Mechanisms of Stress-Induced Spermatogenesis Impairment in Male Rats Following Unpredictable Chronic Mild Stress (uCMS)

Abstract

The negative association between psychological stress and male fertility has been known for many years. This study was aimed at (i) identifying spermatogenesis impairment induced by psychological stress in rats and (ii) exploring the role of glucocorticoid receptor (GR) signaling in these adverse effects (if they exist). Male Sprague Dawley rats were exposed to a six-week period of unpredictable chronic mild stress (uCMS) along with cotreatment of GR antagonist RU486 (1 mg/kg/day). Testicular damage was assessed by testicular pathological evaluation, epididymal sperm concentration, serum testosterone levels, testicular apoptotic cell measurements, and cell cycle progression analyses. Rats in the uCMS group had decreased levels of serum testosterone and decreased epididymal sperm concentration. The uCMS-treated rats also had decreased numbers of spermatids and increased levels of apoptotic seminiferous tubules; additionally, cell cycle progression of spermatogonia was arrested at the G0/G1 phase. Furthermore, uCMS exposure caused an increase in serum corticosterone level and activated GR signaling in the testes including upregulated GR expression. RU486 treatment suppressed GR signaling and alleviated the damaging effects of stress, resulting in an increased epididymal sperm concentration. Overall, this work demonstrated for the first time that the activation of GR signaling mediates stress-induced spermatogenesis impairment and that this outcome is related to cell apoptosis and cell cycle arrest in germ cells.

Reduced spermatozoa functionality during stress is the consequence of adrenergic-mediated disturbance of mitochondrial dynamics markers

“…Besides, secondary infertility was significantly higher in patients with posttraumatic stress disorder 56 . Our results showing the inhibitory role of stress hormones on sperm functionality are supported by the data presenting stress-induced-GRs-signaling-mediate spermatogenesis impairment 57 as well as reduced testosterone and sperm motility in high and moderate male runners 58 . Oppositely, in α1-ADRsknockout-male-mice 22 fertility and spermatogenesis are altered, suggesting the important and complex involvement of adrenergic signaling in spermatogenesis and fertility.…”

Decreased expression of AKAP4 and TyrPho proteins in testis, epididymis, and spermatozoa with low sexual performance of mice induced by modified CUMS

“…The CUMS is a stress model using animals to expose to different mild stressors to mimic the actual stress condition (Antoniuk et al., 2019). Indeed, the significant increase of corticosterone level in this study confirmed actual chronic stress, which was in agreement to others (Silvana & Tatjana, 2019; Zou et al., 2019). In addition, the testosterone level was significantly decreased after stress induction, implicating that CUMS interrupts steroidogenic machinery proteins such as StAR and CYP11A1 as previously described (Fahim et al., 2019; Sakr et al., 2015).…”

“…Moreover, Fahim and coworkers (2019) have also demonstrated the degenerative seminiferous epithelium such as necrotic spermatogenic cells and some tubules shown completely empty in CUMS rats. Similar to depressed patients, low sperm qualities were observed with increased serum corticosterone levels (Hirano et al., 2014; Zou et al., 2019). It has also been demonstrated the significantly lower expressions of testicular steroidogenic proteins such as cytochrome P450 side‐chain cleavage enzyme (P450scc) and steroidogenic acute regulatory (StAR) protein in CUMS rats corroborated with the decreased testosterone levels (Sakr et al., 2015).…”

“…Sixteen male mice were randomly separated into two groups including control (no CUMS) and CUMS groups ( n = 8/group). The induction of CUMS used in this study was modified from previous works (Chen et al., 2019; Hirano et al., 2014; López López et al., 2018; Zou et al., 2019). Briefly, animals in CUMS group were induced by a stressor randomly every day from different 12 stressors including (a) cold water forced swimming for 5 min, (b) immobilisation stress for 6 hr, (c) tail clamping for 1 min, (d) 45° cage tilting for 12 hr, (e) social isolation for 12 hr, (f) reversed light–dark cycle for 24 hr, (g) flashing light for 12 hr, (h) 95 dB noise for 6 hr, (i) wet bedding for 12 hr, (j) food deprivation for 12 hr, (k) water deprivation for 12 hr and (l) electric foot shock for 3 s (performed for 3 rounds).…”

MOTILIPERM Ameliorates Immobilization Stress-Induced Testicular Dysfunction via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway in SD Rats

“…In our day-to-day lives, stress has become an omnipresent phenomenon. Stress plays a key role in alterations in various physiological responses and can even lead to various diseases, including sub-fertility or infertility in men [10,11]. Stress has an adverse effect on endocrine function and the male reproductive system, including alterations in androgenic hormone levels, sperm maturation, and testicular function [12].…”