Embryo manipulation via assisted reproductive technology and epigenetic asymmetry in mammalian early development

The early stage of mammalian development from fertilization to implantation is a period when global and differential changes in the epigenetic landscape occur in paternally and maternally derived genomes, respectively. The sperm and egg DNA methylation profiles are very different from each other, and just after fertilization, only the paternally derived genome is subjected to genome-wide hydroxylation of 5-methylcytosine, resulting in an epigenetic asymmetry in parentally derived genomes. Although most of these differences are not present by the blastocyst stage, presumably due to passive demethylation, the maintenance of genomic imprinting memory and X chromosome inactivation in this stage are of critical importance for post-implantation development. Zygotic gene activation from paternally or maternally derived genomes also starts around the two-cell stage, presumably in a different manner in each of them. It is during this period that embryo manipulation, including assisted reproductive technology, is normally performed; so it is critically important to determine whether embryo manipulation procedures increase developmental risks by disturbing subsequent gene expression during the embryonic and/or neonatal development stages. In this review, we discuss the effects of various embryo manipulation procedures applied at the fertilization stage in relation to the epigenetic asymmetry in pre-implantation development. In particular, we focus on the effects of intracytoplasmic sperm injection that can result in long-lasting transcriptome disturbances, at least in mice.