Prostate is an androgen-dependent accessory sex organ. It contributes to the major portion of seminal fluid, which is essential for sperm viability, motility, and fertilizing capacity . The prostate is divided into three pairs of lobes: ventral, dorsal, and lateral, distributed around the prostatic urethra in rodents [2,3].
Generally, the prostatic lobes exhibit tubuloacinar structures, which are lined by simple columnar epithelium and are surrounded by stroma [4,5]. The prostatic stroma is a complex net of stromal cells, and the extracellular matrix is associated with growth factors, regulatory molecules, and enzymes that provide biological signals and lead to mechanical influence on epithelial cells [6,7].
Diabetes mellitus is a chronic disease that causes protein, carbohydrate, and lipid metabolism alterations leading to hyperglycemia due to insulin deficiency (type I) or inefficient action of insulin on target tissue (type II) [8,9]. It was estimated that there were 150 million diabetic people in the world, and the prediction of the World Health Organization will be 366 million by the year 2030 . Experimental and clinical studies have shown alterations in different systems including the urogenital system. Diabetes mellitus of both types I and II have adverse effects on male sexual and reproductive functions, including impotency, reduced libido, and sterility [11–13]. Although the adverse effects of diabetes on testicular functions are well established , there is relatively less information on the impact of diabetes on the accessory sex organs [2,15].
Selenium is an essential trace element for human health, which plays a structural and enzymatic role . It was stated that some of these enzymes had antioxidant attributes, and selenium deficiency rendered animals susceptible to injuries resulting from oxidative stress . In addition, selenium had been found to alleviate late diabetic complications in the heart , aorta , liver , bone , and testis . Information on the impact of diabetes on the ventral prostate is still a controversial issue. Despite there being signs of an association between the occurrence of prostatic diseases and diabetes , there are still many doubts in this field. Therefore, this study was undertaken to observe the effect of streptozotocin-induced diabetes on the histological structure of albino rats' ventral prostate, and the possible role of selenium supplementation.
Materials and methods
Thirty-six healthy adult male albino rats weighing 180–200 g were used in this experiment. They were housed in stainless steel cages and were maintained at room temperature. They were allowed water ad libitum and were fed standard diet. The rats were randomly divided into three equal groups; 1, 2, and 3.
Group 1 (control group) was subdivided into three subgroups: subgroup 1a included rats that received only distilled water (negative control). Subgroup 1b included rats that received a single intraperitoneal injection of 0.1 ml 0.1 mol/l citrate buffer. Subgroup 1c included the rats that were given 2 mg/kg body weight/day of sodium selenite orally by a gastric tube.
Group 2 (streptozotocin-induced diabetes): the rats received streptozotocin as the diabetogenic agent (Sigma chemical company, Germany), and the vehicle for administration was 0.1 mol/l citrate buffer, pH 4.4. (10 mg dissolved in 0.1 ml of 0.1 mol/l citrate buffer, pH 4.4). The rats were given a single intraperitoneal injection of streptozotocin at a dose of 65 mg/kg body weight after overnight fasting .
Group 3 (diabetic rats received selenium): 1 week after induction of diabetes, the rats received selenium (sodium selenite; Brasan & Odutola Company Imp. & Exp. Ltd., Sao Paulo, Brazil) at a dose of 2 mg/kg body weight/day diluted in distilled water orally by a gastric tube  till the end of the experiment.
Fasting blood samples were taken from the dorsal vein of rats' tails. Blood glucose level of all rats was estimated by glucose-oxidase method using (Accu-chek Active; Roch Diagnostics, Mannheim, Germany) before and 3 days after streptozotocin injection to confirm diabetes induction . All rats that presented with fasting blood glucose level higher than 250 mg/dl were considered as diabetic .
Thirty days after the induction of diabetes, all rats were weighed, anesthetized, and killed. The ventral prostatic lobe were dissected out and weighed. Samples from intermediate and distal regions of the ventral prostatic lobes  were taken and divided into two parts; one was processed for light microscopy the other for electron microscopy.
Specimens for light microscopic examination were fixed in 10% formol saline for 24 h, and were processed to prepare 5-μm thick paraffin sections for hematoxylin and eosin  and Masson's trichrome stains .
Specimens for electron microscopy were immediately fixed in 2.5% phosphate-buffered glutaraldehyde (pH 7.4). Then they were postfixed in 1% osmium tetroxide in the same buffer at 4°C, and were dehydrated and embedded in epoxy resin [28,29]. Semithin sections (1 μm thick) were stained with 1% toluidine blue for light microscopic examination . Ultrathin sections were stained with uranyl acetate and lead citrate [28,29], and were examined and photographed with a JEOL JEM 1010 (Japan) electron microscope in the Electron Microscope Research Laboratory of Histology and Cell Biology Department, Faculty of Medicine, Zagazig University and a JEOL JEM 1200 EXII (Japan) electron microscope at Faculty of Science, Ain Shams University.
