CC BY
16
DOI 10.26724/2079-8334-2019-4-70-228-233 UDC 611.018.1:616.64-089.87:598.445.6
Ye.N. SlilMik. V.O. Kosienko. N.I. Shepilko. A.N. Gollsev1 I krainian Medical Stomatological Academy. Poltava Institute loi I i obli ms ol C i y obio!ogy and C i yomidieini ol N AS ol I kiaiiii* Khai ki\
INFLUENCE OF THE 30-DAYS CENTRAL DEPRIVATION OF TESTOSTERONE SYNTHESIS ON THE MORPHOLOGICAL AND FUNCTIONAL FEATURES OF RAT TESTICULAR INTERSTITIAL ENDOCRINOCYTES AND SUSTENTOCYTES
e-mail: [email protected]
We found out that in the early stages of central deprivation of rat testosterone synthesis cells with ultrastructural signs of functional tension appeared in the population of sustentocytes and interstitial endocrinocytes, which were directed to support testicular secretion function. Central deprivation of testosterone synthesis causes the development of oxidative stress in rat testes, reduces the activity of the arginase pathway of L-arginine metabolism and changes the source of NO production from constitutive isoforms of NO synthase to inducible isoform. Identified metabolic and functional disorders of these cells lead to disorders in spermatogenesis.
Key woids: testes, interstitial endocrinocytes, sustentocytes, NO synthase, iNOS, cNOS, L-arginine, superoxide dismutase, NT-kB-COX2, rats.
The work is a fragment of the research project "Experimental morphological study of cryopreserved placenta transplants action, diferelin, ethanol and 1% methacrylic acid on the morphofunctional status in a number of internal organs", state registration No. 0119U102925.
An actual problem of our time is the study of the morphological and functional state of testes' structural components under conditions of a decrease in the male fertility influenced by internal and external factors, which affect the course of spermatogenesis. One of the internal factors affecting male fertility is deficiency or excess of testosterone production.
Ultramicroscopic studies of the testes help to reveal the cooperative effects of sustentocytes and interstitial endocrinocytes when exposed to various factors, which can lead to infertility. Decreased testosterone production can trigger germ cell apoptosis in testes tissues by activation of granzyme-dependent apoptosis [4].
Testosterone deficiency is observed in men with age and is associated with a decrease in its production by interstitial endocrinocytes. One of the regulators of testosterone synthesis is nitric oxide (NO). A high correlation and associative relationship between the level of testosterone and nitric oxide in the blood was established during sexual stimulation [2]. However, this effect depends on the source of NO production. And is true only in the case of NO production from the endothelial isoform of NO synthase [8].
The features of the ultrastructural organization of spermatogenous epithelium and interstitial tissue of testes with its cellular composition during various phases of spermatogenesis under influence of chemical castration by triptoreline are not fully understood. Testosterone is an important biological regulator of testes tissues homeostasis, therefore, from a theoretical and practical point of view, it is necessary to conduct studies of interstitial endocrinocytes and sustentocytes with the determination of nitric oxide production sources and state of above-mentioned cells during various types of spermatogenesis.
The puipose of the study was to clarify the microscopic organization of interstitial endocrinocytes and sustentocytes, to determine the sources of nitric oxide and the intensity of oxidative stress in rat testes during experimental central deprivation of testosterone synthesis with triptoreline.
Materials and methods. We conducted experiments on 10 mature male white rats of the Wistar line. We divided animals into 2 groups: 5 rats made up the control group, which received subcutaneous administration of saline solution during 30 days; 5 rats made up the experimental group, which received subcutaneous administration of diphereline (Triptorelin embonate) at a dose of 0.3 mg / kg during 30 days [4]. Animals were kept under standard vivarium conditions. Experimental animals were removed from experiment in strict accordance with the provisions of the "European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes" (Strasbourg, 1986), as well as the "General Ethical Principles of Animal Experiments" adopted by the first national congress on bioethics (Kyiv, 2001).
