Dexamethasone Induces Germ Cell Apoptosis in the Human Fetal Ovary
Dexamethasone Induces Germ Cell Apoptosis in the Human Fetal Ovary
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DOI：
10.1210/jc.2012-1681
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发表时间：
2012-10-01
影响因子：
5.8
通讯作者：
Livera, Gabriel
中科院分区：
文献类型：
--
作者：
Poulain, Marine;Frydman, Nelly;Livera, Gabriel
背景：21-羟化酶缺乏是先天性肾上腺皮质增生症最常见的原因。孕妇提出的遗传传播的风险，可以用合成的糖皮质激素，如地塞米松（DEX），以防止女性胎儿男性化。目的：本研究的目的是评估潜在的有害影响DEX暴露对胎儿卵巢development.Settings：人类胎儿卵巢，从受精后8-11周，收获合法人工流产后可用的材料。他们培养在DEX（2，10，或50 μ M）的存在或不存在超过14 d，和组织学分析performed.Results：糖皮质激素受体NR 3C 1的存在和信号传导通路的活性在胎儿卵巢中表现为NR 3C 1的靶基因，如PLZF和FKBP 5，在响应DEX曝光的表达。DEX在10和50 μ M剂量下降低生殖细胞密度。通过5-溴-2 '-脱氧尿苷掺入监测，即使在最高剂量下，暴露于DEX也没有改变卵原细胞增殖，并且通过切割的半胱天冬酶3染色检测，显著增加了凋亡率。有趣的是，在DEX的存在下，在culture.Conclusion的过程中，促生存基因KIT的表达显着下降：我们已经证明了第一次，在体外暴露于高剂量的DEX损害人类胎儿卵子发生通过增加细胞凋亡。这些数据非常重要，需要进行额外的流行病学研究，以调查在胎儿期暴露于DEX的女性的生育能力。（临床内分泌代谢杂志97：E1890-E1897，2012）
Context: The 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. Pregnant women presenting a risk of genetic transmission may be treated with synthetic glucocorticoids such as dexamethasone (DEX) to prevent female fetus virilization.Objective: The aim of this study was to assess the potential deleterious effects of DEX exposure on fetal ovarian development.Settings: Human fetal ovaries, ranging from 8-11 weeks after fertilization, were harvested from material available after legally induced abortions. They were cultured in the absence or presence of DEX (2, 10, or 50 mu M) over 14 d, and histological analyses were performed.Results: The glucocorticoid receptor NR3C1 was present and the signaling pathway active in the fetal ovary as demonstrated by the expression of NR3C1 target genes, such as PLZF and FKBP5, in response to DEX exposure. DEX decreased germ cell density at the 10 and 50 mu M doses. Exposure to DEX, even at the highest dose, did not change oogonial proliferation as monitored by 5-bromo-2'-deoxyuridine incorporation and significantly increased the apoptotic rate, detected with cleaved caspase 3 staining. Interestingly, the expression of the prosurvival gene KIT was significantly decreased in the presence of DEX during the course of the culture.Conclusion: We have demonstrated for the first time that in vitro exposure to high doses of DEX impairs human fetal oogenesis through an increase in apoptosis. These data are of high importance, and additional epidemiological studies are required to investigate the female fertility of those women who have been exposed to DEX during fetal life. (J Clin Endocrinol Metab 97: E1890-E1897, 2012)