Analysis by transcriptomics and metabolomics for the proliferation inhibition and dysfunction through redox imbalance-mediated DNA damage response and ferroptosis in male reproduction of mice and TM4 Sertoli cells exposed to PM2.5
Analysis by transcriptomics and metabolomics for the proliferation inhibition and dysfunction through redox imbalance-mediated DNA damage response and ferroptosis in male reproduction of mice and TM4 Sertoli cells exposed to PM2.5
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通过转录组学和代谢组学分析暴露于 PM2.5 的雄性生殖小鼠和 TM4 Sertoli 细胞中氧化还原失衡介导的 DNA 损伤反应和铁死亡导致的增殖抑制和功能障碍
DOI：
10.1016/j.ecoenv.2022.113569
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发表时间：
2022-05-02
影响因子：
6.8
通讯作者：
Ao, Lin
中科院分区：
文献类型：
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作者：
Shi, Fuquan;Zhang, Zhonghao;Ao, Lin
支持细胞在复杂的精子发生过程中发挥着关键作用。本研究旨在利用TM4细胞系和实时全身PM2.5暴露小鼠模型研究PM(2.5)对支持细胞的影响，并通过代谢组学和转录组学的应用进一步探讨其潜在机制。体内外结果表明，PM2.5减少生精小管内支持细胞数量，抑制细胞增殖。 PM2.5 暴露还通过增加雄激素结合蛋白 (ABP) 浓度、减少血睾屏障 (BTB) 相关蛋白表达以及降低糖酵解能力和乳酸生成来诱导支持细胞功能障碍。 TM4支持细胞的转录组学、代谢组学和多组学综合分析结果揭示了PM2.5暴露后外源代谢的激活以及谷胱甘肽和嘌呤代谢的紊乱。进一步的测试证实，PM2.5暴露的TM4细胞中GSH/GSSG比值降低，黄嘌呤氧化酶（XO）活性升高，表明PM2.5引起的代谢紊乱产生了过量的活性氧（ROS）。此外，线粒体ROS水平、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）活性的增加以及Nrf2抗氧化途径的激活证明了氧化还原失衡。进一步研究发现，PM2.5引起的氧化还原失衡诱导DNA损伤反应和细胞周期停滞。此外，PM2.5 通过铁过载和脂质过氧化诱导铁死亡。总而言之，我们的研究为理解暴露于 PM2.5 的 TM4 Sertoli 细胞通过代谢紊乱和氧化还原失衡介导的 DNA 损伤反应和铁死亡的增殖抑制和功能障碍提供了新的见解。
Sertoli cells play a pivotal role in the complex spermatogenesis process. This study aimed to investigate the effects of PM(2.5)on Sertoli cells using the TM4 cell line and a real time whole-body PM2.5 exposure mouse model, and further explore the underlying mechanisms through the application of metabolomics and transcriptomics. The results in vivo and in vitro showed that PM2.5 reduced Sertoli cells number in seminiferous tubules and inhibited cell proliferation. PM2.5 exposure also induced Sertoli cell dysfunction by increasing androgen binding protein (ABP) concentration, reducing the blood-testis barrier (BTB)-related protein expression, and decreasing glycolysis capacity and lactate production. The results of transcriptomics, metabolomics, and integrative analysis of multi-omics in the TM4 Sertoli cells revealed the activation of xenobiotic metabolism, and the disturbance of glutathione and purine metabolism after PM2.5 exposure. Further tests verified the reduced GSH/GSSG ratio and the elevation of xanthine oxidase (XO) activity in the PM2.5-exposed TM4 cells, indicating that excessive reactive oxygen species (ROS) was generated via metabolic disorder caused by PM2.5. Moreover, the redox imbalance was proved by the increase in the mitochondrial ROS level, superoxide dismutase (SOD) and catalase (CAT) activity, as well as the activation of the Nrf2 antioxidative pathway. Further study found that the redox imbalance caused by PM2.5 induced DNA damage response and cell cycle arrest. Additionally, PM2.5 induced ferroptosis through iron overload and lipid peroxidation. Taken all together, our study provided new insights for understanding proliferation inhibition and dysfunction of TM4 Sertoli cells exposed to PM2.5 via metabolic disorder and redox imbalance-mediated DNA damage response and ferroptosis.