The Effect of Estrogen Usage on Eccentric Exercise-Induced Damage in Rat Testes

AUTHORS

Serpil Can 1 , * , Jale Selli 2 , Basak Buyuk 2 , Sergulen Aydin 3 , Ramazan Kocaaslan 4 , Gulname Findik Guvendi 5

1 Department of Physiology, School of Medicine, Kafkas University, Kars, Turkey

2 Department of Histology and Embryology, School of Medicine, Ataturk University, Erzurum, Turkey

3 Department of Family Medicine, School of Medicine, Kafkas University, Kars, Turkey

4 Department of Urology, School of Medicine, Kafkas University, Kars, Turkey

5 Department of Pathology, School of Medicine, Kafkas University, Kars, Turkey

How to Cite: Can S, Selli J, Buyuk B, Aydin S, Kocaaslan R, et al. The Effect of Estrogen Usage on Eccentric Exercise-Induced Damage in Rat Testes, Iran Red Crescent Med J. 2015 ; 17(4):e22521. doi: 10.5812/ircmj.17(4)2015.22521.

ARTICLE INFORMATION

Iranian Red Crescent Medical Journal: 17 (4); e22521
Published Online: April 25, 2015
Article Type: Research Article
Received: August 4, 2014
Revised: January 24, 2015
Accepted: March 15, 2015
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Abstract

Background: Recent years, lots of scientific studies are focused on the possible mechanism of inflammatory response and oxidative stress which are the mechanism related with tissue damage and exercise fatigue. It is well-known that free oxygen radicals may be induced under invitro conditions as well as oxidative stress by exhaustive physical exercise.

Objectives: The aim of this study was to investigate the effects of anabolic steroids in conjunction with exercise in the process of spermatogenesis in the testes, using histological and stereological methods.

Materials and Methods: Thirty-six male Sprague Dawley rats were divided to six groups, including the control group, the eccentric exercise administered group, the estrogen applied group, the estrogen applied and dissected one hour after eccentric exercise group, the no estrogen applied and dissected 48 hours after eccentric exercise group and the estrogen applied and dissected 48 hours after eccentric exercise group. Eccentric exercise was performed on a motorized rodent treadmill and the estrogen applied groups received daily physiological doses by subcutaneous injections. Testicular tissues were examined using specific histopathological, immunohistochemical and stereological methods. Sections of the testes tissue were stained using the TUNEL method to identify apoptotic cells. Apoptosis was calculated as the percentage of positive cells, using stereological analysis. A statistical analysis of the data was carried out with one-way analysis of variance (ANOVA) for the data obtained from stereological analysis.

Results: Conventional light microscopic results revealed that testes tissues of the eccentric exercise administered group and the estrogen supplemented group exhibited slight impairment. In groups that were both eccentrically exercised and estrogen supplemented, more deterioration was detected in testes tissues. Likewise, immunohistochemistry findings were also more prominent in the eccentrically exercised and estrogen supplemented groups.

Conclusions: The findings suggest that estrogen supplementation increases damage in testicular tissue due to eccentric exercise.

Keywords

Exercise Testis Estrogens Rats

Copyright © 2015, Iranian Red Crescent Medical Journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Exercise, described as any bodily activities that enhance, or maintain physical fitness and overall health and wellness, play an important role in particular in Western societies. It is known that even moderate exercise is a stress situation for which the body must find a new dynamic equilibrium. This process requires, among other things, adaptive responses of the hormonal systems (1). Briefly, during exercise, the body sets up a new system and tries to adapt to it in two ways. One is through the hypothalamic-pituitary axis, which is a major part of the neuroendocrine system that controls and regulates many vital body processes (2). Another is by eliminating, through cellular mechanisms, the increasing levels of Reactive Oxygen Species (ROS), which are highly reactive, toxic and cause damage to proteins, lipids, carbohydrates and DNA (3). These two systems have a close relationship with each other to overcome stress during exercise. At the microenvironment level, antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase defend the cell against the harmful effects of ROS. The hypothalamic-pituitary axis helps cells via hormones such as Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and end products (cortisone, testosterone, estrogen, etc.), which bind to receptors in the cell cytoplasm or nucleus and accelerate the production of various antioxidants (4-7).

