Autophagy may play an important role in varicocele

Abstract

The present study aimed to determine the expression of autophagy and investigate whether the hypoxia-inducible factor 1α (HIF-1α)/BCL2 interacting protein (BNIP3)/Beclin-1 autophagy signaling pathway serves an important role in activating autophagy in varicocele (VC) rat testes cells. Furthermore, the current study aimed to explain the possible association between autophagy and apoptosis. A total of 48 adult male Sprague Dawley rats were divided into group A (control), group B (VC 15-day), group C (VC 30-day) and group D (VC 45-day), with 12 rats in each group. The rats in group A did not receive any interventions, and in groups B, C, and D the VC model was established simultaneously. At 0, 15, 30, and 45 days, an orchidectomy on the left testes was performed in groups A-D, each on its respective day. Transmission electron microscopy was used to investigate the expression of autophagy. Compared with groups A and B, it was demonstrated that the expression of autophagy in groups C, and D was significantly increased. Hematoxylin and eosin staining revealed that as the rats survived VC longer, the testicular tissue damage became more serious. Furthermore, the Johnson score revealed that VC impaired the spermeiogenesis function of the male rats. Additionally, it was demonstrated that the apoptosis index of the seminiferous epithelia cells in VC rat testes increased over time, as measured using TUNEL staining. Immunohistochemical analysis revealed that as the VC was prolonged, the expression of HIF-1α gradually increased while the expression of (apoptosis regulator Bcl-2) Bcl-2 gradually decreased. Furthermore, western blot analysis revealed that the protein expression of Bcl-2 decreased and apoptosis regulator Bax increased. Furthermore, HIF-1α, BNIP3, Beclin1 and microtubule associated protein 1 light chain 3 α (LC3)II/LC3I expression gradually increased. However, significant increases in Beclin 1 and LC3II/LC3I were only observed between the day 0 and day 30 groups. In addition, the expression of p62 significantly increased between day 0 and day 15, but gradually decreased between day 15 and day 45. The results of the present study revealed that VC can lead to testicular tissue hypoxia, and that the HIF-1α/BNIP3/Beclin1 autophagy signaling pathway may upregulate autophagy in VC rats testes. Thus, the association between autophagy and apoptosis may serve an important role in male infertility caused by VC.

Signs of ROS-Associated Autophagy in Testis and Sperm in a Rat Model of Varicocele

“…In accordance with earlier studies [18,31], we show here that the induction of VCL in rat results in reduction of testis weight and testicular volume that have been related to loss of germ cells by apoptosis because of the highly sensitive nature of spermatogenesis to hyperthermia [27]. Indeed, previous reports showed that varicocele activates apoptosis in seminiferous epithelial cells leading to Sertoli-mediated phagocytosis of apoptotic germ cells [21,22,32,33]. The induction of VCL in the present rat model was also accompanied by testicular histopathological defects including reduced germinal epithelium, increased basement membrane thickness, increased interstitial blood vessels, and acidophilic material leading to spermatogenesis disruption as well as poor sperm count and quality as described elsewhere [22,24,34].…”

“…Indeed, previous reports showed that varicocele activates apoptosis in seminiferous epithelial cells leading to Sertoli-mediated phagocytosis of apoptotic germ cells [21,22,32,33]. The induction of VCL in the present rat model was also accompanied by testicular histopathological defects including reduced germinal epithelium, increased basement membrane thickness, increased interstitial blood vessels, and acidophilic material leading to spermatogenesis disruption as well as poor sperm count and quality as described elsewhere [22,24,34].…”

“…Since oxidative stress, heat stress, and hypoxia are the main factors involved not only in the pathophysiology of varicocele [20] but also in the induction of autophagy [21,22], we have sought to understand the relationship between autophagy and varicocele. The aim of this study was to create an experimental model of varicocele in rats to highlight the role of autophagy in VCL testicular tissue and sperm.…”

Melatonin Relations with Energy Metabolism as Possibly Involved in Fatal Mountain Road Traffic Accidents

“…2020). Experimental VC upregulates HIF-1α/BNIP3/Beclin1 autophagy-signaling pathway in testicular tissue, revealing a condition potentially promoting male infertility [203]. Repair of experimental VC, on the other hand, reverts the presence of HIF-1α in rat testis [204].…”

Does varicocelectomy improve semen in men with azoospermia and clinically palpable varicocele?

“…Pathophysiologically, theories explaining the role of varicocele in azoospermia include increased temperature, adrenal hormone and gonadotoxic metabolite refluxes, changed testicular blood flow, development of antisperm antibody, altered hypothalamic–pituitary–gonadal axis and oxidative stress (Dohle et al, ; Esteves et al, ; Hendin, Kolettis, Sharma, Thomas, & Agarwal, ; Inci & Gunay, ; Jensen et al, ; Pasqualotto, Sharma, Nelson, Thomas, & Agarwal, ; Zorgniotti & Macleod, ). These influence the sperm's physiology, reproductive potential and fertilising capacity of the haploid male gamete (Sofikitis et al, ) due to germ cell apoptosis, increased intratesticular cadmium, reduced levels of androgens (Benoff & Gilbert, ; Simsek, Türkeri, Cevik, Bircan, & Akdaş, ; Zhu et al, ) and damage of DNA and proteins in the nucleus of spermatozoa, seminiferous tubule and/or Leydig cells (Esteves et al, ; Fujisawa, Yoshida, Kojima, & Kamidono, ; Gorelick & Goldstein, ).…”