Events That Surround Early Embryo Demise - Article Example

Events that Surround Early Embryo Demise The incidence of human aneuploidy is high and ranges from approximately 50% to 80% (Chavez et al., 1). This has raised interest among experts whose aim is to elucidate some of the key pathways that normal human embryos undergo and more importantly develop an in-depth understanding of factors that contribute to arrest of the normal development of human embryos into the blastocyst stage. With the advent of invitro fertilization technology, initial phases of embryonic development can easily be studied to create a better understanding of the subject matter (Magli et al. 534). During the period that precedes implantation, embryos undergo a series of developmental events that include the initial mitotic divisions, the activation of the genome of embryos, the compaction and cavitation of embryos that lead to the formation of the blastocyst. Several parameters have been used to predict with certainty the failure ot success of human embryos to develop into blastocysts. These parameters include the duration of the first cytokenesis, the time it takes to develop from the two to three cell stage, and sychronicity in appearance of the last two blastomeres, that is, the third and fourth blastomeres. Human embryos may fail to reach the blastocyst stage due to a number of reasons. Some of the reasons that have been cited include early cleavage events, abnormalities in chromosomes, and paternal influences among others. Early events that occur approximately 1 to 2 days after fertilization predict with high certainty the likelihood of an embryo to develop up to the blastocyst stage. During this crucial period, the main events noted are mitosis and cytokinesis. Abnormalities noted include cleavage abnormalities during the first to fourth mitotic events and delays in the beginning of the first phase of cytokinesis. According to Chavez et al (1), early cleavage parameters, specifically P1, P2, and P3 could predict with high certainty the probability of forming an embryo developing into a blastocyst. The authors further noted that the findings of their study indicated that embryos which had P2 durations that were characteristically shorter, were closely associated with errors during the mitotic phase, and were likely to experience mosaicism (Dupont et al. 2547) and aneuploidy. These findings were replicated by Burrel and colleagues (7) who conducted a study to investigate whether oxidative damage to a fertilizing sperm could affect early development events of an embryo. The findings of the study indicated that those embryos which had a P2 duration of more than an hour, had significantly higher chances of reaching the blastocyst stage by around day 7. The study further established that those embryos that had a P3 duration of less than an hour had significantly higher chances of developing abnormal cleavages. The most common types of abnormal cleavage noted is types 1 and type 3 that arrested the development of the embryo. Wong and colleagues (Burrel et al. 7) noted that embryos that were outside the range of p1, P2, and P3 had irregular and abnormal patterns of ribonucleic acids necessary for cytokinesis, abnormal reserves for maternal mRNA and abnormal miRNA biogenesis. Studies have indicated that by around day 6, the embryo must have developed into a blastocyst. However, Chavez et al (2) conducted a study whose findings indicated that slow growth by an embryo and concurrent slow development are closely associated with abnormal blastocyst development and that this could be an indication of abnormalities within the chromosomes. Chavez and colleagues (9) further noted that those embryos that had normal chromosomes had very strict and tightly clustered parameters of the cell cycle. Those embryos that had abnormal chromosomes had diverse parameters that in some cases overlap with those of euploid embryos and in some cases may not necessarily overlap with those of euploid embryos. Cellular fragmentation, formation of embryonic micronuclei, and resorption result from human mosaicism and embryonic aneuploidy of chromosomal content between blastomeres. Chromosomal instability and human embryo aneuploidy are closely related due to chromosomal losses and gains that are seen specifically in embryos that have mitotic errors. In humans, 10 to 30 percent of occoytes carry chromosomal abnormalities that contribute to errors in the highly conserved meotic pathway. Errors in the meiotic pathway often result in abnormalities in the pre-implantation stage of the embryo. Abnormalities in human oocyte chromosomes eventually give rise to approximately 33 percent of spontaneous human abortions which are aneuploid. Chromosomal abnormalities are incompatible with viability (Magli et al. 539; Jones et al. 1784). Embryos that cleave slowly have been found to have a high incidence of chromosomal abnormalities and more importantly contribute significantly to abnormalities in the development of embryos into blastocysts. The findings of a recent study indicated that there is a tight correlation between the development of an embryo and the status of a chromosome. The implication of this finding is that the condition of the nucleus, and how normal it is, affects the timing of the division. That is, in slow dividing embryos, the number of chromosomal abnormalities and subsequent abnormalities in the development of the embryo into the blastocyst is highest. Embryos that grow slowly could be of poor quality and have reduced chances of developing into blastocysts regardless of how normal their pattern of cleavage is. However, in mnay cases, normal cleavage patterns give rise