Abstract
BackgroundThe 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.ResultsEstrogen 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.ConclusionsThese 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.
Highlights
The increasing incidence of reproductive disorders in humans has been attributed to in utero exposure to estrogenic endocrine disruptors
Nuclear localisation indicates the activation of Estrogen receptor α (ERα) in the presence of both 10 and 100 nM of EE2 in our culture system and confirms the ability of the NTERA-2 clone D1 (NT2/D1) cells to respond to estrogen exposures
Together, our data demonstrate that estrogen can alter the bioavailability of SRY-box transcription factor 9 (SOX9) within NT2/D1 cells to cause a suppression of the testis developmental program and promote transcription of key ovarian genes in a human testis-derived cell line (Fig. 6)
Summary
The increasing incidence of reproductive disorders in humans has been attributed to in utero exposure to estrogenic endocrine disruptors. Exposure of the developing testis to exogenous estrogen can negatively impact male reproductive health. 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. Infertility and DSDs can have genetic causes, the recent and rapid decline in overall reproductive health and fertility is unequivocally linked to our exposure to endocrine disrupting chemicals (EDCs) [5,6,7,8,9,10]. Estrogenic EDCs are some of the most pervasive in our environment and include compounds such as bisphenol A, 17α-ethynylestradiol, phthalates, and genistein.
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