After overdosage by ketamine animals were decapitated. Small prepared pieces of testes were fixed in a 2.5% glutaraldehyde solution prepared on phosphate buffer with pH 7.2 - 7.4. Postfixing of the material was carried out with a 1% solution of osmium (IV) oxide, followed by dehydration in propylene oxide and pouring into the mixture of epoxy resins. Ultrathin sections made on an ultramicrorotome were contrasted
© Ye.V. Stetsuk, V.O. Kostenko, 2019 „„„
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with a 1% aqueous solution of uranyl acetate and lead citrate by Reynolds method and studied in an electron microscope. Using standard methods, the material was enclosed in paraffin blocks, from which slices with thickness of 4 pm were made and stained with hematoxylin and eosin. Histological preparations were studied using a light microscope equipped with digital microphotometer Olympus C 3040-ADU and special, adapted for these studies, digital programs (Olympus DP - Soft, license number VJ285302, VT310403, 1AV4U13B26802) and Biorex 3 (serial number 5604).
All biochemical studies were carried out in 10% homogenate of testes tissue using a spectrophotometer Ulab 101. The total activity of NO synthases (NOS) was determined according to the method described in [1]. The activity of constitutive NOS isoforms (cNOS) and inducible isoform (iNOS) were determined according to the procedure described in [11]. The nitrite concentration was determined by the Griss-Hosvay method [1]. The activity of arginases was determined by the increase in the concentration of L-ornithine after a 20-hour incubation in phosphate buffer medium (pH = 7.0) in the presence of a 24 mM solution of L-arginine [1]. Basic production of superoxide anion radical (O2"), its production from the mitochondrial electron transport chain (ETC) and microsomal ETC was determined according to the method proposed in the article [7]. The activity of superoxide dismutase (SOD) and catalase was determined according to the guidelines. The concentration of free malondialdehyde (MDA) was determined by the method [7].
Statistical processing of the research results was carried out using the Microsoft Office Excel program and the Real Statistics 2019 extension. The nonparametric Mann-Whitney test was used to determine the statistical significance of differences between groups. The difference was considered statistically significant if p <0.05.
Results of the study and their discussion. On a micropreparation in the seminiferous tubules of rats of the control group, all cellular associations characteristic of spermatogenic epithelium were noticeable: spermatogonia are located on the basal membrane, further from it are located spermatocytes, spermatids and spermatozoa are located in the lumen of the tubules. Their cellular composition indicated various stages of normal spermatogenesis. On the cross section of the testes of rats of the control group, the seminiferous tubules had a rounded shape. Closer to the basal membrane, the nuclei of the Sustentocytes were well visualized. The testicular stroma was represented by loose fibrous connective tissue, in which groups of interstitial endocrinocytes of 3-5 cells in the field of vision, blood vessels and cellular elements were clearly distinguished. The vessels were moderately filled by blood elements (fig. 1).
The interstitial endocrinocytes had round-shaped nuclei, located near the blood vessels or peritubularly, in groups or singly. They had rounded nuclei with 1-2 nucleoli. In their cytoplasm was well developed smooth endoplasmic reticulum, which was represented by numerous tubes that branched and were filled with a fine fiber substance, on the membranes of which there were numerous ribosomes. Mitochondria were small, with an osmiophilic matrix and a small number of cristae. A characteristic feature was the presence in the cytoplasm of secretory granules of various sizes and electron densities; they were localized in a well-developed plate apparatus of the Golgi cytoplasmic complex. The cytoplasmic membrane had structure of the elementary membrane.
During examination of sustentocytes, we revealed that they were located on the basal membrane of the convoluted seminiferous tubules. In the basal part of the cells was a large nucleus, which had a homogeneous nucleoplasm; karyolemma had a clear outline. In the cytoplasm of the sustentocyte, it was possible to visualize mitochondria, the shape of which was determined by the cut plane. Mitochondria were characterized by the presence of a matrix with a high electron density, against the background of which vesicles- cristae were well contrasted in the
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Fig. 1. Semeniformer tubes of experimental mouse. 1 month. Microimage. H&E stain: Lens: 40: Ocular lens:15.
form of light and round bubbles. The granular endoplasmic reticulum was represented by flattened membrane cisterns whose walls were coated with ribosomes, the elements of the smooth endoplasmic reticulum appeared as membrane vesicles, and numerous lysosomes were also present. Elements of the cytoskeleton were visible in all parts of the cytoplasm of the sustentocytes, with a predominance in the apical fragments, where the heads of maturing spermatids were immersed, fixed with the help of a tubulobulbar complex, and in areas of specialized contacts.
