Long-term environmental exposure of darkness induces hyperandrogenism in PCOS via melatonin receptor 1A and aromatase reduction

被引:12
作者
Chu, Weiwei [1 ,2 ]
Li, Shang [1 ,2 ]
Geng, Xueying [1 ,2 ]
Wang, Dongshuang [1 ,2 ]
Zhai, Junyu [1 ,2 ]
Lu, Gang [3 ]
Chan, Wai-Yee [3 ]
Chen, Zi-Jiang [1 ,2 ,4 ]
Du, Yanzhi [1 ,2 ]
机构
[1] Shanghai Jiao Tong Univ, Ren Ji Hosp, Ctr Reprod Med, Sch Med, Shanghai, Peoples R China
[2] Shanghai Key Lab Assisted Reprod & Reprod Genet, Shanghai, Peoples R China
[3] Chinese Univ Hong Kong, Shandong Univ, Chinese Univ Hong Kong, Sch Biomed Sci,Joint Lab Reprod Genet, Hong Kong, Peoples R China
[4] Shandong Univ, Shandong Prov Hosp, Natl Res Ctr Assisted Reprod Technol & Reprod Gene, Ctr Reprod Med,Key Lab Reprod Endocrinol,Minist E, Jinan, Peoples R China
来源
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY | 2022年 / 10卷
关键词
constant darkness; polycystic ovary syndrome; hyperandrogenism; melatonin receptor 1A; androgen receptor; POLYCYSTIC-OVARY-SYNDROME; GRANULOSA-CELLS; CIRCADIAN-RHYTHMS; RAT MODEL; ANDROGEN; LIGHT; WOMEN;
D O I
10.3389/fcell.2022.954186
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Polycystic ovary syndrome (PCOS) is a common and complex disorder impairing female fertility, yet its etiology remains elusive. It is reported that circadian rhythm disruption might play a crucial role in PCOS pathologic progression. Here, in this research, we investigated the effect of environmental long-term circadian rhythm dysfunction and clarified its pathogenic mechanism in the development of PCOS, which might provide the targeted clinical strategies to patients with PCOS. Female SD rats were used to construct a circadian rhythm misalignment model with constant darkness (12/12-h dark/dark cycle), and the control group was kept under normal circadian rhythm exposure (12/12-h light/dark cycle) for 8 weeks. We measured their reproductive, endocrinal, and metabolic profiles at different zeitgeber times (ZTs). Different rescue methods, including melatonin receptor agonist and normal circadian rhythm restoration, and in vitro experiments on the KGN cell line were performed. We found that long-term darkness caused PCOS-like reproductive abnormalities, including estrous cycle disorder, polycystic ovaries, LH elevation, hyperandrogenism, and glucose intolerance. In addition, the expression of melatonin receptor 1A (Mtnr1a) in ovarian granulosa cells significantly decreased in the darkness group. Normal light/dark cycle and melatonin receptor agonist application relieved hyperandrogenism of darkness-treated rats. In vitro experiments demonstrated that decreased MTNR1A inhibited androgen receptor (AR) and CYP19A1 expression, and AR acted as an essential downstream factor of MTNR1A in modulating aromatase abundance. Overall, our finding demonstrates the significant influence of circadian rhythms on PCOS occurrence, suggests that MTNR1A and AR play vital roles in pathological progression of hyperandrogenism, and broadens current treatment strategies for PCOS in clinical practice.
引用
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页数:17
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