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雌激素抑制 SOX9 并激活人睾丸衍生细胞系中的女性发育标志物。

Estrogen suppresses SOX9 and activates markers of female development in a human testis-derived cell line.

机构信息

School of BioSciences, The University of Melbourne, Parkville, VIC, 3010, Australia.

出版信息

BMC Mol Cell Biol. 2020 Sep 15;21(1):66. doi: 10.1186/s12860-020-00307-9.

DOI:10.1186/s12860-020-00307-9
PMID:32933467
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7493336/
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.

摘要

背景

人类生殖障碍发病率的增加归因于宫内暴露于雌激素类内分泌干扰物。特别是，外源性雌激素对发育中睾丸的暴露会对男性生殖健康产生负面影响。为了确定雌激素如何影响人类性腺功能，我们用雌激素处理人睾丸衍生细胞系 NT2/D1，并研究其对 SOX9 及颗粒细胞（卵巢）和 Sertoli 细胞（睾丸）发育关键标志物表达的影响。

结果

雌激素成功地在 NT2/D1 细胞中激活其同源受体（雌激素受体 α；ESR1）。我们观察到雌激素处理后细胞质 SOX9 显著增加。在雌激素暴露 48 小时后，关键 Sertoli 细胞基因 SOX9、SRY、AMH、FGF9 和 PTGDS 的 mRNA 水平显著降低。随后，在雌激素暴露 96 小时后，关键颗粒细胞基因 FOXL2 和 WNT4 的 mRNA 水平显著增加。

结论

这些结果与雌激素对有袋动物性腺的作用一致，并表明雌激素对性腺细胞命运决定具有高度保守的影响，这种影响在 1.6 亿多年前的哺乳动物中就已经存在。雌激素的这种作用表现为导致最近几十年来报道的男性生育力和生殖健康显著下降的潜在机制。鉴于我们广泛接触雌激素类内分泌干扰物，它们对 SOX9 和 Sertoli 细胞决定的影响可能对成年睾丸产生重大影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/d050eef55d89/12860_2020_307_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/bfbb71b5b086/12860_2020_307_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/ca858296f12f/12860_2020_307_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/ddf28a5551c2/12860_2020_307_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/020dba990f2b/12860_2020_307_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/a3d3eadd7be4/12860_2020_307_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/d050eef55d89/12860_2020_307_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/bfbb71b5b086/12860_2020_307_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/ca858296f12f/12860_2020_307_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/ddf28a5551c2/12860_2020_307_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/020dba990f2b/12860_2020_307_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/a3d3eadd7be4/12860_2020_307_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b99/7493336/d050eef55d89/12860_2020_307_Fig6_HTML.jpg

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