School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The Robinson Institute, The University of Adelaide, Adelaide, South Australia, Australia.
Biol Reprod. 2011 Mar;84(3):572-80. doi: 10.1095/biolreprod.110.087262. Epub 2010 Nov 10.
The preimplantation embryo is sensitive to its environment and, despite having some plasticity to adapt, environmental perturbations can impair embryo development, metabolic homeostasis, fetal and placental development, and offspring health. This study used an in vitro model of embryo culture with increasing mitochondrial inhibition to directly establish the effect of impaired mitochondrial function on embryonic, fetal, and placental development. Culture in the absence of the carbohydrate pyruvate significantly increased blastocyst glucose oxidation via glycolysis to maintain normal levels of ATP and tricarboxylic acid (TCA) cycle activity. This culture resulted in a significant reduction in blastocyst development, trophectoderm cell number, and respiration rate but, importantly, did not impair implantation rates or fetal and placental development. In contrast, increasing concentrations of the mitochondrial inhibitor amino-oxyacetate (AOA) impaired glycolysis, TCA cycle activity, respiration rate, and ATP production; incrementally reduced blastocyst development; and decreased blastocyst inner cell mass and trophectoderm cell numbers. Importantly, AOA did not affect implantation rates; however, 5 μM AOA significantly reduced placental growth but not fetal growth, increasing the fetal:placental weight ratio. Furthermore, 50 μM AOA significantly reduced both placental and fetal growth but not the fetal:placental weight ratio. Hence, this study demonstrates that a threshold of mitochondrial function is required for normal development, and despite developmental plasticity of the embryo, impaired mitochondrial function in the embryo affects subsequent fetal and placental growth. These results highlight the importance of mitochondrial function in regulating pre- and postimplantation development; however, the effect on offspring health remains unknown.
胚胎植入前对其环境敏感，尽管具有一定的适应可塑性，但环境干扰仍可能损害胚胎发育、代谢稳态、胎儿和胎盘发育以及后代健康。本研究使用体外胚胎培养模型，通过增加线粒体抑制来直接确定受损的线粒体功能对胚胎、胎儿和胎盘发育的影响。在缺乏碳水化合物丙酮酸的情况下培养，胚胎通过糖酵解显著增加了囊胚的葡萄糖氧化，以维持正常水平的 ATP 和三羧酸（TCA）循环活性。这种培养导致囊胚发育、滋养外胚层细胞数量和呼吸率显著减少，但重要的是，并未损害着床率或胎儿和胎盘发育。相比之下，增加线粒体抑制剂氨基氧乙酸（AOA）的浓度会损害糖酵解、TCA 循环活性、呼吸率和 ATP 产生；逐渐降低囊胚发育；并减少囊胚内细胞团和滋养外胚层细胞数量。重要的是，AOA 不影响着床率；然而，5μM 的 AOA 显著降低了胎盘生长，但不影响胎儿生长，增加了胎儿与胎盘的重量比。此外，50μM 的 AOA 显著降低了胎盘和胎儿的生长，但不影响胎儿与胎盘的重量比。因此，本研究表明，正常发育需要线粒体功能的阈值，尽管胚胎具有发育可塑性，但胚胎中线粒体功能受损会影响随后的胎儿和胎盘生长。这些结果强调了线粒体功能在调节胚胎植入前和植入后的发育中的重要性；然而，其对后代健康的影响尚不清楚。
