was pipette into a 96-well microplate for analysis. The absorbance was at 32nm.

Calculation:

The MDA standard curve was plotted and MDA amount in the test sample was calculated as follows: concentration (nmol/mg) = [(A/mg)] X 4

Where;

A = sample MDA amount from standard curve in nmol mg = original tissue amount used 4 = correction for using 200pL of the 800pL reaction mix.

2. Estimation of tissue glutathione peroxidase (GPx) activity Principle

Glutathione peroxidase (GPx) converts reduced glutathione (GSH) to oxidized glutathione (GSSG) while reducing lipid hydroperoxides to their corresponding alcohols or free hydrogen peroxide to water.

GPx reduces cumenehydroperoxide while oxidizing GSH to GSSG. The generated GSSG is reduced to GSPI with consumption of NADPH by GR. The decrease of NADPH (easily measured at 340 nm) is proportional to GPx activity.

Reagent composition

Glutathione peroxidase assay buffer, NADPH (hyophilized), Glutathione (GSIT, lyophilized), glutathione reducatase, cumenehydroperoxide, glutathione peroxidase positive control (lyophilized)

Procedure

0.5ml of tissue was homogenized on ice in 0.2ml cold assay buffer and centrifuged at 10,000x9 for 15 minutes at 4°C. The supernatant was collected for assay. 40µL of the samples was added into a 96 well plate and the volume made up to 50µL with assay buffer. The standard curve was prepared by diluting 25µL of the 40nm NADPH solution into 975µL distilled water to generate 1mm NADPH standard. 0, 20, 40, 60, 80 and 10µL of the 1mm NADPH standard was added into 96 well plate in duplicate to generate 0, 20, 40, 60, 80, 100nmol/well standard. The final volume

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is brought to 100µL with assay buffer. The optical density at 340nm was measured and the NADPTI standard curve was plotted.

The positive control was prepared putting 5-l0µL of the GPx positive control into the desired wells and adjusted to 50µL with assay buffer. 50µL of assay buffer was added into the wells as a reagent control (Rc). 40µL of the reaction mix was added to each test samples, positive controls and reagent controls were mixed well and incubated for 15minutes to deplete all GSSG in the sample. L0µL cumenehydroperoxide solution was added to start GPx reaction and then mixed well.

The OD at 340nm at T, was measured to read A, OD at 340nm was measured again at T2 after incubating the reaction of 25°C for 5minutes to read A2

A340nm= [(sample A] - sample A2) - (RCA] - RCA2)]

Calculation:

GPx activity (nM/min/mg protein)

= B x sample dilution T1-T2XV

3. Estimation of serum catalase (CAT) activity Principle

Catalase catalyses the decomposition of hydrogen peroxide (H2O2) to water and oxygen. The unconverted reacts with oxiRed™ probe to produce a product which can be measured calorimetrically at 570nm. The light produced is inversely proportional to the amount of catalase activity.

Reagent composition

Catalase assay buffer (25ml), oxiRed probe (in DMSO) (200µL), HRP (1 vial), I T2O2 (3%, 0.88m), 25pL, Stop solution (lml), Catalase positive control (2µL)

Procedure

0.5ml tissue was homogenized in 0.2ml cold assay buffer and centrifuged at 10,000xg for 15mintues at 4°C. The supernatant was collected for assay. 40µL of samples solution was added into each well and volume adjusted to total 78µL with assay buffer. High control (Hc) was prepared with the same amount of sample in separate wells then made up to 78µL with assay buffer. 10µL of stop solution was added into the sample He, mixed and incubated for 5minutes at 25°C. 12µL fresh lmmol H2O2 is added into each well of both samples and sample HC to start the reaction, then incubated at 250C for 30minutes. 10µL stop solution was then added into each sample vial to stop the reaction. 50µL of the developer mix was added to each test sample, controls and standard. It was mixed well and incubated at 25°C for l0minutes. The OD at 570nm is read in a Mindray Chemistry Analyzer BS-120

Cal culation :

Catalase activity (U/ml) = BB = decomposed 30xv

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H2O2 amount (nmol) from H2O2 standard curve

V = pretreated sample volume (ml) added into the reaction well 30 = reaction time in minutes.

4. Estimation of tissue superoxide dismutase (SOD) activity Principle

Superoxide dismutase (SOD) catalyzes the dismutation of the superoxide anion into hydrogen peroxide and molecular oxygen, also produces a water soluble formazan dye upon reduction with superoxide anion. The rate of the reduction with a superoxide anion is linearly related to the xanthine oxidase (XD) activity, and is inhibited by SOD. Therefore, the inhibition of activity of SOD can be determined by a colorimetric method.

Procedure

Table 2- 1 ml of tissue was homogenized in ice cold 0.1m tris, pH 7.4. The crude tissue homogenate was centrifuged at 14000xg for 5 minutes at 4°C and the cell debris discarded.

