Shi Mingze, Huai Yingxue, Deng Tiantian, Zhang Chuanxin, Song Jinzhu, Wang Jiawei, Zhang Yiwen, Chen Zi-Jiang, Zhao Han, Wu Keliang, Liu Boyang
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China.
Mol Ther Nucleic Acids. 2025 Mar 5;36(2):102499. doi: 10.1016/j.omtn.2025.102499. eCollection 2025 Jun 10.
Assisted reproductive technology (ART) is used widely and efficiently to treat infertility. During the ART procedure, one of the main factors affecting the success rate is abnormal development of preimplantation embryos. The establishment and maintenance of developmental competence are precisely regulated at different levels, while minor errors at early stages may result in adverse outcomes, including developmental arrest and implantation failure. As one of the major inputs, the regulatory mechanisms of metabolites in embryonic development are less known. In this study, we investigated the functional relevance of the metabolic enzyme serine hydroxymethyltransferase 2 (SHMT2) and deoxyribonucleotide (dNTP) metabolites in mouse preimplantation embryonic development. By using a well-characterized SHMT2 inhibitor, SHMT-IN-2, we effectively inhibited the catalytic activity of the SHMT2 enzyme, which led to developmental arrest at the pronuclear stage of the embryo. A low-input liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and applied for detecting dNTP content in embryos. We found that SHMT2 inhibition led to an insufficient dTTP supply and replication stress during the first mitotic cleavage, thereby causing failure of pronuclear fusion and developmental arrest. Our findings demonstrate a specific mechanism where, apart from building blocks of DNA, the availability of dNTPs contributes to the control of mouse preimplantation embryonic development.
辅助生殖技术（ART）被广泛且有效地用于治疗不孕症。在ART过程中，影响成功率的主要因素之一是植入前胚胎的异常发育。发育能力的建立和维持在不同水平上受到精确调控，而早期的微小错误可能导致不良后果，包括发育停滞和着床失败。作为主要输入之一，代谢物在胚胎发育中的调控机制尚不清楚。在本研究中，我们研究了代谢酶丝氨酸羟甲基转移酶2（SHMT2）和脱氧核糖核苷酸（dNTP）代谢物在小鼠植入前胚胎发育中的功能相关性。通过使用一种特性明确的SHMT2抑制剂SHMT-IN-2，我们有效抑制了SHMT2酶的催化活性，这导致胚胎在原核阶段发育停滞。我们开发了一种低输入量液相色谱-串联质谱（LC-MS/MS）方法并用于检测胚胎中的dNTP含量。我们发现，SHMT2抑制导致第一次有丝分裂期dTTP供应不足和复制应激，从而导致原核融合失败和发育停滞。我们的研究结果证明了一种特定机制，即除了作为DNA的组成部分外，dNTP的可用性有助于控制小鼠植入前胚胎发育。
