Endoplasmic Reticulum Stress in Reproductive Function
LIU Kang-sheng1, ZENG Yu1, ZHENG Hang-peng2, CHEN Ya-jun1,*
1. Department of Clinical Laboratory, State key Laboratory of Reproductive Medicine, Nanjing Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, 210029, China
2. School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 210029, China
*Corresponding Author: CHEN Ya-jun, E-mail: fycheyajun201601@163.com

Normal folding requires that unique conditions should be maintained within the endoplasmic reticulum (ER) lumen, and nascent proteins are initially bound to Ca2+ dependent chaperone proteins. Proteins synthesized in the ER are properly folded with the assistance of ER chaperones. misfolded proteins are disposed by ER-associated protein degradation. Accumulation of misfolded proteins in the ER triggers an adaptive ER stress response, which leads to activation of the unfolded protein response (UPR), a conserved pathway that transmits signals to restore homeostasis or eliminate the irreparably damaged cells. It has been shown that ER stress involves in pathophysiological development of many diseases, including neurological diseases. However, nowadays, a few studies have begun to focus on the possibility that the accumulation of misfolded proteins can also contribute to reproductive diseases. In this article, we mainly introduced the involvement of ER stress response in preimplantation embryos, placental development, intrauterine growth restriction (IUGR) and testicular germ cells so as to provide important insights for the molecular mechanisms of ER stress-induced apoptosis in reproductive diseases.

Key words: Endoplasmic reticulum stress Unfolded protein response Preimplantation embryos Placenta; Intrauterine growth restriction Testicular germ cells

Endoplasmic reticulum (ER) is the site of protein synthesis, protein folding, maintainance of calcium homeostasis, synthesis of lipids and sterols. Genetic or environmental insults can alter its function inducing ER stress. During ERS, protein misfolding and accumulation in the ER lumen initiate unfolded protein response(UPR) through a series of signal transduction pathways that produce various effects, including enhancing the ability of proteins to fold properly, accelerating protein degradation, increasing the probability of cell survival, and strengthening the selfrepair ability of the ER[1, 2]. The disruption of ER functions by depletion of ER Ca2+stores, inhibition of asparagine (N)-linked protein glycosylation, disturbance of disulfide bond formation, or viral infection, leads to protein misfolding and subsequent protein aggregation. Over the last few years, it has become clear that accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as well as other age-related illnesses[1]. In a large part, the protein misfolding takes place during synthesis on free ribosomes in the cytoplasm or on ER ribosomes.

In fact, even under optimal conditions, approximately 30% of all newly synthesized proteins are rapidly degraded, which may be related to improper folding. Accordingly, stresses that perturb the protein folding during or soon after synthesis can lead to the accumulation of misfolded proteins and to potential cellular dysfunction and pathological consequences. To avert such outcomes, cells have developed elaborate protein quality-control systems for detecting misfolded proteins and for making appropriate adjustments to the machinery responsible for protein synthesis and/or degradation. For experimental purposes, chemicals such as thapsigargin (which depletes Ca2+ from ER), tunicamycin (which inhibits protein N-linked glycosylation), and dithiothreitol (which disrupts protein disulfide bonds) are used to induce ER stress in cultured cells or animals. There are three distinct signaling pathways that are triggered in response to ER stress, initiated by protein kinase activated by double-stranded RNA (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1). IRE1 has at least two different actions. Firstly, , the endoribonuclease activity of IRE1 cleaves X binding protein-1 (XBP-1) mRNA, converting it into a potent transcriptional activator that, in turn, induces gene expression of proteins involved in protein degradation [3, 4]. Secondly, IRE1 links ER stress to the activation of JNK signaling pathways. Specifically, it binds to tumor necrosis factor receptor-associated factor 2 (TRAF2) and couples ER stress to activation of c-Jun N-terminal kinase (JNK) through the kinase activity [5]. The activation of JNK by ER stress requires the presence of apoptosis signal regulating kinase 1 (ASK1) [6, 7]. Therefore, it has been proposed that ER stress induces the formation of IRE1-TRAF2 complex that leads to ASK1-JNK activation[7]. ER stress response is involved in several physiological and pathological processes, including inflammation[8], immune response[9, 10], and RNA viruses[5] in the pathogenesis of nonalcoholic fatty liver disease [11]. In recent years, ER stress is reported to involve in reproductive diseases. Wang et al. [12] found that ASK1 may mediate the teratogenicity of diabetes through activating the JNK1/2-ER stress pathway and inhibiting cell cycle progression, thereby impeding the cardiogenesis pathways essential for ventricular separation and outflow tract development. In addition, ER stress response pathways can also cause increase secretion of pro-inflammatory cytokines that are known to promote labour. Veerbeek et al. [13] believed that gene expression or other data obtained from placentas exposed to labour may be subjected to stress-induced protein synthesis inhibition and other downstream consequences of ER stress. In this article, we mainly introduced the involvement of ER stress response in preimplantation embryos, placental development, intrauterine growth restriction (IUGR) and testicular germ cells so as to provide important insights for the molecular mechanisms of ER stress-induced apoptosis in reproductive diseases.

