Effect of the spatial-temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse

Christian Secchi; Martina Belli; Tracy N H Harrison; Joseph Swift; CheMyong Ko; Antoni J Duleba; Dwayne Stupack; R Jeffrey Chang; Shunichi Shimasaki

doi:10.1186/s12967-021-03103-x

Effect of the spatial-temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse

J Transl Med. 2021 Oct 15;19(1):428. doi: 10.1186/s12967-021-03103-x.

Authors

Christian Secchi¹, Martina Belli², Tracy N H Harrison², Joseph Swift³, CheMyong Ko⁴, Antoni J Duleba², Dwayne Stupack², R Jeffrey Chang², Shunichi Shimasaki²

Affiliations

¹ Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of California San Diego, La Jolla, CA, USA. chsecchi@health.ucsd.edu.
² Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of California San Diego, La Jolla, CA, USA.
³ The Salk Institute for Biological Studies, La Jolla, CA, USA.
⁴ Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Abstract

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.

Keywords: Androgen excess; CYP17; Fertility; Mouse model; Ovary; Theca cells; Transgender.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Androgens / pharmacology
Animals
Cytochrome P450 Family 17
Female
Humans
Male
Mice
Phenotype
Polycystic Ovary Syndrome*
Steroid 17-alpha-Hydroxylase / genetics
Theca Cells*

Substances

Androgens
Steroid 17-alpha-Hydroxylase
Cytochrome P450 Family 17

Abstract

Publication types

MeSH terms

Substances

Grants and funding