{"title":"KEAP1-NRF2系统调控与年龄相关的精子发生功能障碍","authors":"Sohei Kuribayashi, Shinichiro Fukuhara, Hiroaki Kitakaze, Go Tsujimura, Takahiro Imanaka, Koichi Okada, Norichika Ueda, Kentaro Takezawa, Kotoe Katayama, Rui Yamaguchi, Koichi Matsuda, Norio Nonomura","doi":"10.1002/rmb2.12595","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>The KEAP1-NRF2 system, an oxidative stress response system, is associated with age-related spermatogenesis dysfunction.</p>","PeriodicalId":21116,"journal":{"name":"Reproductive Medicine and Biology","volume":"23 1","pages":"e12595"},"PeriodicalIF":2.7000,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194679/pdf/","citationCount":"0","resultStr":"{\"title\":\"KEAP1-NRF2 system regulates age-related spermatogenesis dysfunction.\",\"authors\":\"Sohei Kuribayashi, Shinichiro Fukuhara, Hiroaki Kitakaze, Go Tsujimura, Takahiro Imanaka, Koichi Okada, Norichika Ueda, Kentaro Takezawa, Kotoe Katayama, Rui Yamaguchi, Koichi Matsuda, Norio Nonomura\",\"doi\":\"10.1002/rmb2.12595\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>The KEAP1-NRF2 system, an oxidative stress response system, is associated with age-related spermatogenesis dysfunction.</p>\",\"PeriodicalId\":21116,\"journal\":{\"name\":\"Reproductive Medicine and Biology\",\"volume\":\"23 1\",\"pages\":\"e12595\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-06-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194679/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Reproductive Medicine and Biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/rmb2.12595\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"OBSTETRICS & GYNECOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reproductive Medicine and Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/rmb2.12595","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"OBSTETRICS & GYNECOLOGY","Score":null,"Total":0}
KEAP1-NRF2 system regulates age-related spermatogenesis dysfunction.
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.
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.
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