Chen Guanghui, Chen Yawen, Ai Can, Bin Li, Wang Hui
Department of Pharmacology, Wuhan University School of Basic Medical Science, Wuhan, 430071, China; Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Pharmacology, Wuhan University School of Basic Medical Science, Wuhan, 430071, China.
Chem Biol Interact. 2025 Oct 8;419:111625. doi: 10.1016/j.cbi.2025.111625. Epub 2025 Jul 9.
Our previous study has confirmed that the occurrence of fetal-originated disease is related to the changes in the developmental programming of adrenal in offspring. The aim of this study was to investigate the effects of prenatal caffeine exposure (PCE) on adrenal developmental programming in offspring rats and the underlying mechanisms. Here, PCE inhibited adrenal morphology and steroidogenic function in female and male offspring, and the suppression persisted in female offspring up to postnatal week 28 (PW28), while no significant changes in male offspring. Besides, adrenal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression was consistently decreased from intrauterine to PW28 in PCE female offspring, while it was decreased in male fetal offspring without significant change in PW28. Meanwhile, the adrenal 11β-HSD2 expression in PCE female offspring was positively correlated with developmental parameters. To explore its intrauterine origin, we found that PCE could elevate serum corticosterone levels in fetal rats. At the cellular level, high concentration of cortisol could inhibit 11β-HSD2 expression, and 11β-HSD2 overexpression could reverse the inhibition of steroidogenesis induced by cortisol. Further, we confirmed the epigenetic mechanism of the reduced adrenal 11β-HSD2 expression in PCE female offspring. On the one hand, high level of intrauterine glucocorticoid induced by PCE could lead to the decrease of H3K14ac level and expression of 11β-HSD2 through GR/HDAC4 pathway, which could last until birth. On the other hand, caffeine could decrease 11β-HSD2 expression through A2AR/cAMP/PKA signal, which synergistically enhanced the inhibitory effect of corticosterone on H3K14ac level and expression of 11β-HSD2. In conclusion, PCE could cause adrenal hypoplasia in female offspring, which was related to the low functional programming of 11β-HSD2 caused by the combination of high levels of glucocorticoids and caffeine.
我们之前的研究已证实，源自胎儿期疾病的发生与子代肾上腺发育编程的变化有关。本研究旨在探讨产前咖啡因暴露（PCE）对子代大鼠肾上腺发育编程的影响及其潜在机制。在此，PCE抑制了雌性和雄性子代的肾上腺形态及类固醇生成功能，这种抑制在雌性子代中持续至出生后第28周（PW28），而雄性子代无显著变化。此外，PCE雌性子代从子宫内期到PW28，肾上腺11β - 羟基类固醇脱氢酶2型（11β - HSD2）表达持续下降，而雄性胎儿子代中该表达下降，在PW28时无显著变化。同时，PCE雌性子代的肾上腺11β - HSD2表达与发育参数呈正相关。为探究其子宫内起源，我们发现PCE可提高胎鼠血清皮质酮水平。在细胞水平上，高浓度皮质醇可抑制11β - HSD2表达，而11β - HSD2过表达可逆转皮质醇对类固醇生成的抑制作用。此外，我们证实了PCE雌性子代肾上腺11β - HSD2表达降低的表观遗传机制。一方面，PCE诱导的子宫内高水平糖皮质激素可通过GR/HDAC4途径导致H3K14ac水平降低及11β - HSD2表达下降，这种情况可持续至出生。另一方面，咖啡因可通过A2AR/cAMP/PKA信号降低11β - HSD2表达，协同增强皮质酮对H3K14ac水平及11β - HSD2表达的抑制作用。总之，PCE可导致雌性子代肾上腺发育不全，这与高水平糖皮质激素和咖啡因共同作用导致的11β - HSD2低功能编程有关。
