Funkcionalnost i obrazac signalnih puteva Lajdigovih ćelija odraslih pacova nakon primene anaboličkih androgenih steroida

Abstract

Lajdigove ćelije intersticijuma testisa su primarno mesto sinteze androgenih hormona, a dominantno testosterona (T). Ovaj hormon je zajedno sa svojim metabolitom dehidrotestosteronom (DHT) neophodan, kako za produženje vrste obezbeđivanjem pravilnog razvoja i funkcionisanja muškog reproduktivnog sistema, tako i za opšte zdravlje individue. U cilju tretiranja brojnih kliničkih poremećaja, kao i u svrhu kontracepcije, sintestisani su derivati androgena čija se primena u klinici zasniva na dejstvu koje ostvaruju posredstvom androgenih i/ili anaboličkih efekata, te su zajedničkim imenom nazvani anabolički androgeni steroidi (AAS). Nažalost, AAS se često zloupotrebljavaju, ne samo od strane profesionalnih i rekreativnih sportista, nego i velike populacije adolescenata, iako je dobro poznato da njihova upotreba u neterapeutske svrhe može izazvati niz neželjenih zdravstvenih posledica. Stoga su AAS svrstani u grupu farmakoloških preparata čija je upotreba strogo regulisana i nisu dostupni bez lekarskog recepta. Uprkos široko rasprostranjenoj kliničkoj upotrebi i zloupotrebi AAS, kao i velikom interesovanju naučne zajednice za ovu problematiku, nisu u potpunosti razjašnjeni molekulski događaji koji su posledica njihove kratkoročne i dugoročne primene. S obzirom na značaj T za reprodukciju i produženje vrste, ali i zdravlje i kvalitet života indivudue, kao i široku primenu i zloupotrebu T i njegovih derivata, neophodno je okarakterisati precizne molekulske događaje nastale kao posledica poremećene homeostaze T. Ovo je važno zbog toga što, prema trenutno dostupnoj literaturi, ne postoji dovoljan broj podataka o funkcionalnosti i obrascima signalnih puteva Lajdigovih ćelija, čija je osnovna uloga sinteza i sekrecija T. Stoga je glavni cilj ovog istraživanja bio da ispita funkcionalnost i obrasce signalnih puteva važnih za održavanje steroidogene funkcije Lajdigovih ćelija, narušene primenom egzogenih agonista i/ili antagonista T u in vivo ili in vitro uslovima. U tu svrhu primenjen je derivat T, testosteron-enantat (TE), koji se najčešće upotrebljava u kliničkoj praksi, ali se i u najvećoj meri zloupotrebljava i najprodavaniji je na tzv. “crnom” tj. ilegalnom tržištu. Ovakav model daje mehanistički pristup, ali ima i translacioni aspekt, s obzirom na to da su upotrebljavane doze/koncentracije T koje se koriste u kliničkoj praksi ili se zloupotrebljavaju. Rezultati su pokazali da in vivo aplikacija TE inhibira steroidogenu funkciju Lajdigovih ćelija odraslih pacova, kao i relativnu ekspresiju gena za komponente cAMP-PRKA signalizacije, kao glavnog regulatora steroidogeneze ovih ćelija...

Leydig cells of testis interstitium represent the major site for synthesis of androgenic hormone, primarily testosterone (T). This hormone, together with its metabolite dihydrotestosterone (DHT), is required, not only for the continuation of the species by ensuring proper development and functioning of male reproductive system, but for overall health of an individual as well. For the purpose of treatment of multiple clinical disorders, as well as for contraception purposes, androgen derivatives have been synthesized, the clinical application of which is based on the influence they have through anabolic and/or androgenic effects, thus having a common name anabolic androgenic steroids (AASs). Unfortunately, AASs are often abused, not only by professional and recreational athletes, but by a large population of adolescents as well, although it is well known that non-therapeutic use thereof may cause a series of adverse health effects. Therefore, AASs are classified into a group of pharmacological preparations, the use of which is strictly regulated and which are not available without a medical prescription. Despite widespread clinical use and abuse of AASs, as well as the great interest shown by the scientific community in this field, molecular events resulting from their short-term and long-term use have not been fully clarified. Given the importance of T for reproduction and continuation of the species, but also for health and quality of life of an individual, and the widespread use and abuse of T and its derivatives, it is necessary to characterize precise molecular events resulting from disturbed T homeostasis. This is important because, according to the currently available literature, there is insufficient data on the functionality and patterns of signaling pathways of Leydig cells, the basic role of which is the synthesis and secretion of T. Therefore, the main aim of this study is to examine the functionality and patterns of signaling pathways relevant for maintaining the steroidogenic function of Leydig cells, impaired by the use of exogenous T agonists and/or antagonists under in vivo or in vitro conditions. To this end, a T derivative known as testosterone-enanthate (TE) is applied, which is most commonly used in clinical practice, but is largely abused and best-selling product in the so-called "black" or illegal market. Such model provides a mechanistic approach, but has also a translational aspect, since the applied T doses/concentrations are used in clinical practice or are abused. The results have shown that in vivo application of TE inhibits the steroidogenic function of Leydig cells in adult rats, as well as gene expression for cAMP-PRKA signaling components, being the main regulator of steroidogenesis of such cells...