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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.1024038/full |
| _version_ | 1797978670462140416 |
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| author | Mengnan Ding Yarong Lu Yarong Lu Xin Huang Chen Xing Shaojun Hou Shaojun Hou Shaojun Hou Dongxue Wang Dongxue Wang Yifan Zhang Wei Wang Wei Wang Chongchong Zhang Chongchong Zhang Min Zhang Min Zhang Fanfei Meng Kun Liu Guangchao Liu Jincheng Zhao Lun Song Lun Song Lun Song Lun Song |
| author_facet | Mengnan Ding Yarong Lu Yarong Lu Xin Huang Chen Xing Shaojun Hou Shaojun Hou Shaojun Hou Dongxue Wang Dongxue Wang Yifan Zhang Wei Wang Wei Wang Chongchong Zhang Chongchong Zhang Min Zhang Min Zhang Fanfei Meng Kun Liu Guangchao Liu Jincheng Zhao Lun Song Lun Song Lun Song Lun Song |
| author_sort | Mengnan Ding |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T05:27:45Z |
| format | Article |
| id | doaj.art-02a43eb0f76f4c7c855b11f33cad5d9b |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-11T05:27:45Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-02a43eb0f76f4c7c855b11f33cad5d9b2022-12-23T04:42:14ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-12-011310.3389/fphys.2022.10240381024038Acute hypoxia induced dysregulation of clock-controlled ovary functionsMengnan Ding0Yarong Lu1Yarong Lu2Xin Huang3Chen Xing4Shaojun Hou5Shaojun Hou6Shaojun Hou7Dongxue Wang8Dongxue Wang9Yifan Zhang10Wei Wang11Wei Wang12Chongchong Zhang13Chongchong Zhang14Min Zhang15Min Zhang16Fanfei Meng17Kun Liu18Guangchao Liu19Jincheng Zhao20Lun Song21Lun Song22Lun Song23Lun Song24Beijing Institute of Basic Medical Sciences, Beijing, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaHenan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaAnhui Medical University, Hefei, ChinaSchool of Pharmacy, Jiamus University, Jiamusi, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaSchool of Pharmacy, Jiamus University, Jiamusi, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaSchool of Pharmacy, Jiamus University, Jiamusi, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaHenan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaAnhui Medical University, Hefei, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaHenan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng, ChinaSchool of Pharmacy, Jiamus University, Jiamusi, ChinaBeijing Institute of Basic Medical Sciences, Beijing, ChinaAnhui Medical University, Hefei, ChinaSchool of Pharmacy, Jiamus University, Jiamusi, ChinaCollege of Life Science, Henan Normal University, Xinxiang, ChinaHigh 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.https://www.frontiersin.org/articles/10.3389/fphys.2022.1024038/fullhypobaric hypoxiacircadian clockreproductive disorderovulationhigh altitude |
| spellingShingle | Mengnan Ding Yarong Lu Yarong Lu Xin Huang Chen Xing Shaojun Hou Shaojun Hou Shaojun Hou Dongxue Wang Dongxue Wang Yifan Zhang Wei Wang Wei Wang Chongchong Zhang Chongchong Zhang Min Zhang Min Zhang Fanfei Meng Kun Liu Guangchao Liu Jincheng Zhao Lun Song Lun Song Lun Song Lun Song Acute hypoxia induced dysregulation of clock-controlled ovary functions Frontiers in Physiology hypobaric hypoxia circadian clock reproductive disorder ovulation high altitude |
| 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 | hypobaric hypoxia circadian clock reproductive disorder ovulation high altitude |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.1024038/full |
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