Vrooman Lisa A, Rhon-Calderon Eric A, Suri Kashviya V, Dahiya Asha K, Lan Yemin, Schultz Richard M, Bartolomei Marisa S
Department of Cell and Developmental Biology, Perelman School of Medicine, Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, United States.
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, United States.
Front Cell Dev Biol. 2022 Apr 25;10:884088. doi: 10.3389/fcell.2022.884088. eCollection 2022.
Assisted Reproductive Technologies (ART) employ gamete/embryo handling and culture to produce offspring. ART pregnancies have an increased risk of low birth weight, abnormal placentation, pregnancy complications, and imprinting disorders. Embryo culture induces low birth weight, abnormal placental morphology, and lower levels of DNA methylation in placentas in a mouse model of ART. Whether preimplantation embryos at specific stages of development are more susceptible to these perturbations remains unresolved. Accordingly, we performed embryo culture for several discrete periods of preimplantation development and following embryo transfer, assessed fetal and placental outcomes at term. We observed a reduction in fetal:placental ratio associated with two distinct windows of preimplantation embryo development, one prior to the morula stage and the other from the morula to blastocyst stage, whereas placental morphological abnormalities and reduced imprinting control region methylation were only associated with culture prior to the morula stage. Extended culture to the blastocyst stage also induces additional placental DNA methylation changes compared to embryos transferred at the morula stage, and female concepti exhibited a higher loss of DNA methylation than males. By identifying specific developmental windows of susceptibility, this study provides a framework to optimize further culture conditions to minimize risks associated with ART pregnancies.
辅助生殖技术（ART）通过配子/胚胎处理和培养来繁育后代。ART妊娠出现低出生体重、胎盘植入异常、妊娠并发症和印记紊乱的风险增加。在ART小鼠模型中，胚胎培养会导致低出生体重、胎盘形态异常以及胎盘DNA甲基化水平降低。发育特定阶段的植入前胚胎是否更容易受到这些干扰仍未明确。因此，我们在植入前发育的几个不同时间段进行胚胎培养，并在胚胎移植后，评估足月时的胎儿和胎盘结局。我们观察到，胎儿与胎盘的比例降低与植入前胚胎发育的两个不同窗口有关，一个在桑葚胚阶段之前，另一个从桑葚胚到囊胚阶段，而胎盘形态异常和印记控制区域甲基化降低仅与桑葚胚阶段之前的培养有关。与在桑葚胚阶段移植的胚胎相比，延长培养至囊胚阶段还会诱导胎盘DNA甲基化发生更多变化，并且雌性胚胎的DNA甲基化损失高于雄性。通过确定特定的易感性发育窗口，本研究提供了一个框架，以进一步优化培养条件，将ART妊娠相关风险降至最低。
