Pathological changes in Sertoli cells and dysregulation of divalent metal transporter 1 with iron responsive element in the testes of idiopathic azoospermia patients

Abstract

Iron is essential for rapidly dividing spermatocytes during normal mammalian spermatogenesis. Decreased transferrin and transferrin receptor levels were observed in seminal plasma from idiopathic azoospermia (IA) patients, suggesting disturbed iron metabolism in IA testes. However, how Sertoli cells (SCs) contribute to the iron homoeostasis in IA is still unclear. In this study, we analysed 30 IA and 30 age-matched obstructive azoospermia (OA) patients undergoing testicular sperm aspiration (TESA). SCs hyperplasia was indicated by higher SC density and Ki-67 labelling index in the IA TESA specimens. The attenuated expression of superoxide dismutase (SOD) suggested an impaired antioxidative capacity in IA testes. We further detected increased levels of iron importer divalent metal transporter 1 with iron responsive element (DMT1 + IRE) in IA testes, whereas the increasing trend of iron exporter ferroportin 1 (FPN1) was not statistically significant. Next, we demonstrated that iron regulatory protein 1 (IRP1) and hypoxia-inducible factor-1α (HIF-1α), which can potentially bind to the IRE and hypoxia-responsive element in the DMT1 + IRE mRNA, were both up-regulated in IA testes. Unexpectedly, HIF-2α was down-regulated in IA testes. These results indicate that there is a dysregulation of DMT1 + IRE in IA testes, which might due to the up-regulation of IRP1 and HIF-1α.

Effect of Wuzi Yanzong Pills on Sertoli cells and blood–testis barrier in heat‐stressed rats based on Akt signalling pathway

“…In the present study, we observed that WYP promoted SC viability in a dose‐dependent manner. Often, Ki67 is used to label SC proliferation (Jing et al., 2018), in the present study, the 43°C heat stress decreased Ki67 expression; conversely, WYP administration ameliorated the downregulation of Ki67 in SCs. Therefore, according to the result of this study, WYP enhanced SC viability and proliferation.…”

Effects of Ferroptosis on Male Reproduction

“…Iron oxide nanoparticles (NPs) are commonly utilized for biomedical applications and have been reported to easily pass through the BTB and enter the testis, causing iron accumulation and testicular tissue damage, thereby resulting in oxidative stress [71]. At the same time, decreased Tf and TfR levels have been observed in the seminal plasma from idiopathic azoospermia (IA) patients, which can also be attributed to the upregulation of IRP1 and HIF-1α, leading to dysregulation of DMT1+IRE in the IA testis [72]. The pituitary gland, on the other hand, is particularly sensitive to iron, and iron overload can also lead to severe impairment of the hypothalamus/pituitary/gonadal axis, thus causing hypogonadism and low testosterone levels [73].…”

Redox Homeostasis and Nrf2-Regulated Mechanisms Are Relevant to Male Infertility

“…It was recently observed that low sperm quality and sperm necrosis positively correlated with iron metabolism indices (ferritin, iron, transferrin evaluated in seminal plasma) in individuals with leukocytospermia and varicocele, both of which are characterized by the presence of inflammatory status and OS condition [53]. Altered iron metabolism is involved in ROS production [54][55][56][57] and drives chronic inflammation affecting male fertility [58,59]. Interestingly, several studies reported that ferroptosis, an iron-dependent programmed cell death, can affect spermatogenetic process leading to male infertility [60,61].…”