KEAP1-NRF2 system regulates age-related spermatogenesis dysfunction.

IF 2.7 3区医学 Q2 OBSTETRICS & GYNECOLOGY Reproductive Medicine and Biology Pub Date : 2024-06-24 eCollection Date: 2024-01-01 DOI:10.1002/rmb2.12595

Sohei Kuribayashi, Shinichiro Fukuhara, Hiroaki Kitakaze, Go Tsujimura, Takahiro Imanaka, Koichi Okada, Norichika Ueda, Kentaro Takezawa, Kotoe Katayama, Rui Yamaguchi, Koichi Matsuda, Norio Nonomura

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Abstract

Purpose: The average fatherhood age has been consistently increasing in developed countries. Aging has been identified as a risk factor for male infertility. However, its impact on various mechanisms remains unclear. This study focused on the KEAP1-NRF2 oxidative stress response system, by investigating the relationship between the KEAP1-NRF2 system and age-related changes in spermatogenesis.

Methods: For examination of age-related changes, we used 10-, 30-, 60-, and 90-week-old mice to compare sperm count, sperm motility, and protein expression. For assessment of Keap1 inhibition, 85-week-old C57BL/6J mice were randomly assigned to the following groups: control and bardoxolone methyl (KEAP1 inhibitor). Whole-exome sequencing of a Japanese cohort of patients with non-obstructive azoospermia was performed for evaluating.

Results: Sperm count decreased significantly with aging. Oxidative stress and KEAP1 expression in the testes were elevated. Inhibition of KEAP1 in aging mice significantly increased sperm count compared with that in the control group. In the human study, the frequency of a missense-type SNP (rs181294188) causing changes in NFE2L2 (NRF2) activity was significantly higher in patients with non-obstructive azoospermia than in healthy control group.

Conclusions: The KEAP1-NRF2 system, an oxidative stress response system, is associated with age-related spermatogenesis dysfunction.

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KEAP1-NRF2系统调控与年龄相关的精子发生功能障碍

目的：在发达国家，平均做父亲的年龄一直在增加。衰老已被确定为男性不育的一个风险因素。然而，其对各种机制的影响仍不清楚。本研究重点关注KEAP1-NRF2氧化应激反应系统，研究KEAP1-NRF2系统与精子发生过程中与年龄相关的变化之间的关系：为了研究与年龄相关的变化，我们使用了10周龄、30周龄、60周龄和90周龄的小鼠来比较精子数量、精子活力和蛋白表达。为了评估Keap1抑制作用，我们将85周大的C57BL/6J小鼠随机分配到以下组别：对照组和甲基巴多索龙组（KEAP1抑制剂）。对一组日本非梗阻性无精子症患者进行了全外显子组测序评估：结果：随着年龄的增长，精子数量明显减少。结果：随着年龄的增长，精子数量明显减少，睾丸中的氧化应激和 KEAP1 表达升高。与对照组相比，抑制老化小鼠的 KEAP1 可明显增加精子数量。在人类研究中，导致 NFE2L2（NRF2）活性变化的错义型 SNP（rs181294188）在非梗阻性无精子症患者中的出现频率明显高于健康对照组：KEAP1-NRF2系统是一种氧化应激反应系统，与年龄相关的精子发生功能障碍有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Reproductive Medicine and Biology Multiple-

CiteScore

5.70

自引率

5.90%

发文量

审稿时长

20 weeks

期刊介绍： Reproductive Medicine and Biology (RMB) is the official English journal of the Japan Society for Reproductive Medicine, the Japan Society of Fertilization and Implantation, the Japan Society of Andrology, and publishes original research articles that report new findings or concepts in all aspects of reproductive phenomena in all kinds of mammals. Papers in any of the following fields will be considered: andrology, endocrinology, oncology, immunology, genetics, function of gonads and genital tracts, erectile dysfunction, gametogenesis, function of accessory sex organs, fertilization, embryogenesis, embryo manipulation, pregnancy, implantation, ontogenesis, infectious disease, contraception, etc.