Estrogen exerts a variety of important physiological effects, which have been suggested to be mediated via two known Estrogen Receptors (ERs), alpha and beta. With a higher affinity than ERβ, 17β-estradiol (E2) binds ERα and promotes higher rates of ERα-mediated transcriptional activity in Estrogen Response Elements (ERE). Estrogen is believed to have a high antioxidant capacity, membrane stabilizing properties and a gene regulatory effect. It has been suggested that estrogen could play a role in reducing tissue damage (8).

In the literature, there are many studies in which exercise as a stress model has been applied to different animals to show its possible effects on different organs through the help of various laboratory techniques (9, 10). However, there is no information about male infertility associated with stress depending on eccentric exercise and the effect of estrogen used on testes tissues.

2. Objectives

In this study, we examined the effects of both extensive exercise and estrogen on rat testes using histological, immunohistochemical and stereological techniques; we also attempted to discover a relationship between infertility and exercise/estrogen.

3. Materials and Methods

Thirty-six male Sprague Dawley rats (12 weeks old, 245 ± 22.89 gr in weight) in groups of six per cage, under controlled conditions of constant temperature/humidity, and exposed to a 12-hour light/dark cycle, were housed in facilities accredited by international guidelines. Studies were approved by and conducted in accordance with the Institutional Animal Care and Use committee of Ataturk University (ATADEM-Approval No: 2010 - 11/65; No. B30.2.ATA.023.85 - 103). Our study was an experimental research study. Thirty-six rats were allocated randomly to six groups, as shown in Figure 1.

Experimental Protocols and Study Groups
Figure 1. Experimental Protocols and Study Groups

3.1. Experimental Model and Named Groups

Exercise was performed on a motorized rodent treadmill with an electric shock grid. Animals ran at 20 m/minute -1 on a 15% grade (downhill) for 90 minutes. All animals in exercise groups completed 90 minutes of exercise (11).

Animals in estrogen groups received daily β-estradiol 3-benzoate (10 µg/kg β-estradiol dissolved in sesame oil) by subcutaneous injections (12). Injections were made to the neck fold and administered for 30 consecutive days. The animals exercised for 24 hours following the final injection (13, 14). All animals were sacrificed at 1 hour or 48 hours after exercise by the perfusion-fixation method under isoflurane anesthesia. All animals were dissected and testicular tissues were removed for histological procedures and kept in appropriate conditions.

3.2. Research Methods

3.2.1. Immunohistochemistry Methods

Immunohistochemistry by NF-κB-p65 and TUNNEL staining in paraffin sections was performed as follows: the sections were deparaffinized and treated with proteinase K solution (20 μg/mL in PBS) for 15 minutes at room temperature. Subsequently, the sections were washed in distilled water and immersed in 3% hydrogen peroxide for 15 minutes. After several washes with PBS (50 mM sodium phosphate and 200 mM NaCl at pH 7.4), the sections were immersed in an equilibration buffer at room temperature for 20 minutes. Some sections were incubated with rabbit anti-human NF-κB/p65 primary antibody (1:50, Santa Cruz Biotechnology, sc-109) at 37°C for one hour in a humidified chamber to detect immune and inflammatory responses. Others were incubated with terminal deoxynucleotidyl transferase and biotinylated dNTP (Life Technologies, Inc.) at 37°C for one hour in a humidified chamber in order to detect DNA breaks. Then, the reaction was stopped by immersion in a stop/wash buffer. After several washes, all sections were incubated in anti-digoxigenin-peroxidase for 30 minutes at room temperature. The reaction was revealed with 0.06% 3, 3-diaminobenzidine tetrahydrochloride (Sigma Chemical, St. Louis, MO) in PBS for three to six minutes, and the sections were counterstained with Mayer’s hematoxylin. The sections were examined and photographed under a light microscope (Olympus BH-40).

3.2.2. Histological Examination of Paraffin Sections

After removing the testes, they were fixed with 10% buffered formalin for 24 to 48 hours in order to prepare them for histopathological examinations. After the fixation and routine preparation of the samples, according to the conventional light microscopic technique, they were embedded in paraffin. Using a microtome (Leica RM2125RT), 5-μm-thick sections were cut and stained with Mallory's triple stain modified by Crossman in order to determine the general structure of testicular connective tissues.

