Ge Caiyun, Yu Luting, Fang Man, Cao Xinrui, Chen Huijun, Wang Hui
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Toxicol Lett. 2025 Jul;410:83-95. doi: 10.1016/j.toxlet.2025.06.007. Epub 2025 Jun 3.
It is known that excessive exposure to maternal glucocorticoids during fetal development can cause fetal intrauterine growth retardation (IUGR) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays an important role in the regulation of fetal glucocorticoid level. Our previous study has found that prenatal caffeine exposure (PCE) can inhibit placental 11β-HSD2 expression. However, the epigenetic mechanism and the role of 11β-HSD2 in PCE-induced IUGR remain undetermined. Pregnant Wistar rats were intragastrically administered caffeine (30 and 120 mg/kg·d) on gestational days 9-20. We found that caffeine decreased the fetal body weights, increased maternal/fetal serum and placental corticosterone levels; moreover, it increased placental early growth response factor 1 (EGR1) expression and decreased 11β-HSD2 expression. Further, in HTR-8/SVneo cells, caffeine inhibited the cAMP/PKA signal pathway, increased EGR1 expression, decreased 11β-HSD2 expression, and changed histone modifications (H3K9ac decrease, H3K9me2 increase) in the HSD11B2 promoter region. Adenylyl cyclase agonist and EGR1 knockdown all reversed the inhibition of 11β-HSD2 expression by caffeine. It is suggested that the cAMP/PKA/EGR1 signaling pathway mediates caffeine-induced 11β-HSD2 expression inhibition in placental trophoblasts. Finally, using clinical specimens, we confirmed the inhibition of cAMP/PKA signaling pathway, the increase of EGR1/SP1 expression ratio, and the decrease of 11β-HSD2 expression in IUGR placentas. Among them, 11β-HSD2 expression and neonatal birth weight were positively correlated with placental cAMP/PKA signaling pathway, but negatively correlated with EGR1/SP1 expression ratio. In conclusion, the cAMP/PKA signaling pathway and its regulated EGR1/SP1 expression ratio are common regulatory mechanisms of placental 11β-HSD2 in IUGR fetuses. This study elucidates the epigenetic mechanism of PCE on placental 11β-HSD2 expression. Combined with clinical verification, the common mechanism of placental 11β-HSD2 expression down-regulation and IUGR occurrence was proposed, which provided a new idea for exploring early warning and prevention targets of IUGR.
已知胎儿发育过程中过度暴露于母体糖皮质激素会导致胎儿宫内生长受限（IUGR），而2型11β-羟基类固醇脱氢酶（11β-HSD2）在调节胎儿糖皮质激素水平中起重要作用。我们之前的研究发现，产前咖啡因暴露（PCE）可抑制胎盘11β-HSD2的表达。然而，11β-HSD2在PCE诱导的IUGR中的表观遗传机制和作用仍未明确。将怀孕的Wistar大鼠在妊娠第9至20天经胃给予咖啡因（30和120 mg/kg·d）。我们发现咖啡因降低了胎儿体重，增加了母/胎血清和胎盘皮质酮水平；此外，它增加了胎盘早期生长反应因子1（EGR1）的表达并降低了11β-HSD2的表达。进一步地，在HTR-8/SVneo细胞中，咖啡因抑制了cAMP/PKA信号通路，增加了EGR1的表达，降低了11β-HSD2的表达，并改变了HSD11B2启动子区域的组蛋白修饰（H3K9ac减少，H3K9me2增加）。腺苷酸环化酶激动剂和EGR1敲低均逆转了咖啡因对11β-HSD2表达的抑制作用。提示cAMP/PKA/EGR1信号通路介导了咖啡因诱导的胎盘滋养层细胞中11β-HSD2表达的抑制。最后，使用临床标本，我们证实了IUGR胎盘组织中cAMP/PKA信号通路的抑制、EGR1/SP1表达比值的增加以及11β-HSD2表达的降低。其中，11β-HSD2表达和新生儿出生体重与胎盘cAMP/PKA信号通路呈正相关，但与EGR1/SP1表达比值呈负相关。总之，cAMP/PKA信号通路及其调节的EGR1/SP1表达比值是IUGR胎儿胎盘11β-HSD2的常见调节机制。本研究阐明了PCE对胎盘11β-HSD2表达的表观遗传机制。结合临床验证，提出了胎盘11β-HSD2表达下调与IUGR发生的共同机制，为探索IUGR的预警和预防靶点提供了新思路。
