炎症体
多囊卵巢
内分泌学
内科学
雄激素受体
卵泡发生
卵泡期
TLR4型
下调和上调
受体
二氢睾酮
生物
雄激素
医学
化学
激素
细胞生物学
胰岛素
胰岛素抵抗
前列腺癌
癌症
基因
低温保存
胚胎
生物化学
作者
Daojuan Wang,Yajing Weng,Yaling Zhang,Rong Wang,Tingyu Wang,Jianjun Zhou,Shanmei Shen,Hongwei Wang,Yong Wang
标识
DOI:10.1016/j.scitotenv.2020.141049
摘要
Hyperandrogenism is the main cause of infertility as a result of polycystic ovary syndrome (PCOS). Long-term and continuous exposure to hyperandrogen can cause follicular developmental disorders. Ovarian granulosa cells (GCs) are critical in shaping the follicular development. To clarify how excessive androgen suppresses folliculogenesis and ovulation, we constructed PCOS mice by implantation of a 35-d testosterone (T) continuous-release pellet. Ovarian toll-like receptor 4 (TLR4) expression and serum IL-6 and IL-1β levels were dramatically increased in T-treated mice. In addition, the expression of NLRP3 inflammasome in the ovary of T-treated mice suggests that pyroptosis may play an essential role in follicular dysfunction. Lipopolysaccharide (LPS) has been extensively studied for activating cells by binding to TLR4. In this study, we demonstrated that LPS-induced inflammation leads to activation of the NLRP3 inflammasome with consequent impacts on follicular dysfunction. Herein we showed that LPS treatment upregulated the expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) and androgen receptor (AR), while suppressed follicle stimulating hormone receptor (FSHR) expression in vitro. Moreover, we overexpressed NLRP3 using nigericin or lentiviral particles in GCs. The protein and mRNA levels of pyroptotic factors were highly enhanced with NLRP3 overexpression. As expected, the expression of Cyp19α1, Cyp11α1, 3β-HSD and FSHR at both the protein and mRNA levels was also markedly increased with excessive NLRP3. After inhibiting NLRP3, dihydrotestosterone (DHT)-treated GCs demonstrated markedly decreased NLRP3, the inflammasome adapter protein ASC, C-terminal fragment of gasdermin D (GSDMD-C), AR and Cyp19α1 at the protein level. Furthermore, with NLRP3 overexpression, the expression of fibrotic factors in ovarian cells was dramatically increased, such as TGF-β, CTGF, α-SMA, β-catenin, collagen I and collagen IV. These findings suggest that hyperandrogen stimulates chronic low-grade inflammation in the ovary to activate the NLRP3 inflammasome, further inducing a series of pathologies including ovarian GC pyroptotic death, follicular dysfunction and ovarian interstitial cell fibrosis.
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