The image analyzer computer system Leica Qwin 500 in the Histology Department, Faculty of Medicine, and Cairo University was used to evaluate the following parameters:
- (1) Using hematoxylin and eosin-stained sections:
- (a) The mean diagonal diameter of prostatic acini: using the interactive measure menu, two diagonal diameters at total magnification ×200 were measured in 10 consecutive fields from each rat in randomly chosen five animals of each group.
- (b) The epithelial height of acini: the same procedure was performed using total magnification ×400.
- (2) Using Masson's trichrome-stained sections: the area percentage of the collagen content in the septa between the acini, ducts, and around blood vessels were measured using the interactive measure menu. The area percentage and standard measuring frame of a standard area equal to 118 476.6 μm2 were chosen from the parameters measuring 10 reading from consecutive 10 sections from each rat in randomly chosen five animals of each group. In each randomly chosen field, the section of the prostate was enclosed inside the standard measuring frame. Then the collagen fiber area was masked by blue binary color to be measured. These measurements were taken using total magnification ×100.
Data for all groups were expressed as mean±standard deviation (X±SD). The obtained data were analyzed by SPSS program version 15 (Chicago, USA; “http//WWW.SPSS.com”). Statistical analysis using one-way analysis of variance (ANOVA) test for comparison between different groups was conducted. In addition, t-test was used in statistical analysis of the glandular epithelial height. The Kruskal–Wallis test was used in statistical analysis of the body weight of different groups. The results were considered to be statistically significant, highly significant, and nonsignificant when the P value was less than 0.05, less than 0.001, and more than 0.05, respectively.
Evaluation of blood glucose level
The difference between the mean values of glucose (mg/dl) levels in subgroups 1a, 1b, and 1c of the control group were statistically insignificant (P>0.05). Thus, we chose subgroup 1a (negative control) as the control group (Table 1).
The mean values of glucose (mg/dl) levels in group 2 (diabetic) showed a highly significant increase in comparison with group 1 (the control). The diabetic rats received selenium showed a significant decrease in comparison with group 2 (diabetic) but still highly significant increase in comparison with group 1 (the control) (Table 2).
Light microscopic examination of the sections of the ventral prostate of the control albino rats revealed multiple adjacent different size acini containing acidophilic secretion in their lumen. Acini were lined by columnar cells with basal oval nuclei and few basal cells are interspersed between them. Many papillary projections were observed in most acini. Sparse stroma was present between the prostatic acini (Figs 1 and 2). Masson's trichrome-stained sections revealed few collagen fibers between prostatic acini (Fig. 3). Electron microscopic examination of the ultrathin sections of the ventral prostate of the same group revealed acinar tall columnar cells resting on the basement membrane. They contained basal euchromatic nuclei, rough endoplasmic reticulum, mitochondria, and secretory granules with different electron densities. Short microvilli were seen on the apical surface (Fig. 4).
Light microscopic examination of the sections of the ventral prostate of rats from this group revealed wide variability in the structure of acini. Most acini were dilated with few papillary projections and were lined by flat-to-low cuboidal epithelial cells with rounded nuclei. Few acini had focal areas of stratification occupying part of their lining, not the whole circumference. Few acini still had columnar epithelial lining with basal nuclei. Congested blood vessels and many interstitial cells were seen (Figs 5–7). Toluidine blue-stained semithin sections revealed few acinar cells with paler or darker cytoplasm. Mast cells with multiple cytoplasmic granules were seen (Fig. 7). Masson's trichrome-stained sections revealed abundant collagen fibers between prostatic acini and around blood vessels (Fig. 8). Electron microscopic examination of the ultrathin sections of the ventral prostate of the group 2 revealed focal areas of stratification of the acinar epithelium, whereas most acini were lined by a simple row of low columnar to cuboidal cells. Most acinar cells had irregular-shaped nuclei, dilated rough endoplasmic reticulum, numerous electron-lucent vacuoles, which might have electron-dense core, and few secretory granules. Few cells have dark cytoplasm. The apical surface of the acinar cells had microvilli (Figs 9–11). Areas of irregular enfolded basement membrane were seen (Fig. 9). Thick bundles of collagen fibers and mononuclear inflammatory cellular infiltrate, most probably lymphocytes, were seen between prostatic acini. The basal cells and fibroblast were noticed (Fig. 11).
