Pre-implantation embryos

Growth at the level of the organism is an increase in cell number, cell mass, extracellular mass, fluid content and other components of the body that result in an increase of body mass. The mammalian body has very different growth phases with different functions. The pre-implantation embryo does not grow, but only divides, fuelled by materials that were deposited in the egg before fertilization. After implantation there is very rapid cell division which is tightly coupled to cell differentiation in the process of gastrulation — the creation of the different lineages... 

Actually ESC, obtained from the embryoblast of pre-implantation embryos of mammals ... 

Treatment starts when the embryo is attached to the uterine wall and has completed the first stages of implantation. Therefore, pre-implantation development should be unaffected by the test substance. However, even in controls, not all fertilized oocytes develop to the hatched blastocyst stage. A loss of up to two preimplantation embryos per female can be considered a normal finding in rats and rabbits. In studies where exposure begins at or before fertilization a dose-dependent increase in the number of females that show larger differences between corpora lutea and implantation sites may indicate toxicity to pre-implantation embryos or the process of implantation itself. 

Cuthbertson KS, Whittingham DG, Cobbold PH 1981 Free Ca2+ increases in exponential phases during mouse oocyte activation. Nature 294 754—757 Day ML, Johnson MH, Cook DI 1998 A cytoplasmic cell cycle controls the activity of a K+ channel in pre-implantation mouse embryos. EMBO J 17 1952—1960 Flach G, Johnson MH, Braude PR, Taylor RA, Bolton VN 1982 The transition from maternal to embryonic control in the 2-cell mouse embryo. EMBO J 1 681-686 Howlett SK 1986 A set of proteins showing cell cycle-dependent modification in the early mouse embryo. Cell 45 387-396... 

Embryonic stem cells are derived from pre-implant-stage human embryos, usually at the blastocyst stage (the blastocyst is a thin-walled hollow structure containing a cluster of cells, known as the inner cell mass, from which the embryo arises). These embryos are invariably ones initially generated as part of in vitro fertilization procedures but which are destined to be discarded, either due to poor quality or because they are in excess to requirement. There are an estimated 400 000 in vitro fertilization-produced embryos in frozen storage in the USA alone, of which some 2.8 per cent are likely to be discarded. 

The aim of the study, often called fertility study , is to assess adverse effects of the test compound on maturation of gametes, mating behavior, fertility, preimplantation stages of the embryo and implantation. Adverse effects can be detected at the estrus cycle, tubal transport, implantation, and development of the pre-implantation stages of the embryo. In males, functional effects on libido and epididymal sperm maturation may be detected which cannot be observed by histological examination of the male reproductive organs. 

The hES cells were shown to fulfill aU the criteria defining embryonic stem cells [28, 29], namely derivation from the pre-or peri-implantation embryo, prolonged undifferentiated proliferation under special conditions, and the capacity to form deri-... 

During pre-implantation mammalian embryos undergo a series of divisions to generate a blastocyst competent for implantation. Within this context maternal factors regulate the plan of divisions by unevenly distribution of cytoplasm. In addition with several key transcriptional factors the different cell lineages, inner cell mass, the trophoblast and the primitive endoderm are probably generated by this mechanism (for review see Rossant 2004). 

Van der Putten et al. (14) and Rubenstein et al. (10) have infected pre-implantation mouse embryos with recombinant replication-incompetent retrovirus without the use of helper virus. 197 denuded 8-cell stages cultivated over psi-2 monolayers for 16 hours and subsequently transferred to foster mothers gave rise to one animal which had incorporated the recombinant provirus including the foreign gene and transmitted it to its offspring (14). Rubenstein et al. (10) co-cultivated 278 4-cell-stage mouse embryos over psi-2 cells and obtained 76 (30%) live fetuses after transfer, of which one contained the recombinant provirus. 

Iyer, R., Lehnert, B.E., Svensson, R., 2000. Factors underlying the cell growth-related bystander responses to a-particles. Cancer Res. 60,1290-1298. Jacquet, R, 2012. Developmental defects and genomic instability after x-irradia-tion of wild type and genetically modified mouse pre-implantation and early post-implantation embryos. J. Radiat. Prot. 32 (4), R13-R36. 

Wrenzycki, C., D. Herrmann, L. Keskintepe et al. 2001. Effects of culture system and protein supplementation on mRNA expression in pre-implantation bovine embryos. Hum Reprod 16(5) 893-901. 

Reproductive and developmental toxicology studies, with information on rangefinding studies and supportive TK evaluations, are to be ordered by nonpivotal studies and pivotal studies, which include fertility and early embryonic development to implantation, effects on embryo-fetal development, effects on pre- and postnatal development including maternal function. If conducted, studies in which juvenile animals are dosed and evaluated are to be included in this section. 

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