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The Egyptian Journal of Histology:
doi: 10.1097/01.EHX.0000414293.32898.f0
Original articles

Harmful effects of arsenic on the cerebral cortex of adult male albino rats: light and electron microscopic studies

Selim, Sally Ahmad; Selim, Assmaa O.; Askar, Eman M.

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Author Information

Department of Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Correspondence to Sally Ahmad Selim, Department of Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt Tel: +20 122 808 7667; e-mail: sa_selim73@yahoo.co

Received October 3, 2011

Accepted January 5, 2012

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Abstract

Introduction: Arsenic is a common environmental contaminant that is available worldwide. It has been reported that human arsenic exposure causes nervous system disturbances such as polyneuropathy and neurobehavioral deficits.

Aim of the work: The purpose of this work was to describe the histological changes induced by arsenic in the cerebral cortex of adult male albino rats and discuss its possible mechanisms of action.

Materials and methods: Twenty adult male albino rats were equally classified into control (I) and experimental (II) groups of 10 animals each. Rats of group II were intraperitoneally injected with 2mg/kg/day of sodium arsenite for 20 days. Samples from the temporal lobes of the cerebrum were taken and processed for light and electron microscopic examination.

Results: Features of neurodegeneration such as shrunken, irregular, and darkly stained nuclei and degenerating organelles were observed in arsenic-treated rats. Good evidence of gliosis and disrupted blood–brain barrier were also detected.

Conclusion: The adult brain is particularly susceptible to arsenic-induced oxidative stress and contributes to the neurodegenerative lesions.

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Introduction

Arsenic is one of the oldest poisons known. Arsenic is widely used in several industries, including mining, pharmaceutical, beverages, food, glass and microelectronics, make-up, paint, and even as a pesticide. Arsenic is released into the environment by smelting of various metals and by combustion of herbicides and fungicides in agricultural products. Chronic arsenic toxicity is a global environmental health problem, affecting millions of people worldwide [1]. However, the drinking water in many countries, which is tapped from natural geological resources, is also contaminated as a result of the high level of arsenic in groundwater. The deleterious environmental effect of arsenic accrues as a result of contamination of surface and groundwater with a contaminant level higher than 10 particle per billion (ppb) as set by the WHO [2].

The clinical manifestations of chronic arsenic exposure may appear in the form of skin lesions and cardiovascular, pulmonary, cerebrovascular, reproductive, and renal disorders. Developmental abnormalities, hematological disorders, diabetes mellitus, and cancers of the skin, lung, liver, kidney, and bladder have also been reported. Low birth weight and adverse pregnancy outcomes are also documented by chronic toxicity of arsenic [3].

Arsenite is more rapidly absorbed by hepatocytes compared with arsenate because it is nonionized in physiological pH. Once inside the cells, arsenite undergoes methylation into monomethylarsonic acid and dimethylarsinic acid, which are excreted along with residual inorganic arsenic through urine [4]. These metabolites are more toxic than inorganic arsenic, as methylation replaces the ionizable hydroxyl group by uncharged methyl groups, which makes the arsenic species less negatively charged and able to interact directly with negatively charged molecules such as DNA at physiological pH. Thus, the methylation of arsenic is considered an activation process rather than detoxification [5].

Acute arsenic toxicity may lead to severe reactions that appear within 30min of exposure, such as diarrhea, vomiting, central and peripheral nervous system disorders, hemolytic anemia, and hemoglobinuria. Nowadays, acute intoxication rarely occurs, and if it does it is usually the result of suicide, homicide, or accidental poisoning. Treatment with chelating agents such as dimercaprol is classical but may have varying effects [2,6].

Developmental neurotoxicity is of crucial public health importance. The vulnerability of the brain originates from a combination of immaturity and ongoing development; the damage incurred is likely to be permanent. Several recent studies have reported links between arsenic exposure and neurobehavioral deficits in school children. This evidence supports the notion that arsenic is a developmental neurotoxicant [7,8], but its effect on adult rat cerebral cortex awaits further investigation. Therefore, the aim of the present study was to clarify the effects of chronic arsenic toxicity on the histological structure of the adult rat cerebral cortex.

