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

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.

BPA induces placental trophoblast proliferation inhibition and fetal growth restriction by inhibiting the expression of SRB1.

Bisphenol-A (BPA) is a common environmental toxicant that is known to be associated with fetal growth restriction (FGR). However, the mechanisms of how BPA induce FGR is poorly characterized. We conducted proteomics to identify the abnormal expression of SRB1 in female placental tissues with high BPA-induced FGR and further verified its decreased expression in human placenta and BeWo cells. Next, the effect of BPA on fetal development was further confirmed in pregnant C57BL/6 mice. The expression of SRB1 was consistently downregulated in human FGR placentas, BPA-exposed trophoblasts and mouse placentas. In addition, we found that SRB1 interacted with PCNA, and BPA exposure indirectly reduced the expression of PCNA and further inhibited placental proliferation. In vitro studies showed that BPA exposure reduced the expression of CDK1, CDK2, cyclin B and phosphorylated Rb in placental trophoblast cells, indicating cell cycle arrest after exposure to BPA. In addition, the expression of γ-H2AX and phosphorylated ATM was upregulated in BPA-exposed trophoblasts, indicating increased DNA damage. Our results indicate that BPA-induced FGR is achieved by reducing the expression of SRB1, inhibiting placental proliferation and increasing DNA damage. Our findings not only explain the mechanism of BPA-associated developmental toxicity but also shed light upon developing novel therapeutic targets.