Specialized contacts of the sustentocytes divided the space of seminiferous tubules into two compartments (basal and adluminal parts). In the course of contacts, there appeared zones of ectoplasmic specialization, which performed an isolating function. Inclusions in the cytoplasm of the sustentocytes consisted from glycogen rosettes and, in the basal sections of the cytoplasm, a moderate amount of lipid drops.
In the experimental group of animals (1 month of the experiment), it we observed minor destructive disorders in the ultrastructural organization of the lamellar cytoplasmic Golgi complex of interstitial endocrinocytes (fig. 2).
Fig. 2. At electron micrograph of intact (A) and experimental mouse of interstitial endocrinocytes (B). 1 - nucleus of interstitial endocrinocytes, 2 - cytoplasm of interstitial endocrinocytes, 3 - mitochondria, 4 - smooth endoplasmic reticulum . Exp. x 10000.
In some interstitial endocrinocytes, the smooth membranes of the Golgi complex were randomly oriented and surrounded by single large electron-transparent vacuoles, lipid inclusions, and secretory granules. The cytoplasmic membrane of glandulocytes was dissolved, thickened, and had a high electron density. A small number of interstitial endocrinocytes had a fragmented smooth endoplasmic reticulum. The hyaloplasm of glandulocytes was significantly more transparent and contained very few free ribosomes and polysomes, compared with the control group of animals.
When studying the ultrastructural organization of sustentocytes from experimental group of rats, the fine structure of which generally corresponded to the control group, we observed appearance of cells with developed adaptive reactions in the cytoplasm, which should be addressed in more detail. Sustentocytes were determined, in the cytoplasm of which we observed hyperplasia of the elements of the smooth endoplasmic reticulum, the morphological equivalent of which were numerous small and expanded round vesicles, localized mainly in the apical
Fig. 3. At electron micrograph experimental mouse sustentocytes. sections of cells. The heads of maturing
1 - nucleus sustentocytes, 2 - cytopkim of sustentocytes, 3 - smooth spermatids with the violation of the structures
endoplasmic reticulum, 4 - mitochondria, 5 - nucleus of spermatocytes,
6 - basal membrane. Exp. x 10000. of the tubulo-bulbar complex with primary
signs of degeneration were also found in these fragments of the sustentocytes. Quite large phagosomes containing fragments of dead cells turned were observed in the cytoplasm of the sustentocytes. The intercellular contacts between the round spermatids and sustentocytes we re not broken, but the deformation of the inner membranes and vacuolization of mitochondria appeared in the cytoplasm of some spermatocytes, round and maturing spermatids (fig.3).
The number of mitochondria decreased in the cytoplasm of the sustentocyte, the electron density of the mitochondrial matrix also decreased. Ultra-structural signs of slight degradation of the membrane structures of the cytoplasm in the form of concentric electron-dense formations were found in the cytoplasm of vacuolated sustentocytes; protein structures were present either inside the vacuoles or independently located in the cell cytoplasm. The number of lipid drops in the basal cytoplasm of the sustentocytes was increased compared with the control group.
Under conditions of central deprivation of testosterone synthesis in the tissues of the testes, the basic O2" production increased by 6.92 times, from mitochondrial ETC O2" production increased by 1.99 times, from microsomal ETC by 1.86 times (table 1). SOD activity decreased 3.46 times, catalase activity decreased 2.04 times. At the same time, the concentration of MDA increases by 3.59 timed.