Figure 1 ER Stress and UPR Signaling Pathway
ER: Endoplasmic reticulum; IRE1α : Inositol-requiring enzyme 1α ; UPR: Unfolded protein response; XBP-1: X binding protein; PERK: Protein kinase RNA-like ER kinase; GRP78: Glucose-regulated protein 78; Tun: Tunicamycin; GADD153: Growth-arrest and DNA damage-inducible gene153; CHOP: CCAAT-enhancer-binding protein homologous protein; ERSE: Endoplasmic reticulum stress element; ASK1: Apoptosis signal-regulating kinase 1; eIF-2alpha: Eukaryotic translation initiation factor 2; IP3: Inositol 1, 4, 5-trisphosphat; ERO1e: Endoplasmic retivulum oxidoreductin 1; TMEM214: Transmembrane protein 214; GADD34: cofactor of eIF2-phosphatase; H1299: Human lung cancer cells; SH-SY5Y: human neuroblastoma cell

Involvement of ER Stress Response in Preimplantation Embryos and Placenta Function

ER stress involved in granulose cell apoptosis is during goat follicular atresia. Epidermal growth factor (EGF) down regulates the expression of ATF4, ATF6 and CCAAT-enhancer-binding protein homologous protein (CHOP) mRNA, which inhibits goat granulose cell apoptosis by ER stress. The increased ER stress in decidual tissue of pregnancy has been shown to be implicated in fetal growth restriction (FGR) and without preeclampsia [14]. Sustained ER stress acts as a cofactor of oxidative stress in decidual cells from patients with early pregnancy loss [15]. In decidual cells, excessive oxidative stress influences UPR pathways to activate endoplasmic reticulum-associated degradation (ERAD) by decreasing valosin containing protein, which is a type II ER-associated protein and a member of the AAA(+)/ATPase family that facilitates delivery of misfolded proteins to the proteasome, resulting in cell damage, inhibition of cell growth, and activation of apoptosis [16]. The results of Abarham et al. [17] indicated that the major ER stress pathway constituents are present at all stages of preimplantation development and that the activation of ER stress pathways can be induced at the 8-cell, morula and blastocyst stage. Luo et al. [18]discovered that the Grp78 promoter was activated in both trophectoderm and inner cell mass (ICM) of embryos at embryonic day 3.5 through a mechanism requiring the ER stress elements, and mouse embryonic fibroblasts from Grp78+/- mice could respond to ER stress, but Grp78-/- embryos that were completely devoid of GRP78 resulted in peri-implantation lethality. These embryos did not hatch from the zona pellucida in vitro, failed to grow in culture, and manifested proliferation defects and a massive increase in apoptosis in the ICM, which was the precursor of embryonic stem cells. IRE1á or XBP1 null mice were unable to produce functional placentas, which was lethal to the embryo, indicating that the IRE1á arm of the UPR coping response is essential for placental development and embryonic viability [18]. Furthermore, ER stress-induced coping responses in the maternal decidua and placenta might counteract developmental problems during implantation and post-implantation development. All these findings provide the first evidence that GRP78 is essential for embryonic cell growth and pluripotent cell survival.

The study of Wong et al. [19] provides the first-hand data to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing a novel insight into the mechanisms underlying nicotine exposure during pregnancy on placental health. Maternal exposure to cadmium leads to activation of PERK, phosphorylation of placental eIF2α and increase in CHOP, indicating that UPR signaling is activated in the placenta due to cadmium-induced toxicity [20]. Among UPR constituents, p-eIF2α , GRP94, and CHOP are increased in the placenta from IUGR and preeclampsia, suggesting that ER stress responses are also inducible under diseased conditions[21]. Therefore, it can be concluded that ER stress is mediated in placental development, but the placenta function is impaired by both loss of ER stress response and excessive ER stress [22].

