Ren Yu-Long, Li Zi-Fa, Chen Kai, Zhang Hai-Jing, Liang Qing, Li Yue, Liu Bao-You, Wang Lin
College of Veterinary Medicine, Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, 7 Panhe Street, Tai'an 271001, Shandong, China.
Laboratory Animal Center, Shandong University of Traditional Chinese Medicine, Ji'nan 250355, Shandong, China.
Environ Sci Technol. 2025 Aug 5;59(30):15705-15719. doi: 10.1021/acs.est.5c03589. Epub 2025 Jul 23.
Extensive use of glyphosate (GLY) has aroused significant public concerns due to its adverse effects on reproductive health, but the toxic mechanism remains unclear. This study was designed to elucidate the effects of GLY on male reproductive health by and studies. Data showed that chronic environmental levels of GLY reduced sperm quality and spermatogenic cell number in mice. Transcriptomic and metabolomic analyses revealed that GLY downregulated key glycolytic rate-limiting enzymes HK2 and PFK1, and decreased lactate abundance, while a strong positive correlation between sperm quality and lactate level was established. Further assays showed that GLY inhibited the expression of four glycolytic key proteins and disrupted the HK2 mitochondrial localization. Molecular docking and immunoprecipitation assays confirmed that HK2 binds to VDAC1 on the mitochondrial outer membrane, which was inhibited by GLY. This inhibition was significantly alleviated by VBIT-4, an inhibitor of VDAC1 oligomerization. Notably, oxidative stress-mediated VDAC1 oligomerization due to excessive mitochondrial fission was identified as a key mechanism by which GLY inhibits glycolysis in Sertoli cells. In summary, this study uncovers a novel metabolic regulatory mechanism by which GLY impairs spermatogenesis via the VDAC1-HK2-glycolysis axis, providing critical insights for preventing GLY-induced reproductive toxicity and related environmental risks.
草甘膦（GLY）的广泛使用因其对生殖健康的不利影响而引起了公众的极大关注，但其毒性机制仍不清楚。本研究旨在通过[具体研究方法1]和[具体研究方法2]研究来阐明GLY对男性生殖健康的影响。数据显示，慢性环境水平的GLY会降低小鼠的精子质量和生精细胞数量。转录组学和代谢组学分析表明，GLY下调了关键糖酵解限速酶HK2和PFK1，并降低了乳酸丰度，同时建立了精子质量与乳酸水平之间的强正相关。进一步的实验表明，GLY抑制了四种糖酵解关键蛋白的表达，并破坏了HK2的线粒体定位。分子对接和免疫沉淀实验证实，HK2与线粒体外膜上的VDAC1结合，而这一过程受到GLY的抑制。VDAC1寡聚化抑制剂VBIT-4可显著缓解这种抑制作用。值得注意的是，由于线粒体过度分裂导致的氧化应激介导的VDAC1寡聚化被确定为GLY抑制支持细胞糖酵解的关键机制。综上所述，本研究揭示了一种新的代谢调节机制，即GLY通过VDAC1-HK2-糖酵解轴损害精子发生，为预防GLY诱导的生殖毒性及相关环境风险提供了关键见解。
