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A higher incidence of cleavage failure in oocytes containing smooth endoplasmic reticulum clusters.

ABSTRACT: PURPOSE:In human oocytes, sERCs are one of the dysmorphic phenotypes that have been reported. Significantly reduced pregnancy rates and a comparatively higher number of abnormities in live births appear to be associated with the presence of sERCs in oocytes. However, some reports have shown that healthy babies can be born, without any reduced pregnancy rates, from oocytes observed to contain sERCs. Thus, the clinical and scientific significance of oocytes that harbor sERCs remains controversial. METHODS:The presence of sERCs was evaluated using a time-lapse system while studying the dynamic changes within oocytes and embryos. Logistic regression analysis was carried out to explore the independent variables for meiotic and mitotic cleavage failure.. RESULTS:The incidence of mitotic cleavage failure and the incidence of meiotic cleavage failure during the second polar body extrusion in oocytes with sERCs were found to be significantly higher than that in oocytes without sERCs. Furthermore, ICSI was found to have a greater frequency of meiotic failure than IVF. CONCLUSIONS:In cases of cleavage failure, an embryonic cell could become tetraploid and may induce abnormal chromosomal configurations. Some cells exposed to cleavage failure may become trophectoderm cells and form placental abnormalities. Even if they develop into trophectoderm cells, the ICM can be susceptible to further cleavage failure and may in turn cause further aneuploidy. For these reasons, it is important to monitor pregnancies and births derived from oocytes that contained sERCs.

SUBMITTER: Otsuki J

PROVIDER: S-EPMC5984874 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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A higher incidence of cleavage failure in oocytes containing smooth endoplasmic reticulum clusters.

Otsuki Junko J Iwasaki T T Katada Y Y Tsutsumi Y Y Tsuji Y Y Furuhashi K K Kokeguchi S S Shiotani M M

Journal of assisted reproduction and genetics 20180122 5

<h4>Purpose</h4>In human oocytes, sERCs are one of the dysmorphic phenotypes that have been reported. Significantly reduced pregnancy rates and a comparatively higher number of abnormities in live births appear to be associated with the presence of sERCs in oocytes. However, some reports have shown that healthy babies can be born, without any reduced pregnancy rates, from oocytes observed to contain sERCs. Thus, the clinical and scientific significance of oocytes that harbor sERCs remains contro ...[more]

PMID: 29357025

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Project description:The oocytes presenting SERa are considered dysmorphic and have been associated with reduced embryological outcome and an increased risk of congenital anomalies. Therefore, in 2011 the Alpha/ESHRE Consensus strongly recommended not to inseminate MII oocytes displaying SERa (SERa+). Not all Centers follow this recommendation and some Authors reported that SERa+ can lead to healthy newborns. Moreover, no experimental data about the effect of SERa presence on the oocyte molecular status are available. To date the question whether or not SERa+ oocytes should be discarded as well as the opportunity to review or not the ESHRE consensus are still open for debate. This study included 28 women, < 38 years aged, without any ovarian pathology, undergoing IVF treatment. Supernumerary MII oocytes with no sign of morphological alterations and SERa+ oocytes were donated after written informed consent. A total of 31 oocytes without SERa (SERa-) and 24 SERa+ oocytes were analyzed. Pools of ≈10 oocytes for both group were prepared. Total RNA was extracted from each pool, amplified, labelled and hybridized on oligonucleotide microarrays. Analyses were performed by R software using the limma package. The expression profiles of SERa+ oocytes significantly differed from those of SERa- oocytes in 488 probe sets corresponding to 102 down-regulated and 283 up-regulated unique transcripts. Gene Ontology analysis by DAVID bioinformatics resource disclosed that three main biological processes were significantly down-regulated in SERa+ oocytes respect to SERa- oocytes: i) genes involved in cell and mitotic nuclear division, spindle assembly, chromosome partition and G2/M transition of mitotic cell cycle; ii) organization of cytoskeleton and microtubules; iii) mitochondrial structure and activity. Among the transcripts up-regulated in SERa+ oocytes, the most significantly (P= 0.002) enriched GO term was “GoLoco motif” including RAP1GAP, GPSM3, and GPSM1 genes. Data validation in a larger cohort of samples would be beneficial, although we applied stringent criteria for gene selection (fold-change >3 or <1/3 and FDR<0.1). Surveys on clinical outcomes, malformation rates, and follow-up of babies born after transfer of embryos from SERa+ oocytes are necessary. For the first time we provide information on molecular status of SERa+ oocytes, highlighting possible correlations among presence of SERa, altered oocyte physiology and reduced developmental competence. Based on our findings, we believe that it is far too early for an eventual revision of the 2011 Alpha/ESHRE Consensus on the issue and presence of SERa should be still a “red flag” in clinical IVF practices.