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Materials and methods

The study was conducted on 20 healthy adult male albino rats. Their weights ranged from 200 to 250g. The rats were obtained from the animal house of the Faculty of Medicine, Zagazig University, and left in controlled laboratory conditions such as a 12h dark and 12h light cycle at 25°C and provided with standard rodent pellet diet and water ad libitum. They were divided into two groups of 10 animals each.

Group I: This group served as the control group and received intraperitoneal injection of ordinary drinking water.

Group II: This group received sodium arsenite (Sigma Chemical Company, Cairo, Egypt) dissolved in distilled water at a dose of 2mg/kg/day by intraperitoneal injection for 20 days [9]. Thereafter, the animals were anesthetized using ether inhalation and the cerebral cortex was excised carefully and processed for light and electron microscopic studies.

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For light microscopy

The specimens were fixed in 10% buffered formalin at pH 7.2 and processed and embedded in paraffin wax. Sections of 5μm thickness were obtained and stained with H&E [10].

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For electron microscopy

Specimens from the temporal lobe of the cerebral cortex for electron microscopic examination were immediately fixed in 2.5% glutaraldehyde buffered with 0.1mol/l phosphate buffer at pH 7.4 for 2h and postfixed in 1% osmium tetroxide in the same buffer for 1h at 4°C. The specimens were processed and embedded in embed -812 resin in BEEM capsules (Polyscience, Warrington, Pennsylvania), at 60°C for 24h. Ultrathin sections were obtained using leica ultracut UCT and stained with uranyl acetate and lead citrate [11]. The ultrathin sections were examined and photographed under a JEOL 1010 electron microscope at the Mycology and Regional Biotechnology Center, Al Azhar University, Cairo, Egypt.

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For immunohistochemical analysis

Paraffin sections were cut at 5 μm and stained using the modified Avidin-Biotin Peroxidase technique for glial fibrillary acidic protein (GFAP) to reveal astrocytes. Primary antibodies were purchased from Thermo scientific company, USA, Rock Ford. Sections underwent deparaffinization and hydration. They were treated with 0.01mol/l citrate buffer (pH 6.0) for 10min to unmask the antigen. Thereafter, they were incubated in 0.3% H2O2 for 30min to abolish endogenous peroxidase activity before blocking with 5% horse serum for 1–2h. The slides were incubated with the primary antibody (1:100 monoclonal mouse anti-GFAP) at 4°C for 18–20h, washed and incubated with biotinylated secondary antibodies, and then with the avidin–biotin complex. Finally, sections were developed with 0.05% diaminobenzidine slides, counterstained with hematoxylin, dehydrated, cleared, and mounted. GFAP-positive cells appeared brown [12].

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Results

The control group I
Light microscopic results

The H&E and toluidine-stained sections revealed the normal histological structure of the cerebral cortex, which was arranged in six successive layers: the outer molecular, external granular, external pyramidal, internal granular, internal pyramidal, and the most inner layer called the multiform layer (Fig. 1). The neuropil contained neuroglia and blood vessels with a narrow perivascular space (Fig. 2). Cortical neurons with distinct nuclei along with well-stained Nissl's granules in their cytoplasm were also observed (Fig. 3).

Figure 1
Figure 1
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Figure 2
Figure 2
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Figure 3
Figure 3
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Immunohistochemical staining for GFAP showed GFAP-positive staining in the cytoplasm of astrocytes and their processes. They appeared small with few short, thin processes (Fig. 4).

