Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Department of Gynaecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Sci Total Environ. 2021 Oct 1;789:147691. doi: 10.1016/j.scitotenv.2021.147691. Epub 2021 May 25.
Ovarian dysfunction has an intrauterine origin, and prenatal caffeine exposure (PCE) could lead to abnormal follicle counts in offspring after birth. However, the effect of PCE on offspring ovarian function and its mechanism of intrauterine programming have not been reported thus far. In this study, pregnant Wistar rats were intragastrically administered caffeine (30 and 120 mg/kg·d) at gestational days 9-20 (GD9-20). Certain tests were performed on the blood, ovaries and hypothalamus of female offspring at different time points. PCE female offspring had ovarian dysfunction in adulthood compared with the control. Further results showed that in utero ovarian morphological development and estradiol synthesis were inhibited but rapidly increased during puberty in the PCE group. The histone 3 lysine 27 acetylation (H3K27ac) level of the insulin-like growth factor 1 (IGF1) promoter region and its expression were decreased in the ovary, which was due to exposure to high levels of fetal blood corticosterone, and the H3K27ac level of IGF1 and its expression shifted to increase after birth with a decrease in serum corticosterone levels. Chronic stress led to increased serum corticosterone levels in adult offspring, whereas ovarian morphological development, the H3K27ac level of IGF1 and its expression, and estradiol synthesis were significantly inhibited. Moreover, the activity of the hypothalamic-pituitary-ovarian (HPO) axis was increased in the early postnatal period of PCE offspring, and chronic stress reversed these changes. In the KGN cell line, it was found that cortisol could promote the translocation of the glucocorticoid receptor (GR) into the nucleus and upregulate histone deacetylase 10 (HDAC10) to inhibit the H3K27ac level of IGF1 and its expression and estradiol synthesis. In summary, PCE is associated with ovarian dysfunction in female adult offspring, and the potential mechanism is related to intrauterine high glucocorticoid exposure by activating the GR and recruiting HDAC10 to affect ovarian glucocorticoid-IGF1 axis programming and to inhibit estradiol synthesis.
卵巢功能障碍具有宫内起源，产前咖啡因暴露（PCE）可能导致出生后后代卵泡计数异常。然而，迄今为止，PCE 对后代卵巢功能的影响及其宫内编程的机制尚未报道。在这项研究中，妊娠 Wistar 大鼠在妊娠第 9-20 天（GD9-20）经胃内给予咖啡因（30 和 120mg/kg·d）。在不同时间点对雌性后代的血液、卵巢和下丘脑进行了某些测试。与对照组相比，PCE 雌性后代在成年期出现卵巢功能障碍。进一步的结果表明，宫内卵巢形态发育和雌二醇合成受到抑制，但在 PCE 组青春期迅速增加。胰岛素样生长因子 1（IGF1）启动子区域的组蛋白 3 赖氨酸 27 乙酰化（H3K27ac）水平及其表达在卵巢中降低，这是由于胎儿血液皮质酮水平升高所致，IGF1 的 H3K27ac 水平及其表达在出生后随着血清皮质酮水平的降低而增加。慢性应激导致成年后代血清皮质酮水平升高，而卵巢形态发育、IGF1 的 H3K27ac 水平及其表达和雌二醇合成均受到显著抑制。此外，PCE 后代新生后期下丘脑-垂体-卵巢（HPO）轴的活性增加，慢性应激逆转了这些变化。在 KGN 细胞系中，发现皮质醇可以促进糖皮质激素受体（GR）向核内易位，并上调组蛋白去乙酰化酶 10（HDAC10），抑制 IGF1 的 H3K27ac 水平及其表达和雌二醇合成。总之，PCE 与雌性成年后代的卵巢功能障碍有关，其潜在机制与宫内高皮质醇暴露有关，通过激活 GR 并募集 HDAC10 来影响卵巢糖皮质激素-IGF1 轴编程并抑制雌二醇合成。