Total NO production from NO synthases did not statistically significantly change (table 2). However, there was a change in the source of NO production, which was manifested by a statistically significant decrease in NO production from constitutive NOS isoforms by 3.73 times. At the same time, there was an increase in iNOS activity by 3.77 times. The activity of arginases was reduced by 7.75 times. The nitrite content in the tissues of the testes did not statistically significantly change.
Table 1
Oxidative stress markers in rat testes during 30-day central testosterone synthesis deprivation (M±m)
Groups Parameters
SOD activity, c.u. Catalase activity, nkat/g of tissue Basic O2" production, nmol/s per g of tissue Production of O2" from mithochondrial ETC, nmol/s per g of tissue Production of O2" from microsonal ETC, nmol/s per g of tissue Free MDA, ^mol/g of tissue
Control 1.87±0.11 182±17 0.26±0.01 7.84±0.13 9.55±0.19 6.64±1.44
Experimental 0.54±0.20* 89±1* 1.8±0.04* 15.60±0.11* 17.81±0.28* 23.82±0.39*
Note: * - indicates that the difference is statistically significant when compared with control group (p<0.05)
Table 2
Nitric oxide cycle function during 30-day cntral testosterone synthesis deprivation (M±m)
Groups Parameters
Total NOS activity, ^mol/min per g of protein iNOS activity, ^mol/min per g of protein cNOS activity, ^mol/min per g of protein Arginase activity, ^mol/min per g of protein NO2-concentration, nmol/L
Control 0.54±0.04 0.13±0.02 0.41±0.03 2.48±0.05 3.83±0.25
Experimental 0.60±0.03 0.49±0.03* 0.11±0.02* 0.32±0.02* 3.83±0.21
Note: * - indicates that the difference is statistically significant when compared with control group (p<0.05)
Given the characteristic changes in the ultrastructure of interstitial endocrinocytes and sustentocytes, it can be assumed that the main producers of O2" from mitochondrial ETC are interstitial endocrinocytes, and from microsomal ETC - sustentocytes. This statement is supported by following ultrastructural changes: a fragmented smooth endoplasmic reticulum in interstitial endocrinocytes and hyperplasia of the elements of the smooth endoplasmic reticulum in sustentocytes cells with a decrease in the number of mitochondria and reduction in the electron density of the mitochondrial matrix.
Thus, the development of oxidative stress is observed in the tissues of the testes. Oxidative stress can lead to a decrease in testosterone production by interstitial endocrinocytes cells through activation of the NF-kB-COX2 cascade [12]. The involvement of the transcription factor NF-kB in the development of changes in the metabolism of the testes is evidenced by an increase in iNOS activity. Nitric oxide, which was produced by iNOS does not enhance, but inhibits the production of testosterone by interstitial endocrinocytes, since it contributes to the development of oxidative-nitrosative stress [3].
Testosterone has the ability to reduce iNOS activity not only in the testes, but throughout the body, especially in the brain tissue, as shown by Atallah A. et al. [2]. A feature of the testes, in this case, is the presence of a local producer of testosterone - interstitial endocrinocytes, which should compensate for testosterone deficiency. However, based on the results obtained in our research, they are exposed to oxidative stress and are not able to fulfill their hormone-producing function.
Another mechanism underlying the decrease in testosterone production is a decrease in the activity of cNOS, namely the endothelial isoform of NOS. Since the activity of arginases in the testes decreases several times, it is not possible to talk about the feasibility of "arginine steal" from cNOS by these enzymes. A decrease in arginase activity is a negative factor that further aggravates malfunctions in spermatogenesis,
since the end products of the arginase pathway of L-arginine metabolism are polyamines (spermine, spermidine, putrescine), necessary for physiological proliferation and sperm maturation [6].
At the same time, some researchers show that inhibition of arginases by polyphenols has a positive effect on spermatogenesis and testosterone production, eliminating erectile dysfunction [5]. Thus, the importance of arginases in the development of spermatogenesis disorders is ambiguous and requires further study.
