Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Bonn, Germany.
Department of Pharmacology, National Organization for Drug Control and Research, Giza, Egypt.
Cell Tissue Res. 2020 Jun;380(3):643-655. doi: 10.1007/s00441-020-03177-x. Epub 2020 Feb 18.
Lead (Pb), one of the pervasive and protracted environmental heavy metals, is believed to affect the female reproductive system in many species. The Nrf2 and NF-κB are the two key transcriptional factors regulating cellular redox status and response against stress and inflammation respectively, showing an interaction between each other. The aim of this study is to investigate the effect of Pb on bovine granulosa cells (GCs) and its association with the regulation of Nrf2 and NF-κB pathways. For this, bovine GCs were cultured in vitro and exposed to different doses of Pb for 2 h. Cellular response to Pb insult was investigated 24 h post treatment. Results showed that exposure of GCs to Pb-induced ROS accumulation and protein carbonylation. Additionally, GCs exhibited reduction in cell viability and decrease in the expression of cell proliferation marker genes (CCND2 and PCNA). This was accompanied by cell cycle arrest at G0/G1 phase. Moreover, Pb downregulated both Nrf2 and NF-κB and their downstream genes. Lead increased the expression of endoplasmic reticulum (ER) stress marker genes (GRP78 and CHOP) and the proapoptotic gene (caspase-3) while the antiapoptotic gene (BCL-2) was reduced. Our findings suggest that Pb-driven oxidative stress affected GCs proliferation, enhances ER stress, induces cell cycle arrest and mediates apoptosis probably via disruption of Nrf2/NF-κB cross-talk. However, further functional analysis is required to explain different aspects of Nrf2 and NF-κB interactions under metal challenge.
铅（Pb）是一种普遍存在且具有持久性的环境重金属，据信它会影响许多物种的雌性生殖系统。Nrf2 和 NF-κB 是两种分别调节细胞氧化还原状态和应对应激与炎症的关键转录因子，它们之间存在相互作用。本研究旨在探讨 Pb 对牛颗粒细胞（GCs）的影响及其与 Nrf2 和 NF-κB 通路调节的关系。为此，我们在体外培养牛 GCs 并使其暴露于不同剂量的 Pb 中 2 小时。在处理后 24 小时，我们研究了细胞对 Pb 损伤的反应。结果表明，GCs 暴露于 Pb 会导致 ROS 积累和蛋白质羰基化。此外，GCs 的细胞活力降低，细胞增殖标志物基因（CCND2 和 PCNA）的表达减少。这伴随着细胞周期停滞在 G0/G1 期。此外，Pb 下调了 Nrf2 和 NF-κB 及其下游基因的表达。Pb 增加了内质网（ER）应激标志物基因（GRP78 和 CHOP）和促凋亡基因（caspase-3）的表达，而抗凋亡基因（BCL-2）则减少。我们的研究结果表明，Pb 引起的氧化应激影响了 GCs 的增殖，增强了 ER 应激，诱导了细胞周期停滞和介导了细胞凋亡，这可能是通过破坏 Nrf2/NF-κB 相互作用来实现的。然而，需要进一步的功能分析来解释金属挑战下 Nrf2 和 NF-κB 相互作用的不同方面。