Amount of solution in each well

Sample Blank 1 Blank 2 Blank 3

Sample solution 20µL -- 20µL --

ddH20 -- 20µL -- 20µL

WST working solution 200µL 200µL 200µL 200µL

Enzyme work solution 20µL 20µL -- --

Dilution buffer -- -- 20µL 20µL

Plates were incubated at 370c for 20mintes and absorbance read at 450nm using a microplate reader.

SOD Activity = {(Ablank1-Ablank3)-(Ablank1-Ablank2) x100}/(Ablank1-Ablank3) (inhibition rate %).

Statistical Analysis

Data analysis was done and the results presented as mean ± standard error of mean (±SEM). One way analysis of variance (ANOVA) was the statistical tool used to analyse data followed by Post hoc comparisons using the Student-Newman-Keuls design among experimental groups. The men values were considered significant at p<0.05.

RESULT

BIOMARKERS OF OXIDATIVE STRESS

Table 3 – Showing the changes in oxidative stress biomarkers following exposure to CdCl2 and treatment with Zinc and Vitamin E compared to control

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Oxidative stress biomarker

Control CdCl

2

CdCl

2

+ Zn CdCl

2

+ Vit E SOD (units/L) 176.30 ± 2.50 84.98 ± 5.97 174.06 ± 5.55 175.90 ± 7.39 CAT (µmol/L) 13.80 ± 0.99 8.72 ± 0.47 12.48 ± 0.73 12.34 ± 0.64 GPx (µmol/L) 3.10 ± 0.17 1.08 ± 0.16 2.50 ± 0.20 2.70 ± 0.19 MDA (mmol/L) 1.32 ± 0.24 2.18 ± 0.14 1.34 ± 0.15 1.33 ± 0.14

Comparison of superoxide dismutase (SOD) concentrations in brain tissue of different experimental groups

Mean ± SEM concentrations of SOD in control, CdCl2, CdCl2 +Zinc and CdCl2 + Vit E was 176.30 ± 2.50, 84.98 ±5.97, 175.06 ±5.55 and 176.10 ±7.39, units/L respectively.

The SOD concentration was significantly lower (P<0.05) in CdCl2 treated group compared to control. SOD activities were higher (p<0.05) in CdCl2 + Zn and CdCl2 + Vit. E treated groups compared to CdCl2 treated group, but significant lower compared to control group (table 3) Comparison of catalase (CAT) concentrations in brain tissue of different experimental groups

Mean ± SEM concentrations of CAT in control, CdCl2, CdCl2 + Zinc, CdCl2 + Vit E were 13.80±0.99, 8.72±0.47, 12.48±0.73, 12.34±0.64 µmol/L respectively.

There was significant decrease (P< 0.05) in mean catalase concentrations in CdCl2 group compared to control. The catalase concentrations in CdCl2 + Zinc and CdCl2 + Vit E treated groups were significantly higher (P<0.05) compared to the CdCl2 treated group but lower compared to control (see table 3)

Comparison of glutathione peroxidation (GPx) concentrations in the brain tissue of different experimental groups

Mean± SEM concentrations of GPx in control, CdCl2, CdCl2 + Zinc, and Cdcl2 + Vit E treated groups were 3.10±0.17, 1.08±0.16, 2.50±0.20, and 2.70 ± 0.19 µmol/L respectively.

GPx concentration was significantly lower (P<0.05) in CdCl2 treated group compared to control.

However, the concentration of GPx in both CdCl2 + Zinc and CdCl2 + Vit E treated groups were significantly higher (P<0.05) compared to CdCl2 treated group but lower than control (see table 3)

Comparison of malondialvehyde (MDA) concentrations in brain tissues of different experimental groups

Mean ± SEM concentrations of MDA in control, CdCl2, CdCl2 + Zinc, and CdCl2 + Vit E treated groups were 1.32±0.24, 2.18±0.14, 1.34±0.15, and 1.33±0.14 md/L.

The malondialdehyde concentration in CdCl2 treated group was significantly higher (P<0.05) compared to control group. The MDA concentrate in both CdCl2 + Zinc and CdCl2 + Vit E

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treated groups were lower (P<0.05) compared to the CdCl2 treated group but slightly higher than the control (See table 3).

DISCUSSION AND CONCLUSION Discussion

Cadmium is a known toxic environmental and industrial pollutant that induces oxidative damage by disrupting pro-oxidant/antioxidant balances in tissues. The severity of intoxication may depend on the route, dose, and duration of exposure to the metal [13,14].

Cd accumulates in the cytosol and nucleus, and minimally in the mitochondria and endoplasmic reticulum of cells. [15].

This study was designed to investigate oxidative stress level of mice exposed to cadmium chloride (CdCl2) and the role of antioxidants such as zinc and vitamin E in reversing such effects.

