(D-07) PCOS Associated Gene TOX3 Regulates Androgenic Cell Differentiation in Chicken Gonads

Abstract Authors: Martin A. Estermann^1,2 and Craig A. Smith<sup>2


1</sup>Reproductive Developmental Biology Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA

²Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Abstract Text: Polycystic ovary syndrome (PCOS) stands out as a prevalent cause of female infertility, impacting approximately 10% of women during their reproductive years. Despite its high incidence, the precise etiology of PCOS remains incompletely understood, involving a complex interplay of genetic and environmental factors. While rodent models have historically been utilized for PCOS research, they do not naturally develop PCOS-like phenotypes. Conversely, hens develop spontaneous Polycystic Ovarian Condition (PCOC), rendering them a promising model for studying this condition. PCOC in layer hens is linked with ovarian inflammation, which affects egg laying/ovulation rates and raises concerns for animal welfare and economic implications within the egg industry.

Unlike mammals, chicken gonads are steroidogenically active during early embryonic stages. Embryonic chicken ovaries not only harbor estrogenic cells but also contain a higher proportion of androgenic cells compared to embryonic testes. We have identified the PCOS-associated gene TOX3 as a novel transcription factor expressed in embryonic Sertoli cells of the chicken embryo testis. Our study focuses on characterizing the expression pattern of TOX3 in developing chicken gonads, elucidating its regulatory mechanisms, and exploring its potential role in gonadal supporting and steroidogenic cell differentiation.

TOX3 knockdown resulted in an increase in CYP17A1-positive androgenic cells. Conversely, TOX3 overexpression in both male and female gonads led to a significant reduction in CYP17A1-positive androgenic cells. Furthermore, TOX3 expression was found to be negatively regulated by estrogens in vivo, while it was not induced during estrogen inhibition-induced masculinization.

These findings suggest a model where TOX3 modulates the androgenic cell population, and its dysregulation may contribute to increased steroidogenic capacity, leading to PCOC/PCOS. In addition, the chicken embryo may serve as a tractable model for studying the etiology and progression of PCOC to identify molecular players and treatment avenues.