3.2.3. Histological Examination in Semi-Thin Plastic Sections

After dividing the testicular tissue to small pieces under a stereomicroscope (Lumiscope No.KS 65893), samples were fixed in 3% glutaraldehyde in 0.1 M phosphate buffer, post-fixed in 1% phosphate-buffered osmium tetroxide, dehydrated in a graded acetone series and washed in propylene oxide. After dehydration, specimens were embedded in fresh Araldite CY 212 (Agar, Cambridge, UK). Sections were cut using an ultramicrotome (Nova LKB Bromma, Sweden). Each araldite-embedded tissue block was cut to sections of about 1 μm thickness and stained with toluidine blue. These sections were photographed by a light photomicroscope (Olympus BH 40) for light microscopy examination.

3.2.4. Stereological Examination

Stereological analysis was carried out on immunopositive germ cells with TUNNEL in testicular tissue sections. For this purpose, a microscope with a camera attachment plus a computerized system and specialized software (Stereoinvestigator V-9 (Leica)) were used. Furthermore, TUNNEL-positive germ cells’ numerical density was estimated via the Fractionator method as described in previous studies (15, 16).

3.2.5. Statistical Analysis

To evaluate the significance of the observed differences, we used the one-way analysis of variance (ANOVA) followed by Tukey’s HSD multiple range test. All statistical calculations were performed using the SPSS 15.0 software for Windows (SPSS Inc., USA). Statistical significance was set at P < 0.05. All data were expressed as mean ± Standard Error of the Mean (SEM) for the six rats in each group.

4. Results

4.1. Conventional Light Microscopic Results

4.1.1. Results of Triple Staining

Histopathological evaluation of the control group’s testes revealed regular-shaped seminiferous tubules with germinal epithelium and underlying basement membranes. Spermatogonia, Sertoli cells, which are located in the basal compartment, and spermatocytes, which are located in the adluminal compartment, were observed as normal. Lumen of seminiferous tubules was filled with mature spermatids tails. Leydig cells located in the interstitial tissue showed regular shape (Figure 2 A). In the examination of the non-estrogen applied and dissected one hour after eccentric exercise group, seminiferous tubules were noticed with reduced thickness of germinal epithelium. Lumen of seminiferous tubules was observed free from spermatids (Figure 2 B). Unlike the control group, spermatocytes with condensed and fragmented nuclei were detected in the local areas of seminiferous tubules (Figure 2 B). Cross-sections of the estrogen applied group exhibited normal structures of seminiferous tubules with small irregularities. Additionally, increased mitotic activity of spermatogonial cells was noticed (Figure 2 C). In the examination of the estrogen applied and dissected one hour after eccentric exercise group, the cross-sectional conspicuous feature of testicular tissues was the increasing number of interstitial tissue cellular components. The border of seminiferous tubules was observed as irregular and a thickening of the underlying basement membrane was also detected (Figure 2 D). Evaluation of the testes of the no estrogen applied and dissected 48 hours after eccentric exercise group revealed a reduction of germinal epithelium in tubules and some tubules were completely distorted (Figure 2 E). Lumen of seminiferous tubules was free of mature spermatid tails (Figure 2 E). In examination of the estrogen applied and dissected 48 hours after eccentric exercise group, an extreme irregularity of tubules and a reduction of germinal epithelium in seminiferous tubules was remarkable (Figure 2 F).

Figure 2. Testes Cross-Sections
Testes Cross-Sections

Staining: Mallory's triple staining method. Ad-C: Adluminal Compartment, Ba-C: Basal Compartment, BaM: Basement Membrane, BV: Blood Vessel, El-Spt: Elongating Spermatids, Ed: Edema, Fl-Spt: Flagella of Spermatid, Gr-Ep: Germinal Epithelium, In: Interstitium, Inc: Inclusion, I-Pt: Peritubular tissue with irregular outline, Le-C: Leydig cell, L-Sem-T: Lumen of Seminiferous Tubule, Ls-GEp: Loss of Germinal Epithelium, Mcn: Myoid cell nucleus, Sem-T: Seminiferous Tubule, Spc: Spermatocyte, Spg: Spermatogonia, Spt: Spermatid, Typ-A-Spg: Type A Spermatogonia, Typ-B-Spg: Type B Spermatogonia, Z-Spc zygotene spermatocyte.