Testosterone deficiency as a result of central inhibition of its synthesis can also be the primary cause of oxidative stress, since testosterone has the ability to reduce the formation of reactive oxygen species by mitochondria and reduce the development of stress of the endoplasmic reticulum [9]. An increase in 02"production from mitochondrial ETC and microsomal ETC indicates a decrease in the inhibitory effect of testosterone on the production of reactive oxygen species from mitochondria and the development of stress of the endoplasmic reticulum, which is infrastructurally clearly manifested in interstitial endocrinocytes.
C |usion
Ar the early stages of central deprivation of testosterone synthesis in animals, we found out that cells with ultrastructural signs of functional stress appear in the population of sustentocytes and interstitial endocrinocytes and that reaction is aimed at supporting the secretory function of the testes.
Central deprivation of testosterone synthesis causes the development of oxidative stress in the testes, reduces the activity of the arginase pathway of L-arginine metabolism and changes the source of NO production from constitutive isoforms of NO synthase to inducible isoform.
Identified metabolic and functional disorders of these cells lead to impaired spermatogenesis.
References
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Рефк-раш
вплив 30 денно! центрально!' депривацп
СИНТЕЗУ ТЕСТОСТЕРОНА НА МОРФОФУНКЦ1ОНАЛЬН1 ОСОБЛИВОСТ1 ШТЕРСТИЩАЛЬНИХ ЕНДОКРИНОЦИТ1В ТА СУСТЕНТОЦИТ1В ЯСЧКА ЩУР1В Стецук С.В., Костенко В. О., Шештько В.1.,
Гольцев А.М. На раншх етапах центрально!' депривацп синтезу тестостерону у щурiв встановлено, що в популяцп сустентоци™ та штерстищальних ендокриноциив
ВЛИЯНИЕ 30 ДНЕВНОЙ ЦЕНТРАЛЬНОЙ ДЕПРИВАЦИИ СИНТЕЗА ТЕСТОСТЕРОНА НА МОРФОФУНКЦИОНАЛЬНЫЕ ОСОБЕННОСТИ ИНТЕРСТИЦИАЛЬНЫХ ЭНДОКРИНОЦИТОВ И СУСТЕНТОЦИТОВ ЯИЧКА КРЫС Стецук Е.В., Костенко В.А., Шепитько В.И.,
Гольцев А.Н. На ранних этапах центральной депривации синтеза тестостерона у крыс установлено, что в популяции сустентоцитив и интерстициальных эндокриноцитов
з'являються клоним з ультраструктурними ознаками функционально! напруги, спрямованих на пiдтримку секреторно! функцп яечка. Центральна депривацiя синтезу тестостерону викликае розвиток оксидативного стресу в Ым'яниках, знижуе активнiсть арпназного шляху метаболiзму L-аргiнiну i змшюе джерело продукцп NO з конституцшних iзоформ NO-синтази на iндуцибельну. Виявлеш порушення метаболiчно'í i функционально! активност цих клiтин i призводять до порушень сперматогенезу.
Ключовi слова: Ым'яники, штерстищальш ендокриноцити, сустентоцити, NO-синтаза, iNOS, cNOS, L-арпнш, супероксиддисмутаза, NF-kB-COX2, щури.
Стаття надшшла 24.05.2019 р.
появляются клетки с ультраструктурными признакам функционального напряжения, направленными на поддержку секреторной функции яичка. Центральная депривация синтеза тестостерона вызывает развитие оксидативного стресса в семенниках, снижает активность аргиназного пути метаболизма Ь-аргинина и меняет источник продукции N0 с конститутивных изоформ N0-синтазы на индуцибельную. Выявленные нарушения метаболической и функциональной активности этих клеток и приводят к нарушениям сперматогенеза.
Ключевые слова: семенники, интерстициальные эндокриноциты, сустентоциты, N0-синтаза, iN0S, cN0S, Ь-аргинин, супероксиддисмутаза, №-кБ-С0Х2, крысы.
Рецензент Гаврилюк А.О.
