Cargando…
Acute hypoxia induced dysregulation of clock-controlled ovary functions
High altitudes or exposure to hypoxia leads to female reproductive disorders. Circadian clocks are intrinsic time-tracking systems that enable organisms to adapt to the Earth’s 24-h light/dark cycle, which can be entrained by other environmental stimuli to regulate physiological and pathological res...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816144/ https://www.ncbi.nlm.nih.gov/pubmed/36620217 http://dx.doi.org/10.3389/fphys.2022.1024038 |
_version_ | 1784864465902108672 |
---|---|
author | Ding, Mengnan Lu, Yarong Huang, Xin Xing, Chen Hou, Shaojun Wang, Dongxue Zhang, Yifan Wang, Wei Zhang, Chongchong Zhang, Min Meng, Fanfei Liu, Kun Liu, Guangchao Zhao, Jincheng Song, Lun |
author_facet | Ding, Mengnan Lu, Yarong Huang, Xin Xing, Chen Hou, Shaojun Wang, Dongxue Zhang, Yifan Wang, Wei Zhang, Chongchong Zhang, Min Meng, Fanfei Liu, Kun Liu, Guangchao Zhao, Jincheng Song, Lun |
author_sort | Ding, Mengnan |
collection | PubMed |
description | High altitudes or exposure to hypoxia leads to female reproductive disorders. Circadian clocks are intrinsic time-tracking systems that enable organisms to adapt to the Earth’s 24-h light/dark cycle, which can be entrained by other environmental stimuli to regulate physiological and pathological responses. In this study, we focused on whether ovarian circadian clock proteins were involved in regulating female reproductive dysfunction under hypoxic conditions. Hypobaric hypoxia was found to induce a significantly prolonged estrous cycle in female mice, accompanied by follicular atresia, pituitary/ovarian hormone synthesis disorder, and decreased LHCGR expression in the ovaries. Under the same conditions, the levels of the ovarian circadian clock proteins, CLOCK and BMAL1, were suppressed, whereas E4BP4 levels were upregulated. Results from granulosa cells (GCs) further demonstrated that CLOCK: BMAL1 and E4BP4 function as transcriptional activators and repressors of LHCGR in ovarian GCs, respectively, whose responses were mediated by HIF1ɑ-dependent (E4BP4 upregulation) and ɑ-independent (CLOCK and BMAL1 downregulation) manners. The LHCGR agonist was shown to efficiently recover the impairment of ovulation-related gene (EREG and PGR) expression in GCs induced by hypoxia. We conclude that hypoxia exposure causes dysregulation of ovarian circadian clock protein (CLOCK, BMAL1, and E4BP4) expression, which mediates female reproductive dysfunction by impairing LHCGR-dependent signaling events. Adjusting the timing system or recovering the LHCGR level in the ovaries may be helpful in overcoming female reproductive disorders occurring in the highlands. |
format | Online Article Text |
id | pubmed-9816144 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98161442023-01-07 Acute hypoxia induced dysregulation of clock-controlled ovary functions Ding, Mengnan Lu, Yarong Huang, Xin Xing, Chen Hou, Shaojun Wang, Dongxue Zhang, Yifan Wang, Wei Zhang, Chongchong Zhang, Min Meng, Fanfei Liu, Kun Liu, Guangchao Zhao, Jincheng Song, Lun Front Physiol Physiology High altitudes or exposure to hypoxia leads to female reproductive disorders. Circadian clocks are intrinsic time-tracking systems that enable organisms to adapt to the Earth’s 24-h light/dark cycle, which can be entrained by other environmental stimuli to regulate physiological and pathological responses. In this study, we focused on whether ovarian circadian clock proteins were involved in regulating female reproductive dysfunction under hypoxic conditions. Hypobaric hypoxia was found to induce a significantly prolonged estrous cycle in female mice, accompanied by follicular atresia, pituitary/ovarian hormone synthesis disorder, and decreased LHCGR expression in the ovaries. Under the same conditions, the levels of the ovarian circadian clock proteins, CLOCK and BMAL1, were suppressed, whereas E4BP4 levels were upregulated. Results from granulosa cells (GCs) further demonstrated that CLOCK: BMAL1 and E4BP4 function as transcriptional activators and repressors of LHCGR in ovarian GCs, respectively, whose responses were mediated by HIF1ɑ-dependent (E4BP4 upregulation) and ɑ-independent (CLOCK and BMAL1 downregulation) manners. The LHCGR agonist was shown to efficiently recover the impairment of ovulation-related gene (EREG and PGR) expression in GCs induced by hypoxia. We conclude that hypoxia exposure causes dysregulation of ovarian circadian clock protein (CLOCK, BMAL1, and E4BP4) expression, which mediates female reproductive dysfunction by impairing LHCGR-dependent signaling events. Adjusting the timing system or recovering the LHCGR level in the ovaries may be helpful in overcoming female reproductive disorders occurring in the highlands. Frontiers Media S.A. 2022-12-23 /pmc/articles/PMC9816144/ /pubmed/36620217 http://dx.doi.org/10.3389/fphys.2022.1024038 Text en Copyright © 2022 Ding, Lu, Huang, Xing, Hou, Wang, Zhang, Wang, Zhang, Zhang, Meng, Liu, Liu, Zhao and Song. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Ding, Mengnan Lu, Yarong Huang, Xin Xing, Chen Hou, Shaojun Wang, Dongxue Zhang, Yifan Wang, Wei Zhang, Chongchong Zhang, Min Meng, Fanfei Liu, Kun Liu, Guangchao Zhao, Jincheng Song, Lun Acute hypoxia induced dysregulation of clock-controlled ovary functions |
title | Acute hypoxia induced dysregulation of clock-controlled ovary functions |
title_full | Acute hypoxia induced dysregulation of clock-controlled ovary functions |
title_fullStr | Acute hypoxia induced dysregulation of clock-controlled ovary functions |
title_full_unstemmed | Acute hypoxia induced dysregulation of clock-controlled ovary functions |
title_short | Acute hypoxia induced dysregulation of clock-controlled ovary functions |
title_sort | acute hypoxia induced dysregulation of clock-controlled ovary functions |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816144/ https://www.ncbi.nlm.nih.gov/pubmed/36620217 http://dx.doi.org/10.3389/fphys.2022.1024038 |
work_keys_str_mv | AT dingmengnan acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT luyarong acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT huangxin acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT xingchen acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT houshaojun acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT wangdongxue acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT zhangyifan acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT wangwei acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT zhangchongchong acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT zhangmin acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT mengfanfei acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT liukun acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT liuguangchao acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT zhaojincheng acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions AT songlun acutehypoxiainduceddysregulationofclockcontrolledovaryfunctions |