to normal blastocysts. The chromosomal abnormities are seen as or represented by multinucleation and mosaicism. Further still, multinucleation and mosaicism result in increased fragmentation and a delay in timing of cleavage (Magli et al. 539). It is worth noting that, when the rate of cleavage is accelerated, the chromosomal patterns that are seen are similar to those that are seen in slow cleaving embryos. Embryos that present with more than 9 blastomeres 62 hours after insemination have an equal chance of having abnormal chromosomes like in embryos that cleave slowly. These findings indicate that timing is a critical component of embryonic development. Deviations from this timing have negative effects on the embryo development and implantation. Genetic disorders and aneuploides have been cited as factors that can result in deviation from the timings. In a study to determine morphokinetic parameters that are specific to embryos that had the capacity to implant, the investigators found out that there is an optimal range of time for those parameters that are characteristics of early embryonic development. The study found out that those embryos that cleaved at intermediate time points had significantly higher chances of developing into blastocysts when compared to those embryos that cleaved either faster or slower (Meseguer et al. 2668; Cantos et al. 474). Further still the study established that early cleavage is a good indicator of competence to develop (Somfai et al. 200). The duration of the 2nd cell cycle as well and the synchrony between the second and the third cell divisions are important predictors and indicators of future possibility of embryos to implant. Timing of cleavage up to the 6th cell is a good predictor of the embryo’s ability to implant. Later cell division events can be used to discriminate between those embryos that can implant and those that cannot implant. Embryos that cannot implant have been closely associated with abnormalities during their cleavage and development into blastocysts (Meseguer et al. 2668). Additionally, the timing of events that occurs following the 5 cell stage could be an indication of the viability of the embryo and an indication on whether the embryo shall reach the blastocyst stage. In close association to timing is synchrony of events that precede and follow fertilization. The viability of the oocyte is dependent on the synchronized maturation of the nucleus and cytoplasm. The cytoplasm and nucleus must mature in synchrony to pave way for meiosis, fertilization and cleavage. In order for normal cleavage to occur, the axes of symmetry ought to be right, the distribution of maternal proteins and transcripts to the developing blastomeres is dependent on the planes of successive cell divisions. Additionally, the differentiation of blastomeres is dependent on the presence and the concentration of maternal proteins and transcripts. Any disturbances in the synchrony of these events of cell division would contribute to the abnormalities in the development of the embryo (Magli et al. 539). The incidence of chromosomal abnormality varies with the cellular stage of development. Chromosomal abnormalities are higher in presence of scattered fragmentation in embryos with 7 to 8 cells. Embryos that have good morphology still have a high abnormality rate and would not develop into blastocysts. The length of the cell cycle would influence the ability of an embryo to develop into a blastocyst. There is a strong correlation between early cleavage and developmental competence. A number of genes are involved in controlling the timing of the first cell cycle such as the Ped gene. The gene regulates the timing of the first cleavage and growth of the embryo before implantation. The timing of the second cycle of cell division is an important indicator of the embryos potential to grow into blastocyst. Thos embryos that had normal cleavage patterns had high chances of developing into blastocysts. Embryos that have unequal blasotmeres have reduced chances of developing into mature blastocysts. The growth of such embryos was arrested before the embryo could pass the third cell division cycle. The number of cells that an embryo has is an indication of its viability and potential to develop into a mature blactocyst. Depending on the stage of cell division in which an embryo is, the higher number of cells it has than the optimum the lower its chances of reaching the blastocysts stage. Similarly, depending on the stage of cell division in which a cell is, the fewer the number of cells below the optimum, the lower the odds of the embryo developing into a blastocyst notes Somfai et al. (6). The findings of Somfai and his colleagues are in agreement with findings by Magil and colleagues. According to Burruel et al (5), when sperms are exposed to high oxidative stress levels, their developmental potential of the embryos they fertilize is compromised. Some of explanations offered for this observation include damage to the sperm DNA, the lipid peroxidation of membraneous organelles such as mitochondria, damage of the centrosome by oxidation, and the possibility that oxidized sperms may carry ROS into the cytoplasm of the oocyte at the point of the interaction. Specifically, oxidized sperms give result in arrest in mitotic activity of the cell division cycle, fragmentation of the blastomere, and apoptosis that is associated with poor quality embryos. ROS impairs the development of embryos. According to recent study, when embryos are cultured under atmospheric oxygen tensions, there is increased ROS production that impairs the development and growth of the embryo into a blastocyst (Guerin et al. 175; Kitagawa