Auvinen Pauliina, Vehviläinen Jussi, Rämö Karita, Laukkanen Ida, Marjonen-Lindblad Heidi, Wallén Essi, Söderström-Anttila Viveca, Kahila Hanna, Hydén-Granskog Christel, Tuuri Timo, Tiitinen Aila, Kaminen-Ahola Nina
Environmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
The Family Federation of Finland, Fertility Clinic and University of Helsinki, Helsinki, Finland.
Commun Med (Lond). 2024 Dec 19;4(1):267. doi: 10.1038/s43856-024-00694-6.
Assisted reproductive technology (ART) has been associated with increased risks for growth disturbance, disrupted imprinting as well as cardiovascular and metabolic disorders. However, the molecular mechanisms and whether they are a result of the ART procedures or the underlying subfertility are unknown.
We performed genome-wide DNA methylation (EPIC Illumina microarrays) and gene expression (mRNA sequencing) analyses for a total of 80 ART and 77 control placentas. The separate analyses for placentas from different ART procedures and sexes were performed. To separate the effects of ART procedures and subfertility, 11 placentas from natural conception of subfertile couples and 12 from intrauterine insemination treatments were included.
Here we show that ART-associated changes in the placenta enriche in the pathways of hormonal regulation, insulin secretion, neuronal development, and vascularization. Observed decreased number of stromal cells as well as downregulated TRIM28 and NOTCH3 expressions in ART placentas indicate impaired angiogenesis and growth. DNA methylation changes in the imprinted regions and downregulation of TRIM28 suggest defective stabilization of the imprinting. Furthermore, downregulated expression of imprinted endocrine signaling molecule DLK1 associates with both ART and subfertility.
Decreased expressions of TRIM28, NOTCH3, and DLK1 bring forth potential mechanisms for several phenotypic features associated with ART. Our results support previous procedure specific findings: the changes associated with growth and metabolism link more prominently to the fresh embryo transfer with smaller placentas and newborns, than to the frozen embryo transfer with larger placentas and newborns. Furthermore, since the observed changes associate also with subfertility, they offer a precious insight to the molecular background of infertility.
辅助生殖技术（ART）与生长发育障碍、印记紊乱以及心血管和代谢疾病风险增加有关。然而，其分子机制以及这些机制是ART操作的结果还是潜在的生育力低下所致尚不清楚。
我们对总共80个ART胎盘和77个对照胎盘进行了全基因组DNA甲基化（EPIC Illumina微阵列）和基因表达（mRNA测序）分析。对来自不同ART操作和性别的胎盘进行了单独分析。为了区分ART操作和生育力低下的影响，纳入了11个来自不育夫妇自然受孕的胎盘和12个来自宫内人工授精治疗的胎盘。
我们在此表明，ART相关的胎盘变化富集于激素调节、胰岛素分泌、神经元发育和血管生成途径。在ART胎盘中观察到的基质细胞数量减少以及TRIM28和NOTCH3表达下调表明血管生成和生长受损。印记区域的DNA甲基化变化和TRIM28的下调表明印记的稳定存在缺陷。此外，印记内分泌信号分子DLK1的表达下调与ART和生育力低下均相关。
TRIM28、NOTCH3和DLK1表达的降低为与ART相关的几种表型特征提出了潜在机制。我们的结果支持先前特定操作的发现：与生长和代谢相关的变化与胎盘和新生儿较小的新鲜胚胎移植的关联比与胎盘和新生儿较大的冷冻胚胎移植更为显著。此外，由于观察到的变化也与生育力低下相关，它们为不育的分子背景提供了宝贵的见解。
