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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 46  |  Issue : 4  |  Page : 264-274

The protective effect of folic acid and Vit B12 supplementation on albino rat lung injury due to cadmium inhalation


1 Department of Anatomy, Faculty of Medicine, Tanta University, Tanta
2 Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission01-Nov-2017
Date of Acceptance10-Feb-2018
Date of Web Publication02-Aug-2019

Correspondence Address:
MD Rabab M Amer
Department of Anatomy, Faculty of Medicine, Tanta University, 25, Botros Street, Tanta, El Gharbia, 31951

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DOI: 10.4103/tmj.tmj_82_17

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  Abstract 


Background Folic acid and vitamin B12 are very important vitamins needed for normal cellular metabolic activities. Cadmium is a heavy metal that occurs naturally in the environment and Cadmium poisoning can occur through man-made pollution through agricultural and industrial activities.
Aim Study of the effect of Cadmium of lung tissue of albino rats and the possible protective effect of administration of both Folic acid and vit B12 combination.
Materials and Methods Thirty adult male albino rats were divided into 3 groups, a control group, Cadmium group, where rats received nebulized Cadmium chloride (CaCl2) and Cadmium + vit. group received Cadmium nebulization and both Folic acid and vit B12 supplementation. The lungs of rats of the 3 groups were collected and prepared for histopathological examination.
Results Cadmium group sections showed disturbed lung architecture, shrunken alveoli and increased thickness of the alveolar wall. Vacuolation of the cytoplasm of some pneumocytes were noticed and some slides showed dilated congested blood sinusoids. Transmission electron microscopic sections revealed type II pneumocyte with hyperchromatic nucleus, perinuclear dilatation, dilated and mildly degenerated lamellar bodies. Cadmium + vit group showed that the lung tissue appears nearly normal with areas of mild thickening of the alveolar wall septa and mild edema inside alveoli.
Conclusion It was concluded that both Folic acid and vit B12 supplementation proved to have a protective role against the harmful effects of Cadmium administration on the lung tissues of albino rats.

Keywords: cadmium, folic acid, lung, rat, vitamin B12


How to cite this article:
Amer RM, Tahoon NM. The protective effect of folic acid and Vit B12 supplementation on albino rat lung injury due to cadmium inhalation. Tanta Med J 2018;46:264-74

How to cite this URL:
Amer RM, Tahoon NM. The protective effect of folic acid and Vit B12 supplementation on albino rat lung injury due to cadmium inhalation. Tanta Med J [serial online] 2018 [cited 2020 Feb 29];46:264-74. Available from: http://www.tdj.eg.net/text.asp?2018/46/4/264/263922




  Introduction Top


Cadmium is a soft, bluish-white heavy metal, It occurs naturally in the environment and has the symbol Cd. It is present in the earth crust as about 25 000 tons of Cd, and are naturally released into the environment [1]. It accumulates in different organs in the human body and has a very long biological half-life (3–10 years), so even low exposure levels can cause adverse health effects[2]. Natural emission of Cd occurs in multiple occasions like the abrasion of rocks, erosion of soil, and volcanic eruptions. Dust particles contaminated with Cd are carried by wind [3].

Cadmium poisoning can occur through man-made pollution through agricultural and industrial activities that cause entry of Cd into the soil and subsequently into the ground and drinking water. The most common forms of Cd found in the environment exist in combinations with other elements such as cadmium oxide, cadmium chloride, and cadmium sulfide [4].

As Cd compounds are highly soluble, they can be absorbed by plants leading to storage of Cd in crops and causing human poisoning. So, this high soil-to-plant transfer rate renders food stuffs in general, it being the main source of Cd exposure in humans [5]. A safe intake limit of about 7 μg cadmium/week/kg body weight was set based on the critical renal Cd concentration [6].

The physical and chemical characteristics of Cd like low melting temperature, noncorrosive properties, rapid exchange of electrical ions, high thermal and electrical conductivity make it suitable for incorporation into batteries, for electroplating, electrical welding, and nuclear fission applications [3]. Nowadays, some batteries are made from nickel cadmium (Cd Ni), and accordingly persons working at factories manufacturing these types of batteries, are vulnerable for frequent occupational inhalation of (Cd Ni) aerosols [7].

Other occupational exposure to Cd contamination can occur in some industries like steel industry, production of pigments, paint production, petroleum refining, and industries of ceramics, plastics, and glazes [8].