Light microscopic examination of the sections of the ventral prostate of rats from this group revealed many acini with acidophilic secretion in their lumina. Acini were lined by columnar cells with basal oval nuclei. Most of acini had papillary projections. Few acini still had no papillary projections. Congested blood vessels were noticed in the moderately thick interstitium. No areas of stratification in the acinar epithelial lining were noticed (Figs 12 and 13). Moderate amount of collagen fibers between prostatic acini and around blood vessels were seen (Fig. 14). Electron microscopic examination of the ultrathin sections of the ventral prostate of the same group revealed acinar cells with euchromatic basal nuclei, rough endoplasmic reticulum, and secretory granules of different sizes and densities. Some secretory granules appeared almost vacuolated with minimum amount of secretory content. Apical microvilli were also noticed (Fig. 15).
Morphometrical and statistical results
The difference between results of subgroups 1a, 1b, and 1c of the control group were statistically insignificant (Table 3). Thus, we chose subgroup 1a as the control group in the statistical analysis for comparing between control group 1, group 2, and group 3 (Table 4).
In this study, the body and the ventral prostate weights were highly significantly decreased in streptozotocin-diabetic rats when compared with control rats. The same parameters were highly significantly higher in rats that received selenium when compared with streptozotocin-diabetic rats. The Kruskal–Wallis test (in the parameter body weight)=25.83. F value of one-way ANOVA test (in the parameter prostatic weight)=67.2. The glandular epithelial height was highly significantly decreased when comparing group 2 versus group 1 or group 3. F value of one-way ANOVA test (in the parameter glandular epithelial height)=38.48 and t-test (with the same parameter)=11.78. The diameter of the prostatic acini was highly significantly increased when comparing group 2 versus group 1 or group 3. F value of one-way ANOVA test (in the parameter diameter of the prostatic acini)=29.637. The area percentage of the collagen fibers content in the septa between the acini and ducts and around blood vessels of the ventral lobe of the prostate was highly significantly increased when comparing group 2 versus group 1 or group 3 (Table 4 and Histogram 1).
Clinical studies showed that diabetes caused alterations in different systems, including the urogenital system . This study showed the mean values of glucose levels in the diabetic group to be highly significantly increased in comparison with the control group. The diabetic rats that received selenium showed a significant decrease in comparison with the diabetic group, but were still highly significantly increased in comparison with the control group.
Several studies observed high serum glucose levels in diabetic rodents . Sodium selenite had been found to significantly decrease the high blood glucose level observed in diabetes . Selenium exerted regulatory effects on glycolysis, gluconeogenesis, and fatty acid metabolism, which were disturbed in diabetic disorder. It might exert an insulin-like effect on glucose metabolism by stimulating the tyrosine kinase and phosphorelation involved in the distal signaling of the insulin-signaling cascade. Moreover, selenium reduced the insulin resistance [32,33]. In contrast, some investigators  suggested that the hypoglycemic role of selenium might relate with its inhibiting effect on augmentation of proinflammatory cytokines, reactive oxygen species, and reactive nitrogen species in the pancreas of streptozotocin-diabetic animals.
In this study, the body and the ventral prostate weights were highly significantly decreased in streptozotocin-diabetic rats when compared with control rats. The same parameters were highly significantly higher in rats that received selenium when compared with streptozotocin-diabetic rats. These results were in accordance with previous researchers [22,24,34] who stated that insulin is an anabolic hormone and its deficiency will have a definite adverse effect on normal metabolic process. Moreover, it had been reported that control of diabetes with insulin treatment did not recover the prostatic weight back to normal levels .
In this study, streptozotocin-diabetic rats revealed wide variability of the structure of acini. Most acini were dilated and were lined by one layer of flat-to-low cuboidal cells with few papillary projections. While, few acini had focal areas of epithelial lining stratification (ie. lined by stratified epithelium). Few acini were still lined by simple columnar cells with basal nuclei. These results were in agreement with previous studies [36,37]. Most of acinar cells had irregular shaped nuclei, dilated rough endoplasmic reticulum, numerous electron-lucent vacuoles which might have electron dense core and few secretory granules. The acinar basement membranes had focal areas of irregular enfolded basement membrane.
In this study, few acinar cells had relatively dark cytoplasm whereas others had pale cytoplasm. These changes were similar to those described for castration . Previous investigators demonstrated that clear cells were negative, but the dark cells were positive for acid phosphatase. These results indicated that the prostatic cells were not equally affected during regression of the prostate (nonuniform regression) [38–40].
