The Role of Endoplasmic Reticulum Stress Response in Male Reproductive Physiology and Pathology: A Review

Abstract

Endoplasmic reticulum (ER) stress, defined as prolonged disturbances in protein folding and accumulation of unfolded proteins in the ER. Perturbation of the ER, such as distribution of oxidative stress, iron imbalance, Ca 2+ leakage, protein overload, and hypoxia, can cause ER stress. The cell reacts to ER stress by activating protective pathways, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed for maintaining cellular homeostasis or, in case of excessively severe stress, at the initiation of cellular apoptosis. The three UPR signaling pathways from the ER stress sensors are initiated by activating transcription factor 6, inositol requiring enzyme 1, and protein kinase RNA-activated-like ER kinase. A number of physiological and pathological conditions, environmental toxicants and variety of pharmacological agents showed disruption of proper ER functions and thereby cause ER stress in male reproductive organ in rat model. The present review summarizes the existing data concerning the molecular and biological mechanism of ER stress in male reproduction and male infertility. ER stress initiated cell death pathway has been related to several diseases, including hypoxia, heath disease, diabetes, and Parkinson's disease. Although there is not enough evidence to prove the relationship between ER stress and male infertility in human, most studies in this review found that ER stress was correlated with male reproduction and infertility in animal models. The ER stress could be novel signaling pathway of regulating male reproductive cellular apoptosis. Infertility might be a result of disturbing the ER stress response during the process of male reproduction. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Effect of Schisandra chinensis Baillon on Cross-Talk between Oxidative Stress, Endoplasmic Reticulum Stress, and Mitochondrial Signaling Pathway in Testes of Varicocele-Induced SD Rat

“…We performed Western blot analysis to check ER stress protein markers for inositol requiring enzyme 1 (IRE1)-C-jun-N-terminal kinase (JNK) pathway in testicular tissues. Excessive ER stress can induce cellular apoptosis through three signaling pathways (ATF6, IRE1, and PERK) [23]. The IRE1-JNK pathway was analyzed to determine VC-induced testicular germ cell apoptosis (Figure 4A,C,D).…”

“…ER stress activation could be key signaling mechanism for germ cell apoptosis [23,42]. A previous study has reported that the ER chaperone Grp 78 is predominately present in pachytene spermatocytes, suggesting that the ER stress signaling pathway has a vital role in the process of spermatogenesis [43].…”

Inhibition of NADPH oxidase alleviates germ cell apoptosis and ER stress during testicular ischemia reperfusion injury

“…To our knowledge, this is the first study to prove the activation of ER-stress mediated apoptosis due to NOX-induced OS following tIRI. The involvement of ER stress-induced apoptosis of both male and female reproductive cells and different diseases has been reported and reviewed in several studies ( Liu et al, 2016 , Karna et al, 2019 ). It was also reported that cadmium-induced GCA resulted from mitochondrial cytochrome-c release, upregulation of GRP67 and CHOP and phosphorylation of eIF2α and JNK in testes ( Ji et al, 2011 ).…”

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

“…Antioxidant enzymes scavenge free radicals and prevent oxidative damage by enhancing cellular defenses [37]. ROS can cause extensive damage to DNA, proteins, and lipids in germ cells [38,39]. Our results show that MOTILIPERM decreases the levels of ROS/RNS and MDA and increases levels of the antioxidant enzymes SOD, GPx, catalase, and GPx 4.…”