Inhalation of Cd compounds forms a high risk for the respiratory system and the whole body, as about 50–90% of the inhaled Cd is absorbed in the lungs to the body, while it is about 5% absorption ratio in the gastrointestinal tract and 5% can be absorbed in minimal amounts throughout the body [9].

Cigarette smoking is an important source of Cd poisoning. It was found that smokers have four to five times the amount of Cd in their blood than nonsmokers. The smoke of a cigarette gives 1–2 μg of Cd and about 0.1–0.2 of this released amount reaches the lungs of the smoker. Nearly after 20 years of smoking about 15 mg of Cd enters the smoker’s body. Milk of smoking, lactating mothers contains Cd twice than that of nonsmoking mothers. Cadmium can accumulate in the lungs, liver, kidney, and parts of the central nervous system and in the pancreas [3],[10].

People who live near the risky sites of Cd contamination or inhalation may complain of impaired health in the form of diarrhea, severe vomiting, impairment of lung functions, fracture of bone, reproductive problems and even infertility and impairment of the central nervous system, possible psychological disorders, or development of cancer in one of the previously affected organs [11],[12].

As cadmium and other heavy metal poisoning is increasing with time, efforts were made to find protective measures, like Folic acid and vitamin B12 supplementation either single or combined and other efforts were made through supplementation with vitamin E [13].

Folic acid and vitamin B12 administration after a short period of arsenic exposure may avoid the pathological changes that may produce cell death of different organs [14].

Administration of Folic acid plus vitamin B12 (0.07 and 4.0 µg, respectively/100 g body weight/day) for 24 days to Wistar rats produces a significant protection against arsenic-induced liver affection in the form of disturbed liver function, distorted hepatic architecture, and DNA fragmentation of hepatocytes [15].

Vitamin B12 and Folic acid ameliorated the biochemical effects of phenytoin on the liver enzymes and lipid profile of albino rats as well. Combined administration of both vitamin B12 and Folic acid produces restoration of the depleted glutathaion levels from the cardiac tissue of albino rats after arsenic exposure and ameliorates the arsenic-induced oxidative damage of the cardiac tissue. The risk of toxicity from Folic acid and vitamin B12 is low, because water-soluble vitamins are regularly removed from the body through urine [16],[17].


  Materials and methods Top


Animals

In this study, 30 adult male albino rats were used, weighing about 180–200 g. The rats were obtained from the National Centre of Research, Cairo, Egypt. The whole rats were housed in clean cages with good ventilation. The rats were fed on a standard common diet under common environmental conditions. They were left for 1 week before the experiment to be acclimatized to the laboratory conditions before the test. The study was approved by the Animal Local Ethics Committee of Faculty of Medicine, Tanta University, Egypt.

Experimental protocol

Rats were randomly divided into three groups:
  • Group I (control group): this group is formed of 10 rats. Animals received nebulized 0.9% NaCl solution for 1 h three times weekly for 3 weeks.
  • Group II (cadmium group): this group is formed of 10 rats that received nebulized Cd via inhalation (0.1% CdCl2 in 0.9% NaCl) for 1 h three times weekly for 3 weeks. Cadmium chloride was obtained from Algomhoria (Tanta, Egypt) company for medicine. The cadmium chloride aerosol was propelled by the nebulizer into a glass chamber, with dimensions (length×width×height; 60 cm×40 cm×40 cm), where groups of six rats were allowed to move freely during the exposure. Two small side wall openings (diameter of 1 cm) in the chamber allow for a regular distribution of aerosol [18].
  • Group III (cadmium+vitamin B12 and folic acid group): this group is formed of 10 rats that received nebulized Cd via inhalation of 0.1% CdCl2 in 0.9% NaCl for 1 h three times weekly for 3 weeks. The animals of the same group received a daily oral dose of folic acid and vitamin B12 combination present in a tablet form, dissolved in distilled water, and given to rats daily via a nasogastric tube for 3 weeks. Vitamin B12 and folic acid tablets were obtained from Swanson Health Products Company (Fargo, North Dakota, United States).


Each tablet delivers 1000 μg of vitamin B12 as cyanocobalamin plus 400 μg of Folic acid (the daily requirement for 60 kg weight human). The rats were given an equivalent dose of human daily dose according to the rat body weight [16].

Histopathological examination

Animals of the three groups were anesthetized by ether and then killed. Their lungs were collected, half of the specimens were fixed in 10% formol saline and prepared for light microscopic examination. The other half of the specimens were fixed in 2% buffered glutraldehyde and prepared for electron mincroscopic examination. The sections were examined and photographed in the electron microscopic unit of Faculty of Medicine in Tanta University [19],[20].

