Cheng Zhao1, Savana Biondic2,3, Katherine Vandal2,3, Åsa K. Björklund4, Michael Hagemann-Jensen5, Theresa Maria Sommer6, Jesica Canizo2,3, Stephen Clark7,11, Pascal Raymond8, Daniel R. Zenklusen8, Nicolas Rivron6, Wolf Reik7,9,10,11 and Sophie Petropoulos1,2,3 1Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, 14186 Stockholm, Sweden; 2Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Axe Immunopathologie, H2X 0A9 Montréal, Canada; 3Département de Médecine, Université de Montréal, H3T 1J4 Montréal, Canada; 4Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, SE-752 37 Uppsala, Sweden; 5Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; 6Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria; 7Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom; 8Département de Biochimie et Médecine Moléculaire, Université de Montréal, H3T 1J4 Montréal, Canada; 9Wellcome Sanger Institute, Cambridge CB10 1RQ, United Kingdom; 10Center for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom

↵11 Present address: Altos Labs Cambridge Institute of Science, Cambridge CB21 6GP, UK

Corresponding author: sophie.petropouloski.se, sophie.petropoulosumontreal.ca Abstract

The preconceptual, 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 used 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 the 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 show that, despite no change in morphology and developmental features, preimplantation glucocorticoid exposure reprograms the molecular profile of the trophectoderm (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 sublineages, supported by the presence of extravillous trophoblast markers in the polar sublineage and presence of X Chromosome dosage compensation. Further, we have elucidated that epigenetic regulation—DNA methylation and microRNAs (miRNAs)—likely underlies 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.

Footnotes

[Supplemental material is available for this article.]

Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.276665.122.

Freely available online through the Genome Research Open Access option.

Received February 4, 2022. Accepted August 4, 2022.