Experimental Varicocele Induces p53-Dependent Germ Cell Apoptosis through Activation of γ-H2AX

Chang, In Youb; Kim, Jin-Ho; Park, Kyeong-Han; Yoon, Sang‐Pil

doi:10.1159/000316356

Cited by 13 publications

(7 citation statements)

References 54 publications

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“…However, this is also a decompensated progress, in which the production of ROS in vivo is beyond the cell antioxidant ability. The intracellular ROS accumulation may damage the protein, DNA and lipid, leading to the impairment of cell functions (Chang et al ., ,b). Carmeliet found that the inducing apoptosis protein p53 would increase in the protecting progress under hypoxia environment.…”

Section: Discussionmentioning

confidence: 99%

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Testicular hypofunction caused by activating p53 expression induced by reactive oxygen species in varicocele rats

et al. 2015

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We investigated the mechanism of the testicular hypofunction induced by hypoxia in varicocele rats. Varicocele was induced by partial ligation of the left renal vein. Seven weeks later, left testis mass index was measured. The sperm counts and motility were tested by CASA. The change of seminiferous tubule tissue was observed by HE staining. The reactive oxygen species (ROS) level in left testicular tissue was measured by ELISA, and the expressions of HIF-1α and p53 were detected by immunohistochemistry and Western blot. The left testis mass index and the sperm motility were significantly lower in surgery group. By HE staining, the left seminiferous epithelial cell arrangement was incompact, disordered and vacuolated in surgery group. The ROS level in surgery group was significantly higher than the other groups. The results of immunohistochemistry and Western blot indicated that the expressions of HIF-1α and p53 increased significantly in surgery group. Our study demonstrated that varicocele caused hypoxia that could cause the rise of ROS level to induce the increase of p53 expression, leading to the decrease of testis mass index and changes of seminiferous tubules, which would reduce sperm motility and result in male infertility eventually.

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Section: Discussionmentioning

confidence: 99%

“…The tumour suppressor protein p53 (p53), first found in tumour tissues, can regulate the cell cycle as a kind of apoptosis‐inducing protein. Excessive expression of p53 will induce apoptosis (Semenza & Wang, ; Kaluzova et al ., ; Chang et al ., ,b; Li et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Testicular hypofunction caused by activating p53 expression induced by reactive oxygen species in varicocele rats

et al. 2015

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“…p53, a master gene in apoptosis and a target of p38 MAPK (Figure 2), is activated in rats with experimental varicocele [156]. In fact, the proapoptotic gene Bax, which is a transcriptional target of p53, is upregulated in experimental varicocele in animal models [47, 157–159]. In addition, the downregulation of Bcl-2 and increased expression of caspase-9 and activated caspase-3 in the ipsilateral testis at eight and 12 weeks after the onset of varicocele has been documented, indicating gradually increased testicular tissue apoptosis through the intrinsic pathway [158].…”

Section: Local Hypoxia: Varicocele and Testicular Torsionmentioning

confidence: 99%

The Hypoxic Testicle: Physiology and Pathophysiology

Reyes

Farías

Henríquez-Olavarrieta

et al. 2012

Oxidative Medicine and Cellular Longevity

183

133

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Mammalian spermatogenesis is a complex biological process occurring in the seminiferous tubules in the testis. This process represents a delicate balance between cell proliferation, differentiation, and apoptosis. In most mammals, the testicles are kept in the scrotum 2 to 7°C below body core temperature, and the spermatogenic process proceeds with a blood and oxygen supply that is fairly independent of changes in other vascular beds in the body. Despite this apparently well-controlled local environment, pathologies such as varicocele or testicular torsion and environmental exposure to low oxygen (hypoxia) can result in changes in blood flow, nutrients, and oxygen supply along with an increased local temperature that may induce adverse effects on Leydig cell function and spermatogenesis. These conditions may lead to male subfertility or infertility. Our literature analyses and our own results suggest that conditions such as germ cell apoptosis and DNA damage are common features in hypoxia and varicocele and testicular torsion. Furthermore, oxidative damage seems to be present in these conditions during the initiation stages of germ cell damage and apoptosis. Other mechanisms like membrane-bound metalloproteinases and phospholipase A2 activation could also be part of the pathophysiological consequences of testicular hypoxia.

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“…Nuclear factor‐kappa B (NF‐κB), a key regulator of the inflammatory gene, was reported to be involved in varicocele‐induced testicular dysfunction (Tuğcu et al, ). The study in an experimental rat varicocele model implied that P53 mediated apoptosis through activation of γ‐H2AX (Chang, Kim, Park, & Yoon, ). However, the studies in varicocele above mainly focused on known apoptosis‐related proteins, and a comprehensive investigation is still necessary to clarify the mechanism of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

14‐3‐3 epsilon plays an important role in testicular germ cell apoptosis: A functional proteomic study of experimental varicocele

Liu

et al. 2019

Andrologia

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The latest perspective indicates that apoptotic dysregulation is an important mechanism in male infertility induced by varicocele. To elucidate the molecular mechanism of apoptosis caused by varicocele, we used proteomics (2D-MALDI-TOF MS) to identify the altered proteins in the testes of experimental varicocele rats compared with the control. Here, 21 significantly different protein spots were detected by proteomics technology. 14-3-3 epsilon (14-3-3ε) was our subsequent research target because of its function in apoptosis. The expression of 14-3-3ε in rat testes was confirmed by Western blot and immunohistochemistry, and the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method was used to analyse the apoptosis of germ cells. GC-1 spg cells transfected with small interfering RNA were used to confirm the function of 14-3-3ε in vitro. 14-3-3ε protein expression decreased, accompanied by a higher apoptosis index in rat testes of the varicocele group. Furthermore, 14-3-3ε siRNA-treated GC-1 spg cells caused the upregulation of the apoptotic rate detected by flow cytometry. The expression of Bax and Bcl-2 was found to be regulated by 14-3-3ε in vitro. Our investigation demonstrated the pro-apoptotic function of the downregulation of 14-3-3ε, which may play an important role in germ cell apoptosis induced by varicocele.

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Experimental Varicocele Induces p53-Dependent Germ Cell Apoptosis through Activation of γ-H2AX

Cited by 13 publications

References 54 publications

Testicular hypofunction caused by activating p53 expression induced by reactive oxygen species in varicocele rats

Testicular hypofunction caused by activating p53 expression induced by reactive oxygen species in varicocele rats

The Hypoxic Testicle: Physiology and Pathophysiology

14‐3‐3 epsilon plays an important role in testicular germ cell apoptosis: A functional proteomic study of experimental varicocele

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