Involvement of ER Stress Response in IUGR

IUGR, defined as failure of a fetus to reach its genetic growth potential, is caused by impaired placental development, frequently related to maternal malperfusion. In recent years, ER stress has been identified as a major regulator of cell homeostasis through its involvement in post-translational protein modifications and folding, and its capacity to activate the UPR[23]. When ER function is severely impaired, apoptosis is induced to eliminate damaged cells. Yung et al. [21]found that low-grade ER stress was present in IUGR and IUGR complicated by preeclampsia by both ultrastructural and molecular analysis, providing a potential mechanism for eukaryotic initiation factor 2alpha phosphorylation. Ishihara et al. [24]discussed whether IUGR and PE were associated with an increase in placental apoptosis, and found that in severe IUGR and PE placentas, decreased expression of Bcl-2 protein in syncytiotrophoblasts may lead to the increase of apoptosis in syncytiotrophoblasts in those placentas. By examining whether the shedding of syncytiotrophoblast microparticles (STBM) in normotensive IUGR occurs to the same extent as in PE, Goswami et al. [25] proposed that increased STBM levels were found in early-onset PE, but not in normotensive IUGR, which provides further evidence for their role in the pathogenesis of the maternal syndrome. Lø set et al. [26] performed a whole-genome transcriptional profi ling of decidual tissue from preeclamptic and normal pregnancies, and found that several transcripts involved in ER stress were up regulated in PE. Thus, it is likely to be concluded that ER stress is involved in the pathogenesis of both PE and IUGR, but whether the degree of ER stress differs between these pregnancy complications is unknown.

In trophoblast-like cell lines, increased levels of pEIF2a are associated with reduced proliferation through suppression of protein synthesis and decreased survival, and the net effect of reduced proliferation and cell survival is proposed as a cause for decreased placental growth in pregnancies with FGR and PE+FGR, which is characterized by decreased placental villous tissue volume and surface area [17]. Lian et al.[14] observed that the pEIF2a/EIF2a ratio was negatively correlated with placental weight ratio, with a similar tendency for ATF6, suggesting an association between ATF6 and PERK-pEIF2a signaling and reduced placental weight. Iwawaki et al. [22] reported that the function of a molecule involved in ER stress, inositol requiring protein 1α in the placenta was essential for placental development and embryonic viability and that ER stress and IRE1α might be involved in other physiological phenomena. The genetic deficiency of UPR transducers has been found to result in prenatal mortality and developmental abnormality. PERK knockout mice showed postnatal growth retardation and permanent neonatal diabetes, whereas ATF6 knockout mice manifested embryonic lethality[16, 27]. Exposure to ER stress may result in increased fetal growth retardation, teratogeny, and preterm delivery, although the critical window and underlying molecular mechanisms are unclear. In fact, exposure to heavy metals results in various effects, including ER stress, oxidative stress, teratogenicity, and apoptosis [21]. The decidua basalis plays a basic role in the separation of the placenta during labor. ER stress induced by oxidative stress may be involved in the development of early pregnancy loss with impairment of decidua function[28].As mentioned above, increased ER stress in decidual tissue is involved in FGR and FGR+PE. Hence, it will be important to elucidate the relationship between alteration of decidua function and late pregnancy in future studies.

Interestingly, passive cigarette smoke during pregnancy, which is reported to induce an ER stress response, increases the mean relative area of spongiotrophoblast cells in the placenta and causes IUGR with a reduction in placental blood flow [29]. Kawakami et al. [30] further examined the formation of a cluster of spongiotrophoblast cells in the labyrinth zone of the placenta of Tun-treated mice, and found that the glycogen content of fetal liver and placenta from Tun-treated mice was lower than that from control mice; Tun treatment decreased mRNA expression of Slc2a1/glucose transporter 1 (GLUT1), which was a major transporter for glucose, but increased placental Mrna levels of Slc2a3/GLUT3. Moreover, Riddle et al. [31]found that IUGR increased circulating and adipose TNF-α , increased mRNA levels of UPR components as well as p-eIF2a, and impaired glucose tolerance after TNF-α increase and UPR activation, which suggested that programmed dysregulation of TNF-α and UPR contributed to the development of glucose intolerance in IUGR rats. All these results suggest that excessive and exogenous ER stress may induce functional abnormalities in the placenta, at least in part, with altered GLUT and vascular-related gene expression, resulting in low infant birth weight. Compared with Caesarean-delivered controls localized mainly in the syncytiotrophoblast, the levels of ER stress markers (GRP78, P-eIF2a and XBP-1) were significantly higher in labored placentas [13]. Wang et al.[32]investigated whether lead-induced placental apoptosis and subsequent toxicity was initiated by ER apoptosis via caspase-12, and discovered that lead exposure contributes to placental apoptosis, as well as increased caspase-12 mRNA expression, which in turn promotes ER stress.