Figure 4
Figure 4
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Electron microscopic results

Ultrastructurally, cortical neurons were distinguished by the large size of the somata and euchromatic nuclei. Their cytoplasm was rich in organelles such as Nissl's granules, numerous mitochondria, and rough endoplasmic reticulum (rER) (Fig. 5). Astrocytes had large well-demarcated euchromatic nuclei and a narrow electron lucent cytoplasm with few cytoplasmic organelles such as ribosomes and glycogen granules (Fig. 6). The normal fine structure of blood–brain barrier (BBB) could be seen. It was formed of the following three structures: (a) endothelial cells of blood capillaries with flat, pale nuclei and very few or no vesicles in their cytoplasm; (b) pericytes enclosed within regular, thin, basal lamina; and (c) small, narrow, perivascular space formed of glial astrocytic processes (Fig. 7).

Figure 5
Figure 5
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Figure 6
Figure 6
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Figure 7
Figure 7
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The arsenic-treated group II
Light microscopic results

The H&E and toluidine-stained sections revealed six cerebral cortical layers, which could not be identified. Congested dilated blood vessels with wide perivascular spaces were noticed (Fig. 8). Deeply stained cortical neurons were seen. Astrocytes with sharply rounded demarcated nuclei surrounded by white irregular cytoplasm and vacuolated neuropils were also observed (Figs 9 and 10), compared with controls.

Figure 8
Figure 8
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Figure 9
Figure 9
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Figure 10
Figure 10
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Immunohistochemical staining for GFAP showed GFAP-positive staining of the cytoplasm and processes of astrocytes. They were apparently increased in number and appeared larger with thick processes (Fig. 11) in comparison with controls.

Figure 11
Figure 11
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Electron microscopic results

After chronic arsenic treatment, features of neuronal insult were prominent. Regarding the cortical neurons, some of them appeared with deformed shrunken heterochromatic nuclei. Their cytoplasm contained deformed mitochondria, few spread Nissl's granules, a few scattered rER, and electron-dense bodies (Fig. 12), as well as other neurons with irregular nuclear envelopes. Their cytoplasm had few dilated cisterna of the rER and multiple vacuoles (Fig. 13). Some astrocytes had many filaments, few cisterna of the rER, swollen mitochondria, many membrane-bound vesicles (lysosomes), and many electron-dense bodies (Fig. 14). Other astrocytes had many glial filaments in their cytoplasm with a significant lack of organelles (Fig. 15).

Figure 12
Figure 12
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Figure 13
Figure 13
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Figure 14
Figure 14
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Figure 15
Figure 15
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Examination of the fine structures of BBB revealed damage in several forms: (a) The endothelial cell had an irregular heterochromatic nucleus and multiple small vesicles in its cytoplasm (Fig. 16b). (b) Irregular thickened basal lamina showed luminal microvilli and numerous endocytotic vesicles (Fig. 16b–d). (c) Pericytes showed multiple vesicles, dense bodies, empty vacuoles, and foamy vacuoles (Fig. 16b and c). (d) The wide perivascular space was formed of glial astrocytic processes containing glial filaments (Fig. 16a and d).

Figure 16
Figure 16
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Discussion

Arsenic is a well-known carcinogen and a notorious killer. The regional arsenic toxicosis is becoming a global public health problem [13]. Several recent studies have reported links between arsenic exposure and neurobehavioral deficits in school children [8]. Moreover, the intelligence quotient of children in an arsenic-rich region was found to be lower than that of children belonging to areas with low arsenic concentration, and the difference was remarkable [14].

Central neuropathy due to arsenic poisoning has been reported to cause impairment to neurological functions such as learning, short-term memory, and concentration. Although there is evidence that arsenic exposure has a toxic effect on the adult nervous system, there are few studies that address this issue [15].

Although many studies have documented cytotoxic effects of sodium arsenite on non-neuronal cells, its effect in neuronal cells is largely unknown [16]. Hence, the purpose of this study was to describe the effects of chronic administration of sodium arsenite in the histological structures of the cerebral cortex of adult rats and discuss its possible mechanisms of action.

