Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
Department of Orthopedic Surgery, Wuhan University Zhongnan Hospital, Wuhan, 430071, China.
Food Chem Toxicol. 2020 Jun;140:111279. doi: 10.1016/j.fct.2020.111279. Epub 2020 Mar 19.
Prenatal caffeine exposure (PCE) induces developmental toxicity of multi-organ and susceptibility to multi-disease in offspring. However, the effects of PCE on osteoarthritis susceptibility in adult offspring and its intrauterine programming mechanism remain to be further investigated. Here, we found that PCE induced susceptibility to osteoarthritis in male adult offspring rats, which was related to the inhibited function of cartilage matrix synthesis from fetuses to adults. Meanwhile, PCE consistently downregulated the H3K9ac and expression levels of transforming growth factor β receptor 1 (TGFβR1), and then blocked TGFβ signaling pathway, which contributed to the suppressed cartilage matrix synthesis. Moreover, the high level of corticosterone caused by PCE reduced the H3K9ac level on TGFβR1 promoter region through acting on glucocorticoids receptor (GR) and recruiting histone deacetylase 2 (HDAC2) into the nucleus of fetal chondrocytes. Taken together, PCE induced osteoarthritis susceptibility in male adult offspring rats, which was attributed to the low-functional programming of TGFβR1 induced by corticosterone via GR/HDAC2 signaling.
产前咖啡因暴露（PCE）可导致多器官发育毒性和后代多种疾病的易感性。然而，PCE 对成年后代骨关节炎易感性的影响及其宫内编程机制仍有待进一步研究。在这里，我们发现 PCE 可诱导雄性成年子代大鼠发生骨关节炎易感性，这与从胎儿到成年软骨基质合成功能受到抑制有关。同时，PCE 持续下调 H3K9ac 和转化生长因子β受体 1（TGFβR1）的表达水平，进而阻断 TGFβ 信号通路，导致软骨基质合成受到抑制。此外，PCE 引起的皮质酮水平升高通过作用于糖皮质激素受体（GR）并将组蛋白去乙酰化酶 2（HDAC2）募集到胎儿软骨细胞的核内，降低了 TGFβR1 启动子区域的 H3K9ac 水平。总之，PCE 可诱导雄性成年子代大鼠发生骨关节炎易感性，这归因于皮质酮通过 GR/HDAC2 信号诱导 TGFβR1 功能低下的编程。
