Ni Heliang, Hu Xiangdong, Yang Nannan, Liu Xiaoyang, Cai Wenyang, Zhong Rui, Wang Tiancheng, Yu Mingxi, Tang Shuang
Laboratory of Animal Cell and Molecular Biology, College of Bioscience and Biotechnology, Shenyang Agricultural University, 120 Dongling Road, Shenhe District, Shenyang, 110866 Liaoning China.
Toxicol Res. 2024 Mar 29;40(3):377-387. doi: 10.1007/s43188-024-00229-0. eCollection 2024 Jul.
Roundup, a glyphosate-based herbicide widely used in agriculture, has raised concerns regarding its potential impact on human health due to the detection of its residues in human urine and serum. Granulosa cells are essential for oocyte growth and follicle development. Previous research has shown that Roundup could affect steroid synthesis, increases oxidative stress, and induces apoptosis in granulosa cells. However, little is known about the effects of Roundup on NLRP3 (nucleotide binding oligomerization domain-like receptor family pyrin-containing domain protein 3) inflammasome activation and cellular senescence in granulosa cells. Here, we provided evidence that exposure to Roundup induced premature senescence in mouse granulosa cells through the activation of NLRP3 inflammasome triggered by mitochondrial ROS. Our findings demonstrated that Roundup significantly reduced the viability of granulosa cells under in vitro culture conditions. It also disrupted mitochondrial function and induced oxidative stress in these cells. Subsequent investigations showed that NLRP3 inflammasome was activated in treated granulosa cells, as evidenced by the upregulation of inflammasome-related genes and the processing of inflammatory cytokines IL-1β and IL-1α into their mature forms. Consequently, premature cellular senescence occurred in response to the challenge posed by Roundup. Notably, direct inhibition of NLRP3 inflammasome with MCC950 does not alleviate mitochondrial damage and oxidative stress. However, supplementation of resveratrol, which has been known to attenuate mitochondrial damage and oxidative stress, effectively mitigated the inflammatory response and the expression of senescence-related markers, and prevented the senescence in granulosa cells. These results suggested that mitochondrial function and oxidative homeostasis might play pivotal roles as upstream regulators of NLRP3 inflammasome. In summary, our findings indicated that the premature senescence of granulosa cells caused by mitochondrial ROS-triggered NLRP3 inflammasome activation might contribute to the ovarian toxicity of Roundup, in addition to its known effects on steroidogenesis and apoptosis.
The online version contains supplementary material available at 10.1007/s43188-024-00229-0.
农达是一种广泛应用于农业的基于草甘膦的除草剂，由于在人类尿液和血清中检测到其残留，人们对其对人类健康的潜在影响表示担忧。颗粒细胞对卵母细胞生长和卵泡发育至关重要。先前的研究表明，农达会影响类固醇合成、增加氧化应激并诱导颗粒细胞凋亡。然而，关于农达对颗粒细胞中NLRP3（含核苷酸结合寡聚化结构域样受体家族吡啉结构域蛋白3）炎性小体激活和细胞衰老的影响知之甚少。在此，我们提供证据表明，暴露于农达会通过线粒体ROS触发的NLRP3炎性小体激活，诱导小鼠颗粒细胞过早衰老。我们的研究结果表明，在体外培养条件下，农达显著降低了颗粒细胞的活力。它还破坏了这些细胞的线粒体功能并诱导了氧化应激。随后的研究表明，处理后的颗粒细胞中NLRP3炎性小体被激活，炎性小体相关基因的上调以及炎性细胞因子IL-1β和IL-1α加工成成熟形式证明了这一点。因此，响应农达带来的挑战，细胞过早衰老发生。值得注意的是，用MCC950直接抑制NLRP3炎性小体并不能减轻线粒体损伤和氧化应激。然而，补充已知可减轻线粒体损伤和氧化应激的白藜芦醇，有效减轻了炎症反应和衰老相关标志物的表达，并防止了颗粒细胞衰老。这些结果表明，线粒体功能和氧化稳态可能作为NLRP3炎性小体的上游调节因子发挥关键作用。总之，我们的研究结果表明，除了其对类固醇生成和凋亡的已知影响外，线粒体ROS触发的NLRP3炎性小体激活导致的颗粒细胞过早衰老可能导致农达的卵巢毒性。
在线版本包含可在10.1007/s43188-024-00229-0获取的补充材料。
