A transcriptomics model of estrogen action in the ovine fetal hypothalamus: evidence for estrogenic effects of ICI 182,780.
A transcriptomics model of estrogen action in the ovine fetal hypothalamus: evidence for estrogenic effects of ICI 182,780.
复制标题
DOI：
10.14814/phy2.13871
复制
发表时间：
2018-09
影响因子：
2.5
通讯作者：
Wood CE
中科院分区：
文献类型：
--
作者：
Rabaglino MB;Keller-Wood M;Wood CE
雌二醇在妊娠末期刺激胎儿下丘脑-垂体-肾上腺轴中起关键作用。雌二醇的作用通过核和膜受体介导，可由ICI 182780（一种纯抗雌激素化合物）调节。本研究的目的是评估雌二醇和ICI 182780的转录组谱，验证ICI 182780在胎儿下丘脑中拮抗雌二醇作用的假设。长期插管的羊胎儿输注48 h：对照（n = 6）、17β‐雌二醇500 μg/kg/d（雌二醇，n = 4）、ICI 182780 5 mg/kg/d （ICI 5 mg, n = 4）和ICI 182780 5 mg/kg/d （ICI 5 mg, n = 5）。随后采集胎儿下丘脑，通过芯片检测基因表达。使用Bioconductor‐R和Cytoscape软件对转录组数据进行统计分析。出乎意料的是，35%和15.5%的雌二醇上调的差异表达基因（DEG）分别与ICI 5 mg和ICI 5 μg上调的DEG显著重叠（P < 0.05）。对于下调的DEG，这两个百分比分别为29.9%和15.5%。雌二醇与ICI 5 mg或ICI 5 μg之间的DEG沿相反方向几乎没有重叠。此外，与对照组相比，雌激素信号通路中的大多数基因在激活表皮生长因子受体后，在雌二醇、ICI 5 μg或ICI 5 mg中遵循相同的方向。综上所述，雌二醇和ICI 182780在发育中的大脑中具有雌激素基因组效应，这表明雌二醇对胎儿下丘脑的主要作用可能涉及另一个受体系统，而不是雌激素受体。
Estradiol plays a critical role in stimulating the fetal hypothalamus–pituitary–adrenal axis at the end of gestation. Estradiol action is mediated through nuclear and membrane receptors that can be modulated by ICI 182,780, a pure antiestrogen compound. The objective of this study was to evaluate the transcriptomic profile of estradiol and ICI 182,780, testing the hypothesis that ICI 182,780 antagonizes the action of estradiol in the fetal hypothalamus. Chronically catheterized ovine fetuses were infused for 48 h with: vehicle (Control, n = 6), 17β‐estradiol 500 μg/kg/day (Estradiol, n = 4), ICI 182,780 5 μg/kg/day (ICI 5 μg, n = 4) and ICI 182,780 5 mg/kg/day (ICI 5 mg, n = 5). Fetal hypothalami were collected afterward, and gene expression was measured through microarray. Statistical analysis of transcriptomic data was performed with Bioconductor‐R and Cytoscape software. Unexpectedly, 35% and 15.5% of the upregulated differentially expressed genes (DEG) by Estradiol significantly overlapped (P < 0.05) with upregulated DEG by ICI 5 mg and ICI 5 μg, respectively. For the downregulated DEG, these percentages were 29.9% and 15.5%, respectively. There was almost no overlap for DEG following opposite directions between Estradiol and ICI ICI 5 mg or ICI 5 μg. Furthermore, most of the genes in the estrogen signaling pathway – after activation of the epidermal growth factor receptor – followed the same direction in Estradiol, ICI 5 μg or ICI 5 mg compared to Control. In conclusion, estradiol and ICI 182,780 have estrogenic genomic effects in the developing brain, suggesting the possibility that the major action of estradiol on the fetal hypothalamus involves another receptor system rather than estrogen receptors.