4.1.2. Results of Toluidine Blue Staining

Evaluation of the control group’s semi-thin plastic sections revealed seminiferous tubules containing normal structured germinal epithelium and the lumen of tubules filled with mature spermatids (Figure 3 A). Cross-sections of the no estrogen applied and dissected one hour after eccentric exercise group exhibited reduced thickness of the germinal epithelium and irregular boundaries of seminiferous tubules (Figure 3 B). In examination of the estrogen applied group, sections of thickening in the basement membrane were observed in the tubules. However, the thickness of the germinal epithelium was found normal, and the number of spermatids was decreased in the lumen of the seminiferous tubules (Figure 3 C). Cross-sections of the estrogen applied and dissected one hour after eccentric exercise group exhibited more irregularity of seminiferous tubules. Additionally, edema was detected between the germinal epithelial cells and basement membranes (Figure 3 D). In examination of the no estrogen applied and dissected 48 hours after eccentric exercise group, sections showed remarkable reduction in the thickness of germinal epithelium. Chromatin condensation was detected particularly in spermatogonia located in the basal compartment. Spermatogenetic arrest was also detected in this group (Figure 3 E). In the evaluation of the estrogen applied and dissected 48 hours after eccentric exercise group, sections revealed excessive irregularity of the seminiferous tubules. Thickness of the basal membranes and germinal epithelium were obviously decreased. Hyperchromasia, vacuolization, edema and spermatogenetic arrest were also determined in the germ cells, which form the germinal epithelium (Figure 3 F).

Figure 3. Testes Cross-Sections
Testes Cross-Sections

Staining: Toluidine Blue, Ac: Acrosome, Ap-C: Apoptotic Cell, BaM: Basement Membrane, Early-Spt: Early Spermatid (cap phase), El-Spt: Elongating Spermatids, I-Pt: Peritubular tissue with irregular outline, Le-C: Leydig Cell, Ls-GEp: Loss of Germinal Epithelium, M: Meiotic figure, Ne-C: Necrotic Cell, Prm-Spc: Primary Spermatocyte, Rb: Residual bodies, Se-C: Sertoli Cells, Typ-B-Spg: Type B Spermatogonia.

4.2. Immunohistochemistry Results

4.2.1. Results of TUNNEL Staining

TUNNEL immunopositivity of germ cells, which form the germinal epithelium and interstitial cells, were not observed in the evaluation of testicular sections of the control group (Figure 4 A). Immunopositivity of most germ cells that make up the germinal epithelium was conspicuous in the examination of sections of the no estrogen applied and dissected one hour after eccentric exercise group. Immunopositivity of Sertoli cells and spermatogonia were detected in the early stage of development (Figure 4 B). In the examination of the estrogen applied group, immunopositivity of cross-sections was remarkable in spermatogonia and in primary spermatocytes (Figure 4 C). Immunopositivity of all germinal cells were only observed in some of the tubules of the estrogen applied and dissected one hour after eccentric exercise group (Figure 4 D). In general, primary spermatocytes do not exhibit immunopositivity, however, some of Sertoli cells had immunopositivity (Figure 4 D). Immunopositivity of Sertoli cells and spermatogonia located in the basal compartment of tubules were remarkable in cross-sections of the no estrogen applied and dissected 48 hours after eccentric exercise group. Spermatids forming the acrosome granules exhibited immunopositivity (Figure 4 E). A strong immunopositivity of spermatogonia and Sertoli cells, which form most of the germinal epithelium of the seminiferous tubules, was detected in the examination of cross-sections of the estrogen applied and dissected 48 hours after eccentric exercise group. Immunopositivity was not determined in sporadic spermatids located close to the lumen. Additionally, giant cell formations were noticed (Figure 4 F).

