A high-androgen microenvironment inhibits granulosa cell proliferation and alters cell identity

Authors

Renee McFee Fee, University of Nebraska-LincolnFollow
Sarah Romereim, University of Nebraska-LincolnFollow
Alexandria P. Snider, University of Nebraska-LincolnFollow
Adam F. Summers, New Mexico State UniversityFollow
William E. Pohlmeier, University of Nebraska-LincolnFollow
Scott G. Kurz, University of Nebraska-LincolnFollow
Robert A. Cushman, USDA, Agricultural Research ServiceFollow
John S. Davis, University of Nebraska Medical CenterFollow
Jennifer R. Wood, University of Nebraska-LincolnFollow
Andrea S. Cupp, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

4-19-2021

Citation

Molecular and Cellular Endocrinology 531 (2021) 111288 https://doi.org/10.1016/j.mce.2021.111288

Comments

CC-BY-NC-ND

Abstract

A naturally occurring bovine model with excess follicular fluid androstenedione (High A4), reduced fertility, and polycystic ovary syndrome (PCOS)-like characteristics has been identified. We hypothesized High A4 granulosa cells (GCs) would exhibit altered cell proliferation and/or steroidogenesis. Microarrays of Control and High A4 GCs combined with Ingenuity Pathway Analysis indicated that High A4 GCs had cell cycle inhibition and increased expression of microRNAs that inhibit cell cycle genes. Granulosa cell culture confirmed that A4 treatment decreased GC proliferation, increased anti-Müllerian hormone, and increased mRNA for CTNNBIP1. Increased CTNNBIP1 prevents CTNNB1 from interacting with members of the WNT signaling pathway thereby inhibiting the cell cycle. Expression of CYP17A1 was upregulated in High A4 GCs presumably due to reduced FOS mRNA expression compared to Control granulosa cells. Furthermore, comparisons of High A4 GC with thecal and luteal cell transcriptomes indicated an altered cellular identity and function contributing to a PCOS-like phenotype.