Yao Tatsuma, Kobayashi Hisato, Hirai Tatsuki, Tokuoka Yuta, Tokoro Mikiko, Asayama Yuta, Suzuki Yuka, Hatano Yu, Ikeda Hiroki, Sugimura Satoshi, Yamamoto Takuya, Yamada Takahiro G, Hosoi Yoshihiko, Funahashi Akira, Fukunaga Noritaka, Asada Yoshimasa, Kurimoto Kazuki, Yamagata Kazuo
Research and Development Center, Fuso Pharmaceutical Industries, Ltd., Joto-ku, Osaka 536-8523, Japan.
Graduate School of Biology-Oriented Science and Technology, Kindai University, Kinokawa, Wakayama 649-6493, Japan.
Biol Reprod. 2025 Jun 15;112(6):1054-1071. doi: 10.1093/biolre/ioaf050.
In assisted reproduction, many factors in the culture environment, including light, temperature, pH, and culture media, can reduce preimplantation embryo viability. Laboratory glassware is also a known risk factor for in vitro embryos; however, the underlying mechanisms that disrupt embryonic development remain unclear. We identified Zn eluted from glassware as an embryotoxic substance. In mouse embryos, Zn induced delayed development, abnormalities in chromosome segregation, cytokinesis, zygotic gene activation (e.g. Zscan4a and murine endogenous retrovirus with leucine, also known as MERVL), and aberrantly upregulated developmental gene expression (e.g. Hoxa1, Hoxb9, T, and Fgf8) that could be mediated through metal regulatory transcription factors (e.g. Mtf1). Subsequently, Zn exposure led to significantly reduced blastocyst formation. Post-implantation, Zn-exposed embryos were associated with normal birth rates, however, the birth weight increased by an average of 18% compared with embryos cultured without Zn. Furthermore, Zn exposure affected the development of bovine and human embryos, with species-based variation in the strength and timing of these effects. To mitigate these embryotoxic effects, we identified a method to prevent glass toxicity using chelating agents. This research not only highlights the importance of risk control in embryo culture but also facilitates the development of safe and effective methods for assisted reproduction.
在辅助生殖中，培养环境中的许多因素，包括光照、温度、pH值和培养基，都会降低植入前胚胎的活力。实验室玻璃器皿也是体外胚胎的一个已知风险因素；然而，破坏胚胎发育的潜在机制仍不清楚。我们确定从玻璃器皿中洗脱的锌是一种胚胎毒性物质。在小鼠胚胎中，锌会导致发育延迟、染色体分离异常、胞质分裂异常、合子基因激活（如Zscan4a和含亮氨酸的小鼠内源性逆转录病毒，也称为MERVL）以及发育基因表达异常上调（如Hoxa1、Hoxb9、T和Fgf8），这些可能通过金属调节转录因子（如Mtf1）介导。随后，锌暴露导致囊胚形成显著减少。植入后，暴露于锌的胚胎出生率正常，然而，与未暴露于锌的胚胎相比，出生体重平均增加了18%。此外，锌暴露会影响牛和人类胚胎的发育，这些影响的强度和时间存在物种差异。为了减轻这些胚胎毒性作用，我们确定了一种使用螯合剂防止玻璃毒性的方法。这项研究不仅突出了胚胎培养中风险控制的重要性，还促进了辅助生殖安全有效方法的发展。
