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.

中文翻译：

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GR / HDAC2 /TGFβR1通路有助于成年后代雄性大鼠咖啡因诱发的骨关节炎敏感性。

产前咖啡因暴露（PCE）会引起后代多器官发育毒性和对多病的易感性。然而，PCE对成年后代骨关节炎易感性及其子宫内编程机制的影响仍有待进一步研究。在这里，我们发现PCE在雄性成年后代大鼠中诱发了对骨关节炎的易感性，这与从胎儿到成年的软骨基质合成功能的抑制有关。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，然后阻断TGFβ信号通路，从而抑制了软骨基质的合成。此外，PCE引起的高皮质酮水平通过作用于糖皮质激素受体（GR）并募集组蛋白脱乙酰基酶2（HDAC2）进入胎儿软骨细胞核，降低了TGFβR1启动子区域的H3K9ac水平。综上所述，PCE诱导了成年雄性后代大鼠的骨关节炎敏感性，这归因于皮质酮通过GR / HDAC2信号传导诱导的TGFβR1功能低下。