Project description:The endoplasmic reticulum (ER) is a multifunctional organelle in the cytoplasm that plays important roles in female mammalian reproduction. The endoplasmic reticulum and mitochondria interact to maintain the normal function of cells by maintaining intracellular calcium homeostasis. As proven by previous research, glycine (Gly) can regulate the intracellular free calcium concentration ([Ca2+]i) and enhance mitochondrial function to improve oocyte maturation in vitro. The effect of Gly on ER function during oocyte in vitro maturation (IVM) is not clear. In this study, we induced an ER stress model with thapsigargin (TG) to explore whether Gly can reverse the ER stress induced by TG treatment and whether it is associated with calcium regulation. The results showed that the addition of Gly could improve the decrease in the average cumulus diameter, the first polar body excretion rate caused by TG-induced ER stress, the cleavage rate and the blastocyst rate. Gly supplementation could reduce the ER stress induced by TG by significantly improving the ER levels and significantly downregulating the expression of genes related to ER stress (Xbp1, ATF4, and ATF6). Moreover, Gly also significantly alleviated the increase in reactive oxygen species (ROS) levels and the decrease in mitochondrial membrane potential (ΔΨ m) to improve mitochondrial function in porcine oocytes exposed to TG. Furthermore, Gly reduced the [Ca2+]i and mitochondrial Ca2+ ([Ca2+]m) levels and restored the ER Ca2+ ([Ca2+]ER) levels in TG-exposed porcine oocytes. Moreover, we found that the increase in [Ca2+]i may be caused by changes in the distribution and expression of inositol 1,4,5-triphosphate receptor (IP3R1) and voltage-dependent anion channel 1 (VDAC1), while Gly can restore the distribution and expression of IP3R1 and VDAC1 to normal levels. Apoptosis-related indexes (Caspase 3 activity and Annexin-V) and gene expression Bax, Cyto C, and Caspase 3) were significantly increased in the TG group, but they could be restored by adding Gly. Our results suggest that Gly can ameliorate ER stress and apoptosis in TG-exposed porcine oocytes and can further enhance the developmental potential of porcine oocytes in vitro.

Project description:Ca(2+) oscillations are a hallmark of mammalian fertilization and play a central role in the activation of development. The calcium required for these oscillations is primarily derived from the endoplasmic reticulum (ER), which accumulates in clusters at the microvillar subcortex during oocyte maturation. The migration of the ER to the cortex during maturation is thought to play an important role in rendering the ER competent to generate the calcium transients, and the redistribution of ER is believed to be primarily mediated by microtubules and microfilaments. We have previously shown that the oocyte- and early embryo-restricted maternal effect gene Mater (Nlrp5) localizes to, and is required for, formation of the oocyte cytoplasmic lattices, a tubulin-containing structure that appears to play an important role in organelle positioning and distribution during oocyte maturation. Given these observations, we hypothesized that Mater may also be required for ER redistribution and Ca(2+) homeostasis in oocytes. To test this hypothesis, we first investigated ER localization in metaphase-II Mater(tm/tm) (hypomorph) oocytes and found ER clusters to be less abundant at the microvillar cortex when compared to wild type oocytes. To examine the potential mechanisms by which MATER mediates ER redistribution, we tested whether tubulin expression levels and localization were affected in the mutant oocytes and found that the Triton-insoluble fraction of tubulin was significantly decreased in Mater(tm/tm) oocytes. To identify potential functional defects associated with these ER abnormalities, we next set out to investigate if the pattern of Ca(2+) oscillations was altered in Mater(tm/tm) oocytes after fertilization in vitro. Intriguingly, Ca(2+) oscillations in Mater(tm/tm) oocytes exhibited a significantly lower first peak amplitude and a higher frequency when compared to wild type oocytes. We then found that the Ca(2+) oscillation defect in Mater(tm/tm) oocytes was likely caused by a reduced amount of Ca(2+) in the ER stores. Taken together, these observations support the hypothesis that MATER is required for ER distribution and Ca(2+) homeostasis in oocytes, likely due to defects in lattice-mediated ER positioning and/or redistribution.

Project description:Accumulation of damaged or misfolded proteins resulted from oxidative protein modification induces endoplasmic reticulum (ER) stress by activating the pathways of unfolded protein response. In pathologic hemolytic conditions, extracellular free hemoglobin is submitted to rapid oxidation causing heme release. Resident cells of atherosclerotic lesions, after intraplaque hemorrhage, are exposed to heme leading to oxidative injury. Therefore, we raised the question whether heme can also provoke ER stress. Smooth muscle cells are one of the key players of atherogenesis; thus, human aortic smooth muscle cells (HAoSMCs) were selected as a model cell to reveal the possible link between heme and ER stress. Using immunoblotting, quantitative polymerase chain reaction and immunocytochemistry, we quantitated the markers of ER stress. These were: phosphorylated eIF2α, Activating transcription factor-4 (ATF4), DNA-damage-inducible transcript 3 (also known as C/EBP homology protein, termed CHOP), X-box binding protein-1 (XBP1), Activating transcription factor-6 (ATF6), GRP78 (glucose-regulated protein, 78kDa) and heme responsive genes heme oxygenase-1 and ferritin. In addition, immunohistochemistry was performed on human carotid artery specimens from patients who had undergone carotid endarterectomy. We demonstrate that heme increases the phosphorylation of eiF2α in HAoSMCs and the expression of ATF4. Heme also enhances the splicing of XBP1 and the proteolytic cleavage of ATF6. Consequently, there is up-regulation of target genes increasing both mRNA and protein levels of CHOP and GRP78. However, TGFβ and collagen type I decreased. When the heme binding proteins, alpha-1-microglobulin (A1M) and hemopexin (Hpx) are present in cell media, the ER stress provoked by heme is inhibited. ER stress pathways are also retarded by the antioxidant N-acetyl cysteine (NAC) indicating that reactive oxygen species are involved in heme-induced ER stress. Consistent with these findings, elevated expression of the ER stress marker GRP78 and CHOP were observed in smooth muscle cells of complicated lesions with hemorrhage compared to either atheromas or healthy arteries. In conclusion, heme triggers ER stress in a time- and dose-dependent manner in HAoSMCs. A1M and Hpx as well as NAC effectively hamper heme-induced ER stress, supporting their use as a potential therapeutic approach to reverse such a deleterious effects of heme toxicity.

Dataset Information

A higher incidence of cleavage failure in oocytes containing smooth endoplasmic reticulum clusters.

Publications

A higher incidence of cleavage failure in oocytes containing smooth endoplasmic reticulum clusters.

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