27-hydroxycholesterol impairs placental development via p53/p21/Cdk6 pathway: Implications for nutrient transport and cellular senescence

Aberrant placental development and function contribute to various pregnancy complications. 27-hydroxycholesterol (27-OHC), a recognized mediator linking hypercholesterolemia and metabolic diseases, has an undefined role in placental development. This study investigates the impact of 27-OHC on placental development and its underlying mechanisms, particularly in relation to cellular senescence. Pregnant mice were subcutaneously administered either 27-OHC (27-OHC group) or normal saline (control group) during gestation. Subsequently, placentas underwent spatial transcriptome (ST) sequencing. The levels of genes and proteins related to nutrient transport, cell cycle and senescence associated secretory phenotype were validated. Additionally, BeWo cells were treated with 27-OHC at concentrations of 2.5, 5 and 10 μM during its differentiation and fusion to observe the effects and mechanisms of trophoblast cell senescence. In the 27-OHC group, the labyrinth zone area and combined fetal-placental weight were significantly reduced compared to the control group. ST analysis revealed alterations in placental cell composition and downregulation of nutrient transport processes, alongside pathways linked to senescence, including the p53/p21/Cdk6 pathway, specifically in Syncytiotrophoblast Type I (SynT I) cells. In both mouse placentas and BeWo cells, mRNA and protein levels of p53 and p21 were reduced in the 27-OHC group compared to controls. During late pregnancy, 27-OHC inhibits the physiological senescence of placental syncytiotrophoblasts and may affect nutrient transport within the placenta. The inhibition of the p53/p21/Cdk6 pathway may represent one of the key mechanisms involved.