DOI 10.26724/2079-8334-2019-4-70-233-236
УДК 616.37-091.8-06:616.379-008.64-085.322:615.349.7
1.1. Фешсмко. С.М. Марчишим. К.С. Волков. О.П. Анфшиим. Н.1. Ярема Тершим, и.ськмп ншпома. iMiuii че.шчмим университет i\ieni 1.Я. I орбачевською МО{
УкраТмп. 1е|>ном1. ii.
ВПЛИВ Л1ОФ1Л1ЗОВАНОГО ЕКСТРАКТУ З ТРАВИ ХАМЕР1Ю ВУЗЬКОЛИСТОГО НА Г1СТОЛОГ1ЧНИЙ СТАН ПЕЧ1НКИ ЩУР1В ЗА УМОВ ГОСТРОГО ТОКСИЧНОГО
УРАЖЕННЯ ТЕТРАХЛОРМЕТАНОМ
e-mail: [email protected]
У дослiдах на бших щурах дослiджена гiстологiчна структура печшки за умов гострого токсичного ураження тсля введення екстракту хамерш та препарату порiвняння «Силiбiнiну». Виявлено, що дослiджуваний екстракт мае виразний захисний вплив на мкроскотчну будову печшки. Одержат морфолопчш данi засвщчили, що екстракт хамерiю суттево зменшуе пошкоджуючу дiю тетрахлорметану та сприяе активному вщновленню паренхiми печiнки, мае кращий позитивний ефект порiвняно з препаратом порiвняння «Силiбiнiн». Позитивний вплив дослщжуваного засобу проявляеться активацiею регенераторних процеЫв, що покращуе структурну оргашзащю печiнки тварин пiсля гострого токсичного ураження тетрахлорметаном.
Ключовi слова: гiстологiчне дослiдження, печiнка, експериментальний токсичний гепатит, тетрахлорметан, люфшзований екстракт трави xaMepiro.
Робота е фрагментом НДР «Фармакологiчнi та фармакогенетичш аспекты протекторного впливу iмунобiологiчних препаратiв, ентеросорбентiв, речовин природного та синтетичного походження за рiзних патологiчних статв», № державноi реестраци 0116U004148.
Печшка - один ¡з провщних оргашв регуляцп вуглеводного та лшщного обмшу, депо глшогену, мюце синтезу лшопроте!шв дуже низько! щшьносп. Близько 20 млн. х1м1чних реакцш щохвилини вщбуваеться в цьому оргаш [3]. Порушення обмшу речовин обов'язково пов'язаш з1 змшами структури i функцш печшки, тому пошук та дослщження засоб1в з гепатопротекторною активнютю е важливим завданням сучасно! експериментально! та клшчно! медицини [5]. Сьогодш одним ¡з джерел одержання препарат1в з гепатопоротекторною д1ею е лшарсью рослини. Вони мають ряд переваг перед синтетичними, тому що пор1вняно легко переносяться оргашзмом, не викликають ютотних поб1чних ефекпв нав1ть при тривалому !х застосуванш. Кр1м того, лшування рослинними засобами е бшьш доступним, що мае важливе значення при хрошчних захворюваннях.
Хамерш вузьколистий (Chamerion angustifolium L.) - рослина роду 1ван-чай (Chamerion), здавна використовуеться у народнш медициш для лшування мпреш, головного болю, безсоння, анемп, виразково! хвороби шлунка та дванадцятипало! кишки, гастриту, кол1ту, як протипухлинний i жовчогшний зас1б; зовшшньо - для лшування та швидшого загоювання ран та опшв [7]. З огляду на те, що люфшзований екстракт з трави хамер1ю (ЛЕТХ) мютить загальнов1дом1 за антиоксидантними властивостями фенольш сполуки (флавонощи, пдроксикоричш кислоти, дубильш речовини) [9], доцшьним було дослщити гепатопротекторну активнють даного засобу.
Метою роботи було вивчити коригуючий вплив ЛЕТХ на мшроскошчну будову паренх1ми печшки та пор1вняти його ефективнють i3 д1ею референс-препарату «Ситбшшу» за умов експериментального токсичного ураження печiнки.
© Г.1. Фещенко, С.М. Марчишин, 2019 233
