Estrogen suppresses SOX9 and activates markers of female development in a human testis-derived cell line
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(2020) 21:66
BMC Molecular and Cell Biology
RESEARCH ARTICLE
Open Access
Estrogen suppresses SOX9 and activates markers of female development in a human testis-derived cell line Melanie K. Stewart, Deidre M. Mattiske and Andrew J. Pask*
Abstract Background: The increasing incidence of reproductive disorders in humans has been attributed to in utero exposure to estrogenic endocrine disruptors. In particular, exposure of the developing testis to exogenous estrogen can negatively impact male reproductive health. To determine how estrogens impact human gonad function, we treated the human testis-derived cell line NT2/D1 with estrogen and examined its impact on SOX9 and the expression of key markers of granulosa (ovarian) and Sertoli (testicular) cell development. Results: Estrogen successfully activated its cognate receptor (estrogen receptor alpha; ESR1) in NT2/D1 cells. We observed a significant increase in cytoplasmic SOX9 following estrogen treatment. After 48 h of estrogen exposure, mRNA levels of the key Sertoli cell genes SOX9, SRY, AMH, FGF9 and PTGDS were significantly reduced. This was followed by a significant increase in mRNA levels for the key granulosa cell genes FOXL2 and WNT4 after 96 h of estrogen exposure. Conclusions: These results are consistent with estrogen's effects on marsupial gonads and show that estrogen has a highly conserved impact on gonadal cell fate decisions that has existed in mammals for over 160 million years. This effect of estrogen presents as a potential mechanism contributing to the significant decrease in male fertility and reproductive health reported over recent decades. Given our widespread exposure to estrogenic endocrine disruptors, their effects on SOX9 and Sertoli cell determination could have considerable impact on the adult testis. Keywords: Estrogen, Sertoli cells, Testis, Sex determination
Background Differences of sexual development (DSDs) are currently some of the most common birth defects in humans and often affect gonadal development and fertility. DSDs occur in 1:200–1:300 live births [1] and are increasing in incidence [2, 3]. In Western countries in particular, DSDs continue to rise while sperm counts have decreased by more than 50% in the last 40 years [4]. This sharp decline in male reproductive health is of major
* Correspondence: [email protected] School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia
concern and there is an urgent need to identify and understand potential contributors to this issue. Although infertility and DSDs can have genetic causes, the recent and rapid decline in overall reproductive health and fertility is now unequivocally linked to our exposure to endocrine disrupting chemicals (EDCs) [5–10]. Estrogenic EDCs are some of the most pervasive in our environment and include compounds such as bisphenol A, 17α-ethynylestradiol, phthalates, and genistein. These EDCs are capable of interacting with estrogen receptors to trigger ectopic activation of estrogen responsive signaling pathways [11]. Elevate
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