时空特异性膜细胞 Cyp17 过表达对新型 TC17 小鼠生殖表型的影响。
Effect of the spatial-temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse.
机构信息
Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of California San Diego, La Jolla, CA, USA.
The Salk Institute for Biological Studies, La Jolla, CA, USA.
出版信息
J Transl Med. 2021 Oct 15;19(1):428. doi: 10.1186/s12967-021-03103-x.
BACKGROUND
In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown.
METHODS
In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system.
RESULTS
Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes (Lhcgr, Fshr, Runx1) and pathways (Extra Cellular Matrix and Steroid Synthesis).
CONCLUSIONS
Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.
背景
在卵巢滤泡中，Theca 细胞（TCs）具有两个主要功能：保持形态完整性，重要的是，分泌类固醇雄激素激素。TCs 表达必需的酶 17α-羟化酶/17,20-脱酶（CYP17），它允许将孕烯醇酮和孕酮转化为雄激素。由于内在卵巢缺陷导致 CYP17 酶活性失调被认为是女性高雄激素血症的原因。多囊卵巢综合征（PCOS）患者存在雄激素过多，这是由于内源性雄激素产生过多所致，而在出生时被女性性别分配后接受外源性睾酮治疗的跨性别男性也存在雄激素过多。然而，Cyp17 过表达和雄激素过多对卵泡发生的分子和形态影响尚不清楚。
方法
在这项工作中，为了全面分析卵巢雄激素过多的局部后果，我们以时空方式在局部诱导四环素（Dox）诱导的 Cyp17 过表达，生成了一种转基因小鼠模型（TC17）。TC17 小鼠是通过 Tet 依赖性表达系统和 Cre/LoxP 基因控制系统的组合获得的。
结果
Dox 处理的 TC17 小鼠的卵巢中 Cyp17 特异性在 TCs 中过表达，导致睾酮水平升高。令人惊讶的是，TC17 卵巢形态类似于接受睾酮治疗的跨性别男性的人类卵巢特征（部分受损的卵泡发生、肥大或黄体化的基质细胞、闭锁卵泡和塌陷的簇）。我们还评估了 TC17 的生育能力，这表明正常生殖功能受到干扰（例如，怀孕率低，每窝幼仔数量少）。最后，RNAseq 分析使我们能够鉴定出失调的基因（Lhcgr、Fshr、Runx1）和途径（细胞外基质和类固醇合成）。
结论
我们的新型小鼠模型是一种多功能工具，可以为研究 Cyp17 过表达和卵巢高雄激素血症的影响提供新的见解。
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