Morphometric study and statistical analysis

  1. Histomorphometry was performed on Hematoxylin-Eosin (H&E)-stained slices of the three experimental group slides for measurement of the alveolar wall thickness.
  2. The numerical data were expressed as means±SD. For comparison, the results were analyzed using unpaired Student’s t test, and analysis of variance and Tukey’s test and differences were regarded as significant if the probability value was less than 0.05. The Statistical Package for the Social Sciences, version 20 (SPSS Inc., Chicago, Illinois, USA) was used.



  Results Top


Light microscopic study

H&E-stained sections from the lungs of adult, male albino rats of the control group (group I) showed the normal spongy lung architecture with clear alveoli and thin alveolar walls ([Figure 1]). The alveolar walls showed type I and type II pneumocytes ([Figure 1] and [Figure 2]).
Figure 1 A photomicrograph of a section in the lung of control adult, male albino rat showing the normal spongy lung architecture with clear alveoli, thin alveolar walls with type I pneumocytes (short arrows), and type II pneumocytes (long arrows) (hematoxylin–eosin, ×400).

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Figure 2 A photomicrograph of a section in the lung of adult control, male, albino rat showing the alveolar walls with type I pneumocytes (short arrows) and type II pneumocytes (long arrows) (hematoxylin–eosin, ×1000).

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In group II (the cadmium group); H&E-stained sections from the lungs of the cadmium-exposed animals showed disturbed lung architecture in the form of shrunken alveoli and increased thickness of the alveolar wall and it showed also vacuolation of the cytoplasm of some pneumocytes ([Figure 3]), dilated congested blood sinusoids, intercellular edema, and areas of hemorrhage were also observed ([Figure 4]).
Figure 3 A photomicrograph of a section in the lung of adult male, albino rat from group II (cadmium group) showing shrunken alveoli (short arrows), increased thickness of the alveolar wall (*asterisk), and vacuolation of the cytoplasm of some pneumocytes (long arrows) (hematoxylin–eosin, ×400).

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Figure 4 A photomicrograph of a section in the lung of adult, male, albino rat from group II (the cadmium group) showing dilated alveoli (*), dilated congested blood sinusoids (blue arrows), intercellular edema (letter o), and areas of hemorrhage (letter H) (hematoxylin–eosin, ×400).

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Also in the same Cd group, H&E-stained sections showed binucleated cells, areas of lymphocytic and eosinophilic infiltration, numerous large macrophages, and fragmentation of the surrounding bronchial muscle layer with shedding of the mucosal lining and the bronchial epithelial cells were desquamated and became hyperplastic ([Figure 5],[Figure 6],[Figure 7],[Figure 8],[Figure 9],[Figure 10]).
Figure 5 A photomicrograph of a section in the lung of adult, male, albino rat from group II (the cadmium group) showing binucleated cells with vacuolation of the cytoplasm (blue arrows) and areas of lymphocytic infiltration (yellow arrow) (hematoxylin–eosin, ×400).

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Figure 6 A photomicrograph of a section in the lung of adult, male albino rat from group II (the cadmium group) showing eosinophilic infiltration (black arrows) (hematoxylin–eosin, ×400).

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Figure 7 A photomicrograph of a section in the lung of adult, male, albino rat from group II (the cadmium group) showing numerous large macrophages with highly vacuolated cytoplasm (long arrows) and fragmentation of the surrounding bronchial muscle layer with shedding of the mucosal lining (short arrows) (hematoxylin–eosin, ×400).

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Figure 8 A photomicrograph of a section in the lung of adult, male albino rat from group II (the cadmium group) showing alveolus fully infiltrated with vacuolated large macrophages (arrows) (hematoxylin–eosin, ×1000).

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Figure 9 A photomicrograph of a section in the lung of adult, male albino rat from group II (the cadmium group) showing cells with pyknotic nuclei (arrows) and cellular debris in the bronchioles (*) (hematoxylin–eosin, ×1000).

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Figure 10 A photomicrograph of a section in the lung of adult, male, albino rat from group II (the cadmium group) showing that the bronchial epithelial cells were desquamated and became hyperplastic (arrow) (hematoxylin–eosin, ×400).

