The pre-conceptual, intrauterine, and early life environments can have a profound and long-lasting impact on the developmental trajectories and health outcomes of the offspring. Given the relatively low success rates of Assisted Reproductive Technologies (ART; ~25%), additives and adjuvants, such as glucocorticoids, are utilized to improve the success rate. Considering the dynamic developmental events that occur during this window, these exposures may alter blastocyst formation at a molecular level, and as such, affect not only the viability of the embryo and ability of the blastocyst to implant, but also the developmental trajectory of the first three cell lineages, ultimately influencing the physiology of the embryo. In this study we present a comprehensive single-cell transcriptome, methylome and small RNA atlas in the day 7 human embryo. We demonstrate that, despite no change in morphology and developmental features, preimplantation glucocorticoid exposure reprograms the molecular profile of the TE lineage and these changes are associated with an altered metabolic and inflammatory response. Our data also suggest that glucocorticoids can precociously mature the TE sub-lineages, supported by the presence of extravillous trophoblast markers in the polar sub-lineage and presence of X Chromosome dosage compensation. Further, we have elucidated that epigenetic regulation (DNA methylation and microRNAs (miRNAs)) likely underlie the transcriptional changes observed. This study suggests that exposures to exogenous compounds during preimplantation may unintentionally reprogram the human embryo, possibly leading to suboptimal development and longer-term health outcomes.
Preimplantation development is arguably one of the most critical stages of embryogenesis. Beginning with the formation of the totipotent zygote post-fertilization, a series of cell divisions and a complex coordination of physical cues, molecular mechanisms and changes in gene expression lead to the formation of the blastocyst, a structure capable of implanting into the uterine wall. The blastocyst is comprised of more specified cellular lineages, that will give rise to every tissue of the developing organism as well as the extra-embryonic lineages which support fetal growth. While the mouse has been used as a model to understand the events of preimplantation development for decades, in recent years an expanding body of work has been conducted using the human embryo. These studies have identified some crucial species differences, particularly in the transcriptional and spatio-temporal regulation of lineage markers and responses to cell signaling perturbations. In this review, recent findings pertaining to the processes of preimplantation development, with an emphasis on specification of the first cellular lineages, in the mouse and human are compared side-by-side. Highlighting differences and noting mechanisms that require further examination in the human embryo is of critical importance for both the accurate translation of results from the mouse model and our overall understanding of mammalian development. We further highlight and critique the latest advancement in Reproductive research, the development of the 3D stem cell-based models known as ‘blastoids’. This knowledge has major clinical implications for assisted reproductive technologies such as in vitro fertilization and for applications in stem cell biology.
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