Administration of Cd with mineral or vitamin supplements diminished the toxic effects of Cd and increased the accumulation of Cd in the brain tissues. [16].

Results showed significant decrease in the activities of SOD, CAT, and GPx, and an increase in MDA with exposure to 20mg/kg body weight of Cd. This shows that exposure to Cd decreases the activity of redox cycling antioxidant enzymes and raises lipid peroxidation in the brain tissues of mice

The activities of SOD and CAT were decreased in Cd-exposed mice, and increased in mice exposed to Cd and given the supplements (Zn and Vit E). The decreased activities of SOD and CAT may be due to the concomitant increase in the generation of free radicals, in the brain tissues of Cd-exposed rats. The interaction between Cd and essential trace elements may be one of the reasons for the decrease in antioxidant enzymes in the brain tissues of the mice because Cd can occupy the Zn site in Cu/Zn-SOD and create inactive forms of the enzyme (Cu/Cd-SOD) [17].

But the activity of Cu/Zn-SOD was increased in the mice group supplemented with Zn or Vit-E because the supplements protect against the cytotoxicity of Cd, permitting the maintenance of the normal cellular redox balance by blocking free radical generation [18,19].

Significant decrease in the activity of GPx in Cd-exposed rats may be due to the enhancement of peroxidative damage to polyunsaturated fatty acids, which would result in higher levels of lipid peroxidation in different tissues, or to the accumulation of ROS with subsequent development of brain injury.

This suggests that free radicals could be involved in the damage caused by long-term exposure to Cd [20]. Cd may reduce the efficiency of GPx only in part via its direct inhibitory effect on the enzyme, which indirectly leads to a shortage of the reduced glutathione and NADPH required for

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its activity [21]. However, changes in GPx activity caused by Ca-Zn or vitamin E supplementation with co-administration of Cd may occur because the supplements enhance the antioxidative defense system, thereby providing protection against Cd toxicity [22].

GR activity was reduced in Cd-exposed rats and increased in Ca-Zn-supplemented and Vit-E- supplemented rats, which could be due to the sensitivity of GR to Cd, even at low levels. GR was present in several tissues in which reduction of glutathione depends on reduction of peroxides.

Cd exposure may slow the process of removing cytotoxicorganic peroxides and cause damage to tissues [23]. The activities of GR were increased in naturally supplemented rats compared with chemically supplemented rats. This may be due to the ability of Zn and Vit E supplements to enhance the efflux and decrease the accumulation of Cd.

Cd roots significant increase in MDS concentrations in the mice brain tissues caused lipid peroxidation [24,25,26], which suggests that Cd may persuade oxidative stress by producing hydroxyl radicals,superoxide ions, nitric oxide and H2O2[27,28]. The activity of MDS was significantly decreased in rats co-supplemented with Zn and Vit-E due to the effects of the antioxidant defense system, which protects cells from Cd-induced toxicity [29,30,31]. Thus, supplements have roles in maintaining the MDS level and in protecting the integrity and function of tissues [32]. The decrease was much lower in mice supplemented with Vit-E, a natural supplement than those supplemented with Zn, which could be because Vit-E is a liposoluble antioxidant that does scavenging of free radicals and stabilizing cell membranes, thereby maintaining membrane permeability. Vit-E therefore functions to break free radical chains, interfering with the initiation and progression of Cd-induced oxidative damage [33]. Moreover, the antioxidants may have acted synergistically to prevent lipid peroxidation and cell destruction [34].

Conclusion

Cd exposure led to significant decrease in the activities of SOD, CAT, and GPx, and to increase in the activities of MDS in the brain tissues.

The decreased activities were due to the concomitant increases in the generation of free radicals in the brain of Cd-exposed mice. Thus, Cd accumulation in the brain mainly increased the level of nascent oxygen species and enhanced the oxidative stress during the subsequent development of brain injury. The activities of the scavenger enzymes (SOD, CAT, and GPx), were increased in Cd-exposed rats supplemented with Zn or Vit-E. These essential mineral and vitamin can reduce the heavy metal burden by competing with Cd for intestinal absorption and prevent heavy metal induced tissue damage by competitive binding to active sites of the enzymes. These supplements protect against the cytotoxicity of Cd by maintaining the cellular redox balance via blockage of free radical generation.

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PLEASE NOTE THE FOLLOWING:

NO CONFLICT OF INTEREST BETWEEN AUTHORS

NO FUNDING SUPPORT FROM ANY INDIVIDUAL OR ORGANISATION

ETHICAL PERMISSION WAS OBTAINED FOR THIS RESEARCH

AUTHORS’ CONTRIBUTIONS: Mfem CC and Seriki SA designed the research, and did the laboratory work. Oyama SE did the literature review, SerikiSA did the writing and revision.

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