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H&E-stained sections of group III, where cadmium, vitamin B12, and folic acid combination were administrated to rats showed that the lung tissue appears nearly normal with areas of little thickening of the alveolar wall septa and mild edema of the alveoli ([Figure 11],[Figure 12],[Figure 13]).
Figure 11 A photomicrograph of a section in the lung of adult, male, albino rat from group III (the cadmium+vitamin group) showing that the lung tissue appears nearly normal with areas of little thickening of the alveolar wall septa (hematoxylin–eosin, ×400).

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Figure 12 A photomicrograph of a section in the lung of adult, male, albino rat from group III (the cadmium+vitamin group) showing little thickening of the alveolar walls with mild edema of the alveoli (hematoxylin–eosin, ×400).

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Figure 13 A photomicrograph of a section in the lung of adult, male, albino rat from group III (the cadmium+vitamin group) showing nearly normal lung architecture (hematoxylin–eosin, ×1000).

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Transmission electron microscopic study

Transmission electron microscopic examination of ultrathin sections from the lungs of the control group (group I) showed type II pneumocyte with irregular euchromatic nucleus, lamellar bodies, normally shaped mitochondria, rough endoplasmic reticulum, and microvilli ([Figure 14]).
Figure 14 An electron micrograph of an ultrathin section in the lung of an adult, male albino rat from the control group showing type II pneumocyte with irregular euchromatic nucleus (N), lamellar bodies (long arrows), mitochondria (M), rough endoplasmic reticulum (RER), and microvilli (short arrow) (transmission electron microscopic, ×3000).

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In group II (the cadmium group), electron microscopic sections showed type II pneumocyte with a hyperchromatic nucleus, perinuclear dilatation, dilated and mildly degenerated lamellar bodies, area of rarefaction of the cytoplasm, and some microvilli were detached ([Figure 15]). Other pneumocytes of type II showed cytoplasmic vacuoles, degenerated mitochondrial cristae, and pyknotic hyperchromatic nucleus ([Figure 16],[Figure 17],[Figure 18]).
Figure 15 An electron micrograph of an ultrathin section in the lung of an adult, male, albino rat from group II (cadmium group) showing type II pneumocyte with hyperchromatic nucleus, perinuclear dilatation (long arrow), dilated RER, mildly degenerated lamellar bodies, area of rarefaction of cytoplasm (R) and some microvilli that are detached (short arrow) (transmission electron microscopic, ×4000).

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Figure 16 An electron micrograph of an ultrathin section in the lung of an adult, male, albino rat from group II (the cadmium group) showing type II pneumocyte with cytoplasmic vacuoles (V) and degenerated mitochondria (M) (transmission electron microscopic, ×3000).

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Figure 17 An electron micrograph of an ultrathin section in the lung of an adult, male, albino rat from group II (the cadmium group) showing type II pneumocyte with degenerated lamellar bodies (L) and pyknotic hyperchromatic nucleus (N) (transmission electron microscopic, ×3000).

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Figure 18 An electron micrograph of an ultrathin section in the lung of an adult, male, albino rat from group II (the cadmium group) showing type II pneumocyte with degenerated cristae of the mitochondria (M) and rarefaction of the cytoplasm (R) (transmission electron microscopic, ×6000).

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In group III (the cadmium+vitamin group), transmission electron microscopic examination of the sections showed type II pneumocyte with a nearly normal irregular nucleus, normally shaped mitochondria, and slightly degenerated lamellar bodies ([Figure 19] and [Figure 20]).
Figure 19 An electron micrograph of an ultrathin section in the lung of an adult, male, albino rat from group III (the cadmium+vitamin group) showing type II pneumocyte with nearly normal irregular nucleus (N), mitochondria (M), and slightly degenerated lamellar bodies (arrow) (transmission electron microscopic, ×3000).

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Figure 20 An electron micrograph of an ultrathin section in the lung of an adult, male, albino rat from group III (the cadmium+vitamin group) showing type II pneumocyte normal irregular nucleus (N) (transmission electron microscopic, ×4000).

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Morphometric study

Measurement of alveolar wall thickness showed a significant increase (P<0.001) in thickness of the alveolar wall in the (cadmium group) lungs and a significant increase in thickness of the alveolar wall in the (cadmium+vitamin group), but to a lesser extend than that in the cadmium group and more than the alveolar wall thickness measured in the control group ([Table 1] and [Table 2], Histograms 1 and 2).
Table 1 Comparison of the alveolar wall thickness of the three groups

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Table 2 Comparison of the alveolar wall thickness of the cadmium and control groups

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  Discussion Top


Cadmium and other heavy metal compounds can cause various tissue injuries and hence the need for finding protecting and curing agents to avoid these injuries.

