Bilateral varicocele leads to ferroptosis, pyroptosis and necroptosis of human spermatozoa and affects semen quality in infertile men

Sun, Tie; Li, Dong Mei; Yu, Haiyang; Song, Lijuan; Jia, Yan; Li, Lin; Zhou, Shan

doi:10.3389/fcell.2023.1091438

Cited by 12 publications

(5 citation statements)

References 45 publications

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“…The bilateral nature of varicoceles can be elucidated by examining the venous anastomotic channel connecting the left and right gonadal veins. [9,20]. Moreover, the lack of valves in the gonadal veins is seen as a contributing factor to varicocele being a bilateral condition.…”

Section: Resultsmentioning

confidence: 99%

Effectiveness of Bilateral Varicocelectomy on Male Infertility; a Case Series Study in Southern Iran

Eslahi,

Omidbakhsh

2024

Preprint

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Background and Objective: Varicocele is a common cause of male infertility. The impact of varicocele treatment on fertility has been a topic of debate. Bilateral varicocele has been identified as a significant factor in infertility, offering hope for positive treatment results. This study aimed to assess the effectiveness of bilateral varicocelectomy on male infertility. Methods: A prospective study was conducted from January 2020 to January 2023, involving infertile men with varicocele. Varicocele diagnosis was performed using Color Doppler ultrasonography, and the contralateral maximum vein diameter was measured using an intraoperative Doppler device. Sperm parameters were assessed 6 months post-surgery, with fertility outcomes evaluated 12 months post-surgery. Results: A total of 180 patients participated in the study. Among them, 55 individuals (30.55%) had unilateral varicocele, while 125 cases (69.44%) presented with bilateral varicocele. Intraoperative measurements revealed a bilateral varicocele prevalence of 93.88% (169/180). Patient follow-up showed significant improvements in sperm parameters at 3 and 6 months post-varicocele surgery, with 59 patients (32.77%) achieving successful pregnancies 12 months after the procedure. Conclusions: The significance of bilateral varicocele in infertile men is often underestimated. Bilateral varicocelectomy has shown substantial benefits for male fertility. Thorough evaluation by experienced radiologists and andrologists is crucial to avoid missing important pathological findings or adverse treatment outcomes.

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Section: Resultsmentioning

confidence: 99%

Effectiveness of Bilateral Varicocelectomy on Male Infertility; a Case Series Study in Southern Iran

Eslahi,

Omidbakhsh

2024

Preprint

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“…This suggests a complementary relationship between the different pathways causing ferroptosis. Besides this, bilateral varicocele causes ferroptosis of human spermatozoa and affects semen quality in males with infertility [ 60 ]. In the future, whether fertility males accompanying testis or sperm ferroptosis will be worth exploring.…”

Section: Discussionmentioning

confidence: 99%

Gss deficiency causes age-related fertility impairment via ROS-triggered ferroptosis in the testes of mice

Zhu,

Cheng,

Wang

et al. 2023

Cell Death Dis

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Glutathione synthetase (GSS) catalyzes the final step in the synthesis of glutathione (GSH), a well-established antioxidant. Research on the specific roles of the Gss gene during spermatogenesis remains limited due to the intricate structure of testis. In this study, we identified pachytene spermatocytes as the primary site of GSS expression and generated a mouse model with postnatal deletion of Gss using Stra8-Cre (S8) to investigate the role of GSS in germ cells. The impact of Gss knockout on reducing male fertility is age-dependent and caused by ferroptosis in the testis. The 2-month-old S8/Gss−/− male mice exhibited normal fertility, due to a compensatory increase in GPX4, which prevented the accumulation of ROS. With aging, there was a decline in GPX4 and an increase in ALOX15 levels observed in 8-month-old S8/Gss−/− mice, resulting in the accumulation of ROS, lipid peroxidation, and ultimately testicular ferroptosis. We found that testicular ferroptosis did not affect spermatogonia, but caused meiosis disruption and acrosome heterotopia. Then the resulting aberrant sperm showed lower concentration and abnormal morphology, leading to reduced fertility. Furthermore, these injuries could be functionally rescued by inhibiting ferroptosis through intraperitoneal injection of GSH or Fer-1. In summary, Gss in germ cells play a crucial role in the resistance to oxidative stress injury in aged mice. Our findings deepen the understanding of ferroptosis during spermatogenesis and suggest that inhibiting ferroptosis may be a potential strategy for the treatment of male infertility.

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“…15 Another study revealed that semen quality was reduced in bilateral varicocele and that activating RIPK1, RIPK3, and HSP 90 was effective. 27 A study it was shown that SnS2 nanoflowers increased the necroptosis-related RIPK1-RIPK3-MLKL signal in testicular tissue by inducing oxidative stress. 28 As in these studies, RIPK1 activation, which we detected in our study, may adversely affect sperm quality and number motility.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical investigation of the effects of different doses of some endocrine-disrupting chemicals on receptorinteracting serine/threonine-protein kinase 1 (RIPK1) levels in the testis

Tüfekci

2023

KMJ

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Aims: The reproductive toxicity of endocrine-disrupting chemicals (EDCs) is well known, but the underlying mechanism remains unclear. Receptor-interacting serine/threonine protein kinase 1 (RIPK1) mainly mediates cell death and inflammation. It is crucial to both necroptosis and apoptosis. Therefore, in this study, we aimed to investigate the changes in RIPK1 expression levels immunohistochemically in the adverse mechanism of EDCs on spermatogenic cells. Methods: Forty-two Wistar Albino male rats (10 weeks old, 250±50 g) were assigned into seven groups. Bisphenol A (BPA), 4-Nonylphenol (NP), and their mixtures at low 25 mg/kg doses and high 100 mg/kg doses were used. The control group received corn oil via gastric tube. At the end of the 21 days of the experimental protocol, the testis tissues were extracted and immersed in Bouin's solution. Five µm sections were taken from the tissue and stained immunohistochemically with an anti-RIPK1 antibody. Histo (H)-score was calculated by determining the intensity of immunoreactivity in the sections. Results: The results showed that the mixed dose group and all high-dose group round spermatids had excessive RIPK1 immunoreactivities compared to the control group and individually low-dose group of both (p<0.01). This result might be responsible for poor sperm quality, motility disruptions, or other reproductive consequences. Conclusion: In conclusion, RIPK1 overactivation may be essential in pathophysiological conditions caused by EDC exposure at high doses and their mixture. Further studies are now needed to evaluate RIPK1 overactivation in testis tissues.

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Bilateral varicocele leads to ferroptosis, pyroptosis and necroptosis of human spermatozoa and affects semen quality in infertile men

Cited by 12 publications

References 45 publications

Effectiveness of Bilateral Varicocelectomy on Male Infertility; a Case Series Study in Southern Iran

Effectiveness of Bilateral Varicocelectomy on Male Infertility; a Case Series Study in Southern Iran

Gss deficiency causes age-related fertility impairment via ROS-triggered ferroptosis in the testes of mice

Immunohistochemical investigation of the effects of different doses of some endocrine-disrupting chemicals on receptorinteracting serine/threonine-protein kinase 1 (RIPK1) levels in the testis

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