Figure 4. Testes Cross-Sections
Testes Cross-Sections

Staining: TUNNEL. Ap-n: Apoptotic nucleus, Ap-B: Apoptotic Bodies, Ap-C: Apoptotic Cell, BV: Blood Vessel, C-Cr: Condensed Chromosomes, F-n: Fragmented nucleus, Gi-C: Giant Cell formation, Tn (-)-Ge-C: Tunnel negative germinal cell, Tn (+) -Ge-C: Tunnel positive germinal cell, In: Interstitium, Tn (-) -In-C: Tunnel negative interstitial cell, Tn (+) -In-C: Tunnel positive interstitial cell, Rb: Residual bodies, Se-C: Sertoli Cell, Tn (+) -Se-C: Tunnel positive Sertoli cell, Typ-A-Spg: Type A spermatogonia, Typ-B-Spg: Type B spermatogonia, Tn (-) -Typ-A-Spg: Tunnel negative Type A spermatogonia, Tn (-) -Typ-B-Spg: Tunnel negative Type B spermatogonia, Tn (+) -Typ-A-Spg: Tunnel positive Type A spermatogonia, Tn (+) -Typ-B-Spg: Tunnel positive Type B spermatogonia, Tn (+) Spc: Tunnel positive spermatocyte, Tn (+) -Typ Spg: Tunnel positive spermatogonia.

4.2.2. Results of NF-kB Staining

In examination of the control group, weak NF-κB immunopositivity was revealed (Figure 5 A). In the evaluation of the no estrogen applied and dissected one hour after eccentric exercise group, sections revealed mild cytoplasmic immunopositivity in primary spermatocytes (Figure 5 B). Although spermatids exhibit mild immunopositivity, in the examination of the estrogen applied group, cytoplasmic and nuclear immunopositivity in Type A and B spermatogonia were observed (Figure 5 C). Remarkable immunopositivity was found in the majority of Type A and B spermatogonia, primary spermatocytes and early spermatids in testes sections of the estrogen applied and dissected one hour after eccentric exercise group (Figure 5 D). In the examination of the no estrogen applied and dissected 48 hours after eccentric exercise group, strong cytoplasmic and nuclear immunopositivity was detected in spermatogonia, primary spermatocytes and Sertoli cells (Figure 5 E). In the evaluation of the estrogen applied and dissected 48 hours after eccentric exercise group, the sections revealed strong cytoplasmic and nuclear immunopositivity of spermatogonia, Sertoli cells, primary spermatocytes and early developing spermatids in some tubules (Figure 5 F).

Figure 5. Testes Cross-Sections
Testes Cross-Sections

Staining: NF-κB-p65. Dr-Spg-A: dark Type A spermatogonia, Ed: Edema, El-Spt: Elongating Spermatids, I-Pt: Peritubular tissue with irregularly outlined, Ls-GEp: loss of germinal epithelium, M: Meiotic figure, Ne-C: Necrotic Cell, NF-κB (+)-Cy: Nuclear Factor kappa b expression positive cytoplasm, NF-κB (+) -n: Nuclear Factor kappa b expression positive nucleus, NF-κB (+) -Typ-B-Spg: Nuclear Factor kappa b expression positive type b spermatogonia, Pl-Spg-A: pale Type A spermatogonia, Se-C: Sertoli Cell, Spc: Spermatocyte, Spg: Spermatogonia, Spt: Spermatid.

4.3. Stereological Results

Assessment results of the numerical density of immunopositive cells in the testes samples of all groups used in this study are summarized in the table below (Table 1).

Table 1. The Numerical Density of Tunnel Immunopositive Cells a, b, c
GroupsMean Numerical Density of Immunopositive CellsP Value (ANOVA)P Value (Tukey)
Control5.02 ± 0.270.0000.000
Group 211.26 ± 0.620.0000.000
Group 312.85 ± 0.290.0000.132
Group 412.95 ± 0.210.0000.132
Group 516.34 ± 0.190.0000.000
Group 618.54 ± 0.290.0000.000

aOne Way ANOVA test (Tukey’s HSD) was used for analysis of all the data.

bData are presented as Mean ± SEM.

cResults of the statistical analysis of quantitative numerical density of all experimental groups revealed a significant increase of TUNNEL immunopositive cells compared to the control group.

Acknowledgements

Footnote

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