Abstract
BackgroundIn 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.MethodsIn 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.ResultsOvaries 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).ConclusionsOur novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.
Highlights
Ovarian follicles are comprised of three diverse cell populations: oocytes, granulosa cells (GCs), and theca cells (TCs) [1,2,3,4,5]
We have used Cyp17 promoter-iCre mice [60] crossed with transactivator mice (R26-STOP-rtTA-IRES-EGFP transgene at the ROSA26 locus, Jackson Lab) and with responder mice carrying the TRE-Cyp17 transgene created at the University of California, San Diego (UCSD) transgenic mouse and embryonic stem cell core facility
Dox treatment in TC17 transgenic mice induced expression of Cyp17 in a local and temporal manner and increased Testosterone blood levels After in vitro validation of the trans genetic constructs used in the present work (Fig. 1A) and the execution of breeding strategy to obtain TC17 mice, the novel TC17 model was doxtreated by i.p. injection for a dose–response (Additional file 1: Figure S1)
Summary
Ovarian follicles are comprised of three diverse cell populations: oocytes, granulosa cells (GCs), and theca cells (TCs) [1,2,3,4,5]. TCs comprise the outer portion of the follicle (3–5 layers) and have two main functions: preserving the morphological integrity of follicles and, importantly, the production of androgen steroids [6, 7]. Terminal differentiation of the theca interna is characterized by development of theca interstitial cells that produce androgens. Understanding this developmental process is important because theca-derived androgens are obligatory precursors for follicle estrogen production, and are essential for normal folliculogenesis, ovulation, and reproduction [10]. The Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. The molecular and morphological effects of Cyp overexpression and androgen excess on folliculogenesis is unknown
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