Unraveling the mysteries of early embryonic arrest: genetic factors and molecular mechanisms

Abstract

Early embryonic arrest (EEA) is a critical impediment in assisted reproductive technology (ART), affecting 40% of infertile patients by halting the development of early embryos from the zygote to blastocyst stage, resulting in a lack of viable embryos for successful pregnancy. Despite its prevalence, the molecular mechanism underlying EEA remains elusive. This review synthesizes the latest research on the genetic and molecular factors contributing to EEA, with a focus on maternal, paternal, and embryonic factors. Maternal factors such as irregularities in follicular development and endometrial environment, along with mutations in genes like NLRP5, PADI6, KPNA7, IGF2, and TUBB8, have been implicated in EEA. Specifically, PATL2 mutations are hypothesized to disrupt the maternal-zygotic transition, impairing embryo development. Paternal contributions to EEA are linked to chromosomal variations, epigenetic modifications, and mutations in genes such as CFAP69, ACTL7A, and M1AP, which interfere with sperm development and lead to infertility. Aneuploidy may disrupt spindle assembly checkpoints and pathways including Wnt, MAPK, and Hippo signaling, thereby contributing to EEA. Additionally, key genes involved in embryonic genome activation-such as ZSCAN4, DUXB, DUXA, NANOGNB, DPPA4, GATA6, ARGFX, RBP7, and KLF5-alongside functional disruptions in epigenetic modifications, mitochondrial DNA, and small non-coding RNAs, play critical roles in the onset of EEA. This review provides a comprehensive understanding of the genetic and molecular underpinnings of EEA, offering a theoretical foundation for the diagnosis and potential therapeutic strategies aimed at improving pregnancy outcomes.

Keywords: Early embryonic arrest; Embryonic genome activation; Epigenetics; Mitochondrial DNA; Small non-coding RNA.

Fig. 1

Genetic factors affecting oocyte maturation and early embryonic development. This diagram depicts the genetic factors related to EEA that affect the process of oocyte maturation and early embryonic development. The factors that affect egg development include genes such as TUBB8, Mei1, and PATL2, while the factors that affect endometrium and implantation include genes such as HOXA11, PKM1, and PKM2. It is worth noting that these pathogenic genes play a role in all stages of oocyte and early embryonic development, and extend beyond the aforementioned early embryonic development stages

Fig. 2

Embryonic factors associated with EEA during embryonic development. Early embryos in mitosis undergo key events such as embryonic genome activation, mitotic checkpoints, epigenetic modifications, and mtDNA expression. The relevant factors that play a role in these events are indicated by orange, blue, green, and yellow respectively. The transformation of gene expression patterns from oocytes to early embryos, known as the material to zygotic transition, is the first key event in early embryonic development. The large amount of maternal mRNA accumulated in human oocytes undergoes degradation in two waves during the mother to zygote transition, namely M-decay and Z-decay. The transformation factor TPRXL plays a role in M-decay, while TPRX1 and TPRX2 play a role in Z-decay and activate related genes such as ZSCAN4, DUXB, and DPPA4 in embryonic development. In mitotic checkpoint events, the spindle checkpoint is activated by MCC, and NFP2 activates the Hippo pathway. In epigenetic modification events, the interaction between CFP1 and ZFP296 proteins and regulatory factors causes differential methylation of gDMRs in the control region, thereby regulating the expression of imprinted genes. MtDNA affects mitochondrial metabolic activity by affecting the expression of mitochondrial genes