Estrogen suppresses SOX9 and activates markers of female development in a human testis-derived cell line
Estrogen suppresses SOX9 and activates markers of female development in a human testis-derived cell line
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DOI：
10.1186/s12860-020-00307-9
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发表时间：
2020-09-15
影响因子：
2.8
通讯作者：
Pask, Andrew J.
中科院分区：
文献类型：
--
作者：
Stewart, Melanie K.;Mattiske, Deidre M.;Pask, Andrew J.
人类生殖系统疾病发病率的增加归因于子宫内暴露于雌激素性内分泌干扰物。特别是，发育中的睾丸暴露于外源性雌激素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，我们用雌激素处理了人类睾丸来源的细胞系NT 2/D1，并检查了其对SOX 9的影响以及颗粒（卵巢）和支持（睾丸）细胞发育的关键标志物的表达。结果在NT 2/D1细胞中，雌激素成功地激活了其同源受体（雌激素受体α; ESR 1）。我们观察到雌激素治疗后细胞质SOX 9显著增加。雌激素作用48 h后，支持细胞关键基因SOX 9、SRY、AMH、FGF 9和PTGDS的mRNA水平显著降低。雌激素暴露96小时后，关键颗粒细胞基因FOXL 2和WNT 4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影响一致，并表明雌激素对性腺细胞命运决定具有高度保守的影响，这种影响在哺乳动物中已经存在了1.6亿多年。雌激素的这种作用是近几十年来报告的导致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性内分泌干扰物，它们对SOX 9和支持细胞测定的影响可能对成年睾丸产生相当大的影响。
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 genesSOX9, SRY, AMH, FGF9andPTGDSwere significantly reduced. This was followed by a significant increase in mRNA levels for the key granulosa cell genesFOXL2andWNT4after 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.