Involvement of ER Stress Response in Testicular Germ Cells

Redox relays in oxidative protein folding in the ER sustentacular cells, such as sertoli cells and Leydig cells, produces many humoral factors that support spermatogenesis. The ER is the place where nascent proteins are synthesized and subjected to proteolytic cleavage, oxidative folding by disulfide bonds and addition of sugar chains [33]. Dysfunction of the UPR system leads to defects in the secretion of humoral factors that are essential for spermatogenesis. ER stress down-regulates essential humoral factors and may impair sperm morphogenesis [34]. The receptor molecules for hydrophilic humoral factors are localized in the plasma membrane with the largest portion exposed to the surface of the target cell. A proper alignment of the ligands and receptors is essential for their interaction. In the processes involving either protein secretion from cells or membrane localization, a significant portion of nascent proteins is misfolded in the ER, and the accumulation induces the UPR in the cells. However, when the misfolded proteins are too much to handle under extreme situations, cell death is induced. Both extrinsic causes, such as toxicants, and intrinsic causes, such as ischemia and heat, induce UPR and may ultimately induce spermatogenic cell death. So do ROS signaling and oxidative protein folding in the ER, as well as unique phenomenon to the spermatogenic process, such as the sulfoxidation of protamines during sperm maturation [35, 36]. The insect male accessory gland (AG) is a secretary tissue involved in male fertility. The AG secretes many seminal fluid proteins (SFPs) essential for male reproduction [37]. Kim JH et al. [38] found that the 3β -HSD expression was decreased by heat-stress and hCG treatment. While the GRP78/BiP and CHOP levels were increased by ER-stress inducers, those of the steroidogenic enzyme and progesterone were decreased. In contrast, an ER-stress inhibitor rescued the testosterone levels, even under heat-stress conditions. Moreover, the Leydig cells were randomly scattered, and severely damaged upon repetitive testicular heat-treatment. Additionally, immunohistochemical analyses revealed that cleaved caspase-3 was elevated in the testicular Leydig cells, and rescued by TUDCA. The repetitive testicular heat-treatment in mice promotes excessive ER-stress, thereby leading to apoptosis of the Leydig cells and thus, decreased testosterone production.

In recent years, Zhang et al. [39]reported that fluoride treatment increased MDA accumulation, decreased SOD activity, and enhanced germ cell apoptosis. Fluoride elevated mRNA and protein levels of GRP78, IRE1, and CHOP, indicating activation of ER stress signaling. Furthermore, fluoride also induced testicular inflammation, as manifested by gene up-regulation of tumor necrosis factor-α (TNF-α ), interleukin-1β (IL-1β ), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in a nuclear factor-κ B (NF-κ B)-dependent manner. These were associated with marked histopathological lesions including injury of spermatogonia, decrease of spermatocytes and absence of elongated spermatids, as well as severe ultrastructural abnormalities in testes. Another study made by Li et al.[40]showed that the apoptosis of testicular germ cells was increased in hyperlipidemic rats, which may be attributed to ER stress.


ER, one of the major organelles of eukaryotic cells, is an important place of protein folding and modification. ER stress can be caused by various physiological and pathological factors when ER homeostasis is broken. In the presence of ER stress, the data in the following are important for a better understanding of the regulatory mechanisms of mammalian reproduction.(1) The major ER stress pathway constituents are present at all stages of preimplantation and placenta development; (2) The reproductive toxicants (lead and fluoride) exposure can significantly cause eIF-2alpha and JNK phosphorylation in testes. Meanwhile, the article also provides a theoretical reference to reveal the mechanism of early embryonic development stagnation, abortion and abnormal placenta treatment.

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