In this study, examination of streptozotocin-diabetic rats revealed mononuclear cellular infiltration most probably lymphocytes and also mast cells in the interstitial tissue close to congested blood vessels. Some researchers clarified that mast cells would facilitate the arrival and maintenance of infiltrating mononuclear cells in prostate through degranulation and releasing their mediators . Other researchers [42,43] referred the presence of inflammatory cells in diabetic glands to high levels of glucose caused by diabetes that can block the correct function of immunological cells. Moreover, the inflammatory process can create a microenvironment rich in cytokines and growth factors increasing morphological and genetic damage. This may induce marked cellular proliferation and could lead to hyperplasia or even neoplastic transformation [44–46].
In this study, inflammatory cellular infiltration was not sever. These results were in contrary to those of other investigators  who documented that the area presenting prostatitis was larger in diabetic animals compared with controls, and occupied most of the gland. The difference between this study and previous study may be due to the difference of the material used to induce diabetes, ie. in this study we used streptozotocin whereas alloxan was used by previous researchers . This suggestion was confirmed by other investigators  who showed that alloxan-induced diabetes promoted a high incidence of stomach infection that would act as precursors for local carcinogenesis.
In this study, examination of the same group revealed the presence of stratification in some foci of the prostatic epithelium. These results were previously detected by other researchers [36,37]. Furthermore, chronic inflammation is frequently associated with focal atrophy and postatrophic hyperplasia of the prostate . The term proliferative inflammatory atrophy (PIA) was proposed by some researchers  to unify the atrophic processes that are highly proliferative and occur in the prostatic epithelium. Histological studies suggested that PIA could be a precursor or a risk factor for prostate cancer . Epithelial proliferative cells from PIA express high levels of the glutathione S-transferase (GSTP1) enzyme . The high expression of GSTP1 acts as a defense against oxidative damage in the genome. Areas with inflammation surrounding PIA can induce mutation in GSTP1 genes in atrophic epithelial cells rendering them vulnerable to oxidants, thus damaging DNA and promoting neoplastic transformation to develop prostatic intraepithelial neoplasia lesions then malignant progression , which is more frequent in cases of adenocarcinoma [49,54]. Proliferative activity in the rat prostate is not confined to the basal cells, which were isolated and often absent in some portions of the acini. It has been reported that the main proliferating cells in the prostate are the columnar (luminal) cells . Previous researchers  had shown no positive relation between diabetes and development of prostate cancer. Other researchers  suggested that in diabetic animals, the absence of insulin, which acts as a growth factor for cell proliferation, should be a protective factor against tumor.
In this study, examination of streptozotocin-diabetic rats' ventral prostate showed increase of area percentage of the collagen fibers content compared with the control and diabetic rats that received selenium groups. This was confirmed by statistical analysis. These results were in accordance with other investigators [22,24,37]. They found increase of the interstitial tissue in diabetes. The changes in the accessory sex glands from a diabetic rodent occurred due to two aspects; decreased testosterone levels and lack of insulin that could alter the cellular mechanism, damaging the normal androgen action [24,58,59]. Afterwards, other researchers  demonstrated that diabetes caused altered gonadotrophic hormones, resulting in reduced testicular hormone secretion. The prostatic stroma is an important component for glandular activity influencing the maintenance of glandular homeostasis. The imbalance of the stromal–epithelium interaction induces the development of benign prostatic hyperplasia and prostatic cancer. The increased extracellular matrix element production especially collagen fibers, growth factors, and stromal element reorganization is called reactive stroma, creating a positive microenvironment for hyperplasia and tumor development. This is a complex event, which involves endocrine, paracrine, and autocrine mechanisms [61–65].
In this study, examination of the sections of the ventral prostate of diabetic rats that received selenium revealed that acini regained back nearly its normal appearance. They were lined by columnar cells with basal oval nuclei. Most acini had many papillary projections. No areas of stratification in the lining epithelium were noticed. Acinar cells had euchromatic basal nuclei, apical microvilli, rough endoplasmic reticulum, and secretory granules of different sizes and densities. Some secretory granules appeared almost vacuolated with minimum amounts of secretory content. Moderate amounts of collagen fibers were seen.
The mechanism by which selenium decreases the damaging effects of diabetes on the prostatic structure could be due to its ability to reduce levels of hydrogen peroxides and damaging lipids and phospholipid hydroperoxides. Moreover, selenium could convert these harmful products to harmless residual products . Selenium has been proved to have a role in prevention of cancer , provide optimal endocrine and immune function, and moderate the inflammatory response [35,67]. Selenium had been proven to act as an insulin mimetic by activating key selenoproteins involved in the insulin-signal cascade [68–70].
This study showed deleterious effect of experimental diabetes on the structure of albino rats' prostate. In addition, it showed that administration of selenium ameliorated the structural damage to the prostate. Therefore, selenium treatment might be a promising therapeutic option guard against the damaging effect of diabetes. We recommend further clinical studies using combination of insulin and selenium therapy for long-term diabetes.
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