et al. 1186). Nuclear abnormalities are common in embryos and contribute to embryo development arrest. The nuclear abnormalities include anucleate, binucleate, and multinucleate blastomeres. Binucleate nucleus are believed to arise from a failed process of cytokenesis (Chatzimeletiou et al 677; Hardy et al. 549). Spindle abnormalities have been observed that can impair the development of an embryo into a blastocyst. A commonly observed spindle abnormalities include spindles that have abnormal shape. Abnormally shaped spindles are poorly organized and lack poles that are well defined. One or more chromosomes may separate from the spindle due to a lag in anaphase or a failure in congression. Multipolar spindles and loss of chromosomes lead to chromosomal malsegregation. This may account for postzygotic chromosomal mosaicism. However what remains unclear is whether observed postzygomatic chromosomal and nuclear arrests are the product of developmental arrest or are the cause of developmental arrest (Chatzimeletiou et al 680). The need to understand embryo development and the surrounding events that may impair the development of an embryo into a blastocyst is on the increase. With the advent of invitro fertilization, it is now possible to develop an in-depth understanding of the pathways that normal human embryos undergo and more importantly develop an understanding of factors that contribute to arrest of the normal development of human embryos into the blastocyst stage. Several factors have been cited as to be contributing factors to the arrest of development of the human embryo during the pre-implantation period. Some of the factors include abnormalities in chromosomes, problems with the timing and synchrony of the events that occur during cell devision, improper maturation of oocytes, and oxidized sperms, and abnormalities of the mitotic spindle. Chromosomal abnormalities have been cited as the most common cause of developmental abnormalities of the embryo pre-implantation. Slow or fast embryo cleavage rates have also been associated with abnormalities in embryo development pre-implantation. Deviations from the events of the cell division cycle have also been found to contribute to arrest of the embryo development process. Oxidized sperms carry ROS into the cytoplasm of the ovum at the time of fertilization. ROS impairs the embryo development process pre-implantation. Nuclear abnormalities are common in embryos and contribute to embryo development arrest. The nuclear abnormalities include anucleate, binucleate, and multinucleate blastomeres. Binucleate nucleuses are believed to arise from a failed process of cytokenesis. Spindle abnormalities have been observed that can impair the development of an embryo into a blastocyst. Abnormally shaped spindles are poorly organized and lack poles that are well defined. With more studies being conducted, methods to address these problems can be developed and implemented. Works Cited Burruel, V., K. L. Klooster, J. Chitwood, P. J. Ross, and S. A. Meyers. "Oxidative Damage to Rhesus Macaque Spermatozoa Results in Mitotic Arrest and Transcript Abundance Changes in Early Embryos." Biology of Reproduction 89.3 (2013): 72. Print. http://www.ncbi.nlm.nih.gov/pubmed/23904511 Burruel, V., Klooster, K., Barker, C., Reneer, R., and Meyers, S. “Early embryo demise: Sperm oxidative stress and early abnormal cleavage.” Scientific Reports 2014 4: 6598. Print http://www.nature.com/srep/2014/141013/srep06598/full/srep06598.html Canto, Mariabeatrice Dal, Giovanni Coticchio, Mario Mignini Renzini, Elena De Ponti, Paola Vittoria Novara, Fausta Brambillasca, Ruggero Comi, and Rubens Fadini. "Cleavage Kinetics Analysis of Human Embryos Predicts Development to Blastocyst and Implantation." Reproductive BioMedicine Online 25.5: 474-80. Print. http://www.ncbi.nlm.nih.gov/pubmed/22995750 Chatzimeletiou, K. "Spindle Abnormalities in Normally Developing and Arrested Human Preimplantation Embryos in Vitro Identified by Confocal Laser Scanning Microscopy." Human Reproduction 20.3 (2005): 672-82. Print http://www.ncbi.nlm.nih.gov/pubmed/15689349 Chavez, Shawn L., Kevin E. Loewke, Jinnuo Han, Farshid Moussavi, Pere Colls, Santiago Munne, Barry Behr, and Renee A. Reijo Pera. "Dynamic Blastomere Behaviour Reflects Human Embryo Ploidy by the Four-cell Stage." Nature Communications 3 (2012): 1251. 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Print http://www.ncbi.nlm.nih.gov/pubmed/8410824 Kitagawa Y, Suzuki K, Yoneda A, Watanabe T. Effects of oxygen concentration and antioxidants on the in vitro developmental ability, production of reactive oxygen species (ROS), and DNA fragmentation in porcine embryos. Theriogenology 2004; 62:1186– 1197. Print. http://www.ncbi.nlm.nih.gov/pubmed/15325546 Magli, M. Cristina, Luca Gianaroli, Anna Pia Ferraretti, Michela Lappi, Alessandra Ruberti, and Valeria Farfalli. "Embryo Morphology and Development Are Dependent on the Chromosomal Complement." Fertility and Sterility 87 (2007): 534-41. Print. http://www.ncbi.nlm.nih.gov/pubmed/17123520 Meseguer, M., J. Herrero, A. Tejera, K. M. Hilligsoe, N. B. Ramsing, and J. Remohi. "The Use of Morphokinetics as a Predictor of Embryo Implantation." Human Reproduction 26.10 (2011): 2658-671. Print. http://www.ncbi.nlm.nih.gov/pubmed/21828117 Somfai, Tamás, Yasushi Inaba, Yoshio Aikawa, Masaki Ohtake, Shuji Kobayashi, Kazuyuki Konishi, and Kei Imai. "Relationship Between the Length of Cell Cycles, Cleavage Pattern and Developmental Competence in Bovine Embryos Generated by In Vitro Fertilization or Parthenogenesis." Journal of Reproduction and Development 56.2: 200- 07. Print. http://www.ncbi.nlm.nih.gov/pubmed/20035110 Read More