In this study, the rats were exposed to nebulized Cd for 3 weeks resulting in various lung injuries in the form of shrunken alveoli and increased thickness of the alveolar wall. These results coincide with the study of El-Refaiy and Eissa [11], who stated that Cd produced edema, thickening of interalveolar septa, and congestion of the pulmonary veins.

In the present research, light microscopic examination of cadmium-exposed lung slides showed dilated, congested blood sinusoids, intercellular edema, and areas of hemorrhage. These results were in agreement with those reported by Kundu et al. [21] and Ikechukwu and Ajeh [22].

Olszowski et al. [10] reported that Cd exposure results in the production of a chemokine which in turn recruits neutrophils and macrophages to the site of inflammation. These findings were in agreement with our microscopic results which identified areas of lymphocytic and eosinophilic infiltration with numerous large macrophages.

In our work, fragmentation of the surrounding bronchial wall muscle layer with shedding of the mucosal lining and desquamation of some bronchial epithelial cells were reported, and these results were in accordance with the results achieved by Kirschvink et al. [18], who reported bronchial wall injury with accumulation of inflammatory cells and peribronchial collagen deposition after Cd inhalation.

In this study, vacuolation of the cytoplasm of some pneumocytes with the presence of numerous large vacuolated macrophages were noticed, and these results were in agreement with Roberts et al. [23] who reported cellular vacuoles containing Cd and also observed macrophages with engulfed Cd particles.

Our electron microscopic examination of cadmium-exposed lung tissue showed rarefaction of the cytoplasm of type II pneumocytes with vacuoles and degenerated mitochondrial cristae. These results coincide with Zhang et al. [24] and Bai et al. [25] who reported findings similar to the lung tissue with heavy metal exposure.

In the present research, light microscopic examination showed binucleated cells in some Cd sections and ultrastuctural examination showed hyperchromatic nuclei with perinucliar dilatation. These findings are in agreement with those reported by Yang et al. [26] and Bishop et al. [27] who stated that Cd administration was associated with DNA damage of lung cells.

Bai et al. [25] reported karyopyknosis in pneumocyte II with swollen mitochondria and decreased ridges and empty lamellar bodies. These results coincide with our electron microscopic results, where degenerated mitochondrial cristae and dilated mildly degenerated lamellar bodies were seen.

The mechanism of occurrence of these lesions were supposed to be due to oxidative stress mechanism, as Cd produces reactive oxygen species which are partly responsible for cellular toxicity, oxidative damage of DNA, and blocking of DNA repair mechanism. Cadmium could replace iron and copper from a number of cytoplasmic and membrane proteins, resulting in oxidative cell damage [28].

In an attempt to protect tissues from the harmful effect of cadmium, the combined administration of both Folic acid and vitamin B12 had performed some sort of protection for lung tissues against the damaging effect of cadmium. These results coincide with the protective effect of Folic acid and vitamin B12 against different heavy metal injuries [29],[30]. In our study, supplementation of Folic acid and vitamin B12 with cadmium to rats was successful in decreasing the harmful effect of Cd on the lung tissue, showing minimal tissue damage. These findings were in agreement with Bhattacharjee et al. [31], who proved the protective role of the combination of Folic acid and vitamin B12 against the damaging effect of nicotine on the pancreatic islets of rats and reducing DNA damage.

The mechanism by which both Folic acid and vitamin B12 can protect tissue injury was thought to be due to reduction in oxidative stress biomarkers and hence decreased inflammation [32], while the mechanism was described by Grarup et al. [33] as both vitamin B12 and Folic acid being enzyme cofactors or substrates in the one-carbon mechanism process, which plays a role in a range of biological process like DNA synthesis, methylation, and homocysteine metabolism, while Majumdar et al. [14] stated that the role of Folic acid and vitamin B12 is by reducing the incidence of mitochondrial damage, cellular injury, and decreasing apoptosis.


  Conclusion Top


Therefore, the results from the present study suggested that Cd inhalation results in histopatiological changes in the lung tissue of adult male, albino rats and both Folic acid and vitamin B12 supplementation proved to have a protective role against these harmful effects of Cd administration on the lung tissues.





Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20]
 
 
    Tables

  [Table 1], [Table 2]



 

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Abstract
Introduction
Materials and me...
Results
Discussion
Conclusion
References
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