Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats.
Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats.
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咖啡因诱导的海马糖皮质激素代谢激活导致胎鼠下丘脑-垂体-肾上腺轴抑制
DOI：
10.1371/journal.pone.0044497
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Xu D;Zhang B;Liang G;Ping J;Kou H;Li X;Xiong J;Hu D;Chen L;Magdalou J;Wang H
流行病学调查表明，胎儿宫内发育迟缓（IUGR）易患成人代谢综合征。临床调查和实验表明，咖啡因是IUGR的明确诱导剂，因为摄入含咖啡因的食物或饮料的儿童极易患成人肥胖和高血压。本研究的目的是探讨产前摄入咖啡因对胎儿海马和下丘脑-垂体-肾上腺（HPA）轴功能发育的影响，并阐明咖啡因诱导的宫内HPA轴相关神经内分泌改变。孕11 ~ 20天Wistar大鼠分别灌胃给予20、60和180 mg/kg·d咖啡因。结果表明，产前摄入咖啡因显着降低胎儿下丘脑促肾上腺皮质激素释放激素的表达。咖啡因治疗后，胎儿肾上腺皮质变化轻微，胎儿肾上腺皮质类固醇急性调节蛋白（星星）和胆固醇侧链裂解酶（P450 SCC）的表达以及胎儿肾上腺内源性皮质酮（CORT）水平均显著降低。此外，摄入咖啡因显著增加母体和胎儿血CORT水平，降低胎盘11β-羟基类固醇脱氢酶-2（11β-HSD-2）的表达。此外，体内和体外研究均表明，咖啡因可下调胎儿海马11β-HSD-2的表达，促进11β-羟类固醇脱氢酶1和糖皮质激素受体（GR）的表达，并增强海马11β-HSD-2启动子内的DNA甲基化。这些结果表明，产前摄入咖啡因抑制胎儿HPA轴的发展，这可能与胎儿过度表达母亲的糖皮质激素和激活的糖皮质激素代谢在胎儿海马。这些结果将有助于阐明咖啡因的发育毒性，并探讨胎儿起源的成人HPA轴功能障碍和代谢综合征的易感性，胎儿胎儿宫内发育迟缓的后代咖啡因诱导。
Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg·d caffeine from gestational days 11–20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.
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DOI：
10.1590/s0034-89102008000100002
发表时间：
2008-02-01
期刊：
Revista de Saúde Pública
影响因子：
--
作者：
Silveira, Vera Maria Freitas da;Horta, Bernardo Lessa
通讯作者：
Horta, Bernardo Lessa
影响因子：
15.9
作者：
Alikhani-Koopaei, R;Fouladkou, F;Frey, BM
通讯作者：
Frey, BM
影响因子：
2.9
作者：
Kjaer, S. L.;Wegener, G.;Hougaard, K. S.
通讯作者：
Hougaard, K. S.
DOI：
10.1152/ajpregu.00122.2010
发表时间：
2010-07-01
影响因子：
2.8
作者：
Baserga, Mariana;Kaur, Rajwinderjit;Lane, Robert H.
通讯作者：
Lane, Robert H.
影响因子：
4.2
作者：
Gavrieli, Anna;Yannakoulia, Mary;Mantzoros, Christos S.
通讯作者：
Mantzoros, Christos S.