It was shown in animal experiments that arsenic passes through the BBB and invades the brain parenchyma. There was a noticeable correlation between the extent of arsenic exposure and the concentration of arsenic in the brain of guinea pigs and rats [16,17]. Increased arsenic levels in the frontal cortex (6.3-fold), corpus striatum (6.5-fold), and hippocampus or temporal lobe (7.0-fold) associated with enhanced oxidative stress in these brain regions, as evident by an increase in lipid perioxidation and a decrease in glutathione levels with differential effects, were observed in arsenic-treated rats compared with controls [18]. Hence, the temporal lobe was the preferred site of investigation in this study.

It can be concluded from the histological studies in this work that arsenic induced histological changes in the brain. These findings were in agreement with [19–21], who showed apoptosis in some neurons and irregularity in the nuclear envelope in others, as well as showed disrupted normal arrangement of the cellular layers of the cerebrum. Other changes were revealed in the form of vacuolization in the neural cytoplasm, degeneration in the mitochondria, electron-dense inclusion bodies, and dilatations in the rER. The blood vessels appeared thickened, dilated, and congested with widening in their perivascular space.

Tumor necrosis factor is a proinflammatory cytokine, which is produced by various cell types, for example macrophages and lymphocytes. Tumor necrosis factor is a potent vasodilator in various experimental models. The increased lumen diameter is suggested to be a compensatory mechanism for maintaining normal cerebral perfusion and transport despite the increased rigidity and thickness of the microvascular wall caused by massive collagen deposition [22].

Our results were in accordance with those of previous researchers [19–21], who suggested that arsenic can induce apoptosis in the cortical neurons of rats by activating the p38 mitogen-activated protein kinase (P38 MAPK), which is a stress-activated enzyme responsible for transducing inflammatory signals and initiating apoptosis. Arsenic can also activate the c-jun N-terminal kinase 3 (JNK3), which causes tau phosphorylation. Both enzymes lead to the formation of neurofibrillary tangles and neuritic plaques, which are involved in the pathogenesis of Alzheimer's disease [23,24].

Further, some researchers have implied that arsenic exposure induces overproduction of reactive oxygen species in the body. Reactive oxygen species is the major mechanism by which inorganic arsenic exerts its toxicity in neural cells and other tissues [25,26]. In rats, inorganic arsenic exposure causes a decrease in the concentration of brain glutathione (GSH) and a reduction in antioxidant enzyme activity but an increase in oxidant production. Oxidative stress has been implicated as an important element in many neuronal dysfunctions [27,28]. Furthermore, other researchers stated that arsenic induces nitric oxide generation through activation of inducible nitric oxide synthase (iNOS). A high concentration of NO reacts with oxyradicals to product reactive nitrogen species including ONOO, resulting in derangement of cell metabolism, breakage of DNA/RNA chains, and tissue damage [29,30].

In our study, simultaneous quantitative evaluation of two components involved in astrocytic response to central nervous system (CNS) injury was carried out: cell activation as depicted by the strong positive expression of GFAP; and the characterization of phagocytic activity as disclosed by the presence of dense bodies and lysosomes. Astrocytes become activated in response to many CNS injuries. The process of astrocyte activation results in so-called ‘reactive gliosis’, a reaction with specific structural and functional characteristics [31–33]. The predominant process is the vigorous reaction of astrocytes, and the signs are increased number of glial cells, hypertrophy of astrocytes, and accumulation of cytoplasmic glial fibrillary proteins [34–37]. These results were confirmed in our findings. Although the morphological phenomena are attributed mainly to astroglia, the contribution of macrophages/microglia seems to be essential in the very early phase [37].

Astrocytes form a major glial cell population and play important physiological roles in brain functions. Astrocyte–neuron cross-talk through the release of several neurotrophic factors is a primary event in the maintenance of CNS homeostasis. Furthermore, astrocytes react to various neurodegenerative insults rapidly, leading to vigorous astrogliosis [34,35]. Although activated astrocytes secrete different neurotrophic factors for neuronal survival, it is believed that rapid and severe activation initiates an inflammatory response, leading to neuronal death and brain injury [38,39].

