Inhibition of ferroptosis attenuates oligospermia in male Nrf2 knockout mice

GCLC公司 GCLM公司 化学 精子活力 精子 磷脂过氧化氢谷胱甘肽过氧化物酶 内分泌学 内科学 NPSH 少精子症 男科 谷胱甘肽 分子生物学 谷胱甘肽过氧化物酶 生物 男性不育 过氧化氢酶 氧化应激 生物化学 医学 不育 怀孕 遗传学
作者
Ping Han,Xia Wang,Tianqiu Zhou,Jinmei Cheng,Chengniu Wang,Fei Sun,Xi Zhao
出处
期刊:Free Radical Biology and Medicine [Elsevier BV]
卷期号:193: 421-429 被引量:32
标识
DOI:10.1016/j.freeradbiomed.2022.10.314
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.
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