Inhibition of ferroptosis attenuates oligospermia in male Nrf2 knockout mice

被引：29
作者：
Han, Ping [1 ]
Wang, Xia [2 ]
Zhou, Tianqiu [3 ]
Cheng, Jinmei [1 ]
Wang, Chengniu [1 ]
Sun, Fei [1 ,4 ]
Zhao, Xi [1 ,4 ]
机构：
[1] Nantong Univ, Inst Reprod Med, Med Sch, Nantong 226001, Jiangsu, Peoples R China
[2] Nantong Univ, Ctr Reprod Med, Affiliated Hosp, Nantong 226001, Jiangsu, Peoples R China
[3] Nantong Univ, Dept Ophthalmol, Affiliated Hosp, Nantong 226001, Jiangsu, Peoples R China
[4] Nantong Univ, Inst Reprod Med, Med Sch, 19 Qixiu Rd, Nantong 226001, Jiangsu, Peoples R China
来源：
FREE RADICAL BIOLOGY AND MEDICINE | 2022年 / 193卷
关键词：
Nrf2; GPX4; Oligospermia; Ferroptosis; TfR1; CELL-DEATH; IRON; SPERMATOZOA; EXPRESSION; IMPROVES; FAILURE; DAMAGE; NADPH; FORM;
D O I：
10.1016/j.freeradbiomed.2022.10.314
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
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 obvi-ously 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.
引用
收藏
页码：421 / 429
页数：9
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