Simbulan R K, Liu X, Feuer S K, Maltepe E, Donjacour A, Rinaudo P
1Department of Obstetrics,Gynecology and Reproductive Sciences,University of California San Francisco,San Francisco,CA,USA.
2Department of Pediatrics,University of California San Francisco,San Francisco,CA,USA.
J Dev Orig Health Dis. 2016 Feb;7(1):73-82. doi: 10.1017/S2040174415007825. Epub 2015 Oct 29.
Prenatal development is highly plastic and readily influenced by the environment. Adverse conditions have been shown to alter organ development and predispose offspring to chronic diseases, including diabetes and hypertension. Notably, it appears that the changes in glucocorticoid hormones or glucocorticoid receptor (GR) levels in peripheral tissues could play a role in the development of chronic diseases. We have previously demonstrated that in vitro fertilization (IVF) and preimplantation embryo culture is associated with growth alterations and glucose intolerance in mice. However, it is unknown if GR signaling is affected in adult IVF offspring. Here we show that GR expression is increased in inbred (C57Bl6/J) and outbred (CF-1× B6D2F1/J) blastocysts following in vitro culture and elevated levels are also present in the adipose tissue of adult male mice. Importantly, genes involved in lipolysis and triglyceride synthesis and responsive to GR were also increased in adipose tissue, indicating that increased GR activates downstream gene pathways. The promoter region of GR, previously reported to be epigenetically modified by perinatal manipulation, showed no changes in DNA methylation status. Our findings demonstrate that IVF results in a long-term change in GR gene expression in a sex- and tissue-specific manner. These changes in adipose tissues may well contribute to the metabolic phenotype in mice conceived by IVF.
产前发育具有高度可塑性，且极易受到环境影响。已有研究表明，不良环境会改变器官发育，并使后代易患慢性疾病，包括糖尿病和高血压。值得注意的是，外周组织中糖皮质激素或糖皮质激素受体（GR）水平的变化似乎可能在慢性疾病的发生发展中起作用。我们之前已经证明，体外受精（IVF）和植入前胚胎培养与小鼠的生长改变和葡萄糖不耐受有关。然而，尚不清楚成年IVF后代的GR信号是否受到影响。在此我们表明，体外培养后，近交系（C57Bl6/J）和远交系（CF-1×B6D2F1/J）囊胚中的GR表达增加，成年雄性小鼠的脂肪组织中也存在GR水平升高的情况。重要的是，脂肪组织中参与脂肪分解和甘油三酯合成且对GR有反应的基因也增加了，这表明GR增加会激活下游基因通路。之前报道称GR启动子区域会因围产期操作发生表观遗传修饰，而我们的研究显示其DNA甲基化状态没有变化。我们的研究结果表明，IVF会以性别和组织特异性的方式导致GR基因表达发生长期变化。脂肪组织中的这些变化很可能促成了IVF受孕小鼠的代谢表型。
