Chemerin Suppresses Ovarian Follicular Development and Its Potential Involvement in Follicular Arrest in Rats Treated Chronically With Dihydrotestosterone

被引:52
作者
Kim, Ji Young [1 ,2 ,3 ,4 ]
Xue, Kai [3 ,5 ]
Cao, Mingju [1 ,2 ,3 ]
Wang, Qi [1 ,2 ,3 ]
Liu, Jia-yin [5 ]
Leader, Arthur [1 ,2 ,3 ,6 ]
Han, Jae Yong [4 ]
Tsang, Benjamin K. [1 ,2 ,3 ,4 ]
机构
[1] Univ Ottawa, Dept Obstet & Gynecol, Ottawa, ON K1H 8L6, Canada
[2] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8L6, Canada
[3] Ottawa Hosp Res Inst, Chron Dis Program, Ottawa, ON K1H 8L6, Canada
[4] Seoul Natl Univ, Dept Agr Biotechnol, Coll Agr & Life Sci, WCU Biomodulat Major, Seoul 151742, South Korea
[5] Nanjing Med Univ, Clin Reprod Med Ctr, State Key Lab Reprod Med, Nanjing 210029, Jiangsu, Peoples R China
[6] Ottawa Fertil Ctr, Ottawa, ON K2C 3V4, Canada
基金
加拿大健康研究院; 新加坡国家研究基金会;
关键词
X-LINKED INHIBITOR; APOPTOSIS PROTEIN EXPRESSION; GRANULOSA-CELLS; GROWTH-FACTOR; DIFFERENTIATION; LIGAND; LIFE; PROTEOLYSIS; FOLLICLES; PATHWAY;
D O I
10.1210/en.2013-1001
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
In the present study, we have investigated the cellular mechanisms of androgen-induced antral follicular growth arrest and the possible involvement of chemerin and its receptor chemokine-like receptor 1 (CMKLR1) in this process, using a chronically androgenized rat model. We hypothesize that hyperandrogenism induces antral follicle growth arrest via the action of chemerin and ovarian structural changes, resulting from granulosa cell and oocyte apoptosis and theca cell survival. Dihydrotestosterone (DHT) treatment resulted in increased expression of chemerin and CMKLR1 in antral follicles, absence of corpus luteum, and increased atypical follicles. Addition of chemerin to follicle cultures induced granulosa cell apoptosis and suppressed basal, FSH- and growth differentiation factor-9-stimulated follicular growth. DHT down-regulated aromatase expression and increased active caspase-3 content and DNA fragmentation in granulosa cells in vivo. These changes were accompanied by higher phosphatase and tensin homolog and lower phospho-Akt (Ser473) content in antral follicles and higher calpain expression and down-regulation of cytoskeletal proteins in atypical follicles, which were constituted predominantly of theca cells. DHT also activated granulosa cell caspase-3, decreased X-linked inhibitor of apoptosis protein, poly(ADP-ribose) polymerase, and phospho-Akt contents and induced apoptosis in vitro, responses readily attenuated by forced X-linked inhibitor of apoptosis protein expression. These findings are consistent with our hypothesis that antral follicular growth arrest in DHT-treated rats results from increased chemerin expression and action, as well as changes in follicular cell fate and structure, which are a consequence of dysregulated interactions of pro-survival and pro-apoptotic modulators in a cell-specific manner. Our observations suggest that this chronically androgenized rat model may be useful for studies on the long-term effects of androgens on folliculogenesis and may have implications for the female reproductive disorders associated with hyperandrogenism.
引用
收藏
页码:2912 / 2923
页数:12
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