摘要
Nuclear factor-E2-related factor 2 (Nrf2) expression in sperm decreases in some oligospermia patients. However, the mechanism of reduced Nrf2 expression in sperm of oligospermia men is not elucidated. In the present study, our clinical trial results showed that Nrf2 and glutathione peroxidase 4 (GPX4) protein expressions in sperm of oligospermia men significantly decreased than those of healthy men. In animal experiments, mice were randomly divided into 3 groups: wild type (WT), Nrf2 knockout (Nrf2−/−) and Nrf2−/− + ferroptosis inhibitor (Fer-1) groups. Fer-1 was intraperitoneally injected in Nrf2−/− mice for 4 weeks. The results showed that male Nrf2−/− mice displayed decreased sperm concentration and motility, and significantly lower fertility. Compared with WT mice, malondialdehyde (MDA) content and prostaglandin-endoperoxide synthase 2 (Ptgs2) mRNA expression increased, but nicotinamide adenine dinucleotide phosphate oxidase (NADPH) content decreased in the testes of Nrf2−/− mice, which were biomarkers of ferroptosis. Furthermore, treatment with Fer-1 in Nrf2−/− mice reversed the decreased sperm concentration and motility. Meanwhile, histology showed that spermatogenic cells obviously decreased, and vacuolization formed in the testes of Nrf2−/− mice, which were reversed by Fer-1 treatment. Additionally, compared with WT mice, GPX4, solute carrier family 7 member 11 (SLC7A11), glutamate-cysteine ligase, catalytic subunit (Gclc), glutamate-cysteine ligase, modifier subunit (Gclm) and ferroportin 1 (FPN1) mRNA and protein expressions significantly decreased, but transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) mRNA and protein expressions increased in testicular tissues in Nrf2−/− mice. After treatment with Fer-1, only Gclc and Gclm mRNA and protein expressions increased. Taken together, our data suggested that deletion of Nrf2 leads to downregulation of GPX4 and regulation of other ferroptosis-related genes, resulting in ferroptosis occurrence in spermatogenic cells and ultimately oligospermia.
摘要译文
一些寡头症患者的精子中与核因子-E2相关因子2（NRF2）的表达降低。然而，尚未阐明寡头植物男性精子中NRF2表达降低的机制。在本研究中，我们的临床试验结果表明，与健康男性相比，寡糖男性精子中的NRF2和谷胱甘肽过氧化物酶4（GPX4）蛋白表达显着降低。在动物实验中，将小鼠随机分为3组：野生型（WT），NRF2敲除（NRF2 - - / - ）和NRF2 - / - / - +肥大抑制剂（FER液毒抑制剂（FER）-1）组。将FER-1腹膜内注射在NRF2 - / - 小鼠中4周。结果表明，雄性NRF2 - / - 小鼠的精子浓度和运动率降低，生育力显着降低。与WT小鼠相比，丙二醛（MDA）含量和前列腺素 - 耐氧化甲醛合酶2（PTGS2）mRNA表达增加，但在NRF2 - // - - / - - - mice的测试中，烟酰胺二核苷酸二核苷酸磷酸氧化酶（NADPH）含量降低，这是铁凋亡的生物标志物。此外，在NRF2 - / - 小鼠中用FER-1处理逆转了精子浓度和运动性的降低。同时，组织学表明，精子生成细胞明显降低，并在NRF2 - / - / - 小鼠的睾丸中形成液泡，这些小鼠被FER-1处理逆转。此外，与WT小鼠，GPX4，Solute Carrier家族7成员11（SLC7A11），谷氨酸 - 半胱氨酸连接酶，催化亚基（GCLC），谷氨酸 - 半胱氨酸连接酶，修饰剂亚基（GCLM）（GCLM）和蛋白质1（FPN1）MRNA和蛋白质Expressions相比在NRF2 - / - / - 小鼠中，转铁蛋白受体1（TFR1）和二价金属转运蛋白1（DMT1）mRNA和蛋白质表达增加。用FER-1处理后，仅GCLC和GCLM mRNA和蛋白质表达增加。综上所述，我们的数据表明，NRF2的缺失导致GPX4的下调和其他与铁毒相关的基因的调节，从而导致精子生成细胞和最终寡植物的铁腐病发生。
Ping Han; Xia Wang; Tianqiu Zhou; Jinmei Cheng; ... Xi Zhao. Inhibition of ferroptosis attenuates oligospermia in male Nrf2 knockout mice[J]. Free Radical Biology and Medicine, 2022,193(Part1): 421-429