After prolonged activation, astrocytes secrete various neurotoxic substances and express an enhanced level of GFAP, which is considered a marker protein for astrogliosis. However, the mechanism by which astroglial expression of GFAP is increased in neurodegenerative CNS remains unclear [40,41]. Here, Brahmachari et al. [42] reported that NO is instrumental in inducing the expression of GFAP in astrocytes. Different inducers of NO production, such as lipopolysaccharides, interferon, and interleukin-1, induced the expression of GFAP in primary mouse astrocytes by means of NO, suggesting that specific targeting of NO either by iNOS inhibitors or by NO scavengers may be an important step for the attenuation of astrogliosis in neurodegenerative disorders. Furthermore, they also demonstrated that NO used the guanylate cyclase, cyclic GMP, and cyclic GMP-activated protein kinase signaling pathway to induce the expression of GFAP in astrocytes.

Whether microglia is entirely responsible for the removal of cell detritus subsequent to CNS injury, or whether astrocytes are partly involved, is still a matter of controversy. Ultrastructural studies of induced lesions have clearly shown the phagocytic role of astrocytes [31]. In the study carried out by Al-Ali and Al-Hussain [43], adult astrocytes were seen to function as phagocytes after carbon injections, the engulfment of carbon particles by astrocytes and the formation of phagolysosomes being very similar to that occurring in macrophages in the brain and spleen, thus representing definite evidence of phagocytic activity in adult astrocytes, whereas others have either denied or minimized their role in removal of cell debris [44,45].

Astrocytes may contribute to the integrity of the BBB in three ways: (a) formation of BBB in early development; (b) maintaining the intactness of the BBB structure; and (c) participating in the transport of substances across the BBB. As the astrocyte–endothelium interaction is essential to BBB function, the consequences of the interruption of this close association are quite obvious. Chemicals that directly act on astrocyte–endothelium interactions can compromise the BBB integrity [46]. Cerebral capillaries have a unique ultrastructure, which forms and serves BBB. There are three main cellular components of BBB: endothelial cells, pericytes, and finally astrocytic endfeet surrounding the capillaries. The cellular units are surrounded by an accessory basement membrane. BBB breakdown is thought to be a key component in CNS-associated pathologies [47].

Our results indicate that arsenic induces BBB dysfunction. The changes, as revealed by light microscopy and confirmed by electron microscopic studies, are typical for ‘leaky’ microvessels, as reported for a variety of neuropathological conditions associated with BBB damage. Enhanced pinocytotic activity of the endothelial cells, enormous phagocytizing action of the pericytes, and the presence of dense droplets of lipids in its cytoplasm are the most characteristic ultrastructural features noted. These results are in agreement with [48,49], who added that changes in the phospholipid profile in brain capillaries may be responsible for changes in membrane permeability. Further, in the present study, the swelling of astrocytic endfeet and the apical surface of the endothelial cells appeared irregular, displayed microvillus-like processes in the lumen, and empty vacuoles formed occasionally. In addition, thickness of the microvascular wall because of massive collagen deposition and accumulation of extracellular matrix proteins was observed. These data agree with previous observations made in models of cerebral ischemia by Süle [22]. He added that fibrous collagen deposition was observed around microvessels, either associated with the basement membrane or extending deep into the perivascular space, and endothelial microvilli might increase microvascular resistance, leading to moderate hemodynamic impediments.

Therefore, it can be concluded that arsenic can induce neuronal damages and may lead to Alzheimer's disease, and using protective masks and improving work atmospheric conditions are necessary for reducing the exposure to this environmental hazard. Further, it is also necessary to measure the arsenic levels in any groundwater that is intended for human use and purify it before consumption. It is vital to involve the local community in the decision and, even more important, in the follow-up process to overcome this problem.

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Acknowledgements
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Conflicts of interest

There are no conflicts of interest.

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Keywords:

arsenic; cerebrum; light and electron microscopes

© 2012 The Egyptian Journal of Histology

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