Karl P I, Divald A, Fisher S E
Department of Pediatrics, North Shore University Hospital, Cornell University Medical College, Manhasset, NY 11030.
Biochem Pharmacol. 1994 Oct 7;48(7):1493-500. doi: 10.1016/0006-2952(94)90575-4.
Chronic ethanol (EtOH) use during pregnancy can be associated with fetal injury including the fetal alcohol syndrome (FAS). A contributing factor in this fetal injury may be the effect of EtOH on the placenta. In this study, we have examined the effect of in vitro EtOH treatment on adenosine 3':5'-cyclic monophosphate (cAMP) production by cultured trophoblasts, in response to various ligands. Epinephrine (10(-6) M) rapidly stimulated cAMP with a peak between 2.5 and 5 min, which gradually returned to basal levels over 3-4 hr. EtOH treatment for > 16 hr resulted in an up-regulation of epinephrine-stimulated cAMP production. Inhibition of phosphodiesterase with Rolipram enhanced the effect of EtOH on cAMP production, suggesting that the effect of EtOH treatment was not due to phosphodiesterase inhibition. In cultured trophoblasts, EtOH treatment increased both epinephrine and 16,16'-dimethylprostaglandin E2 (dm-PGE2)-dependent cAMP production at varying ligand concentrations, suggesting an increased capacity to respond. When trophoblasts were treated with forskolin, a stimulator of adenylyl cyclase, cAMP production was enhanced in EtOH-treated cells. This suggests that EtOH treatment enhances adenylyl cyclase activity in these intact, cultured cells. Unlike trophoblasts from term human placenta, JAR choriocarcinoma cells did not respond to epinephrine, adenosine, or dm-PGE2. The choriocarcinoma cells appeared to have lost the ability to respond to these ligands. Although the JAR cell adenylyl cyclase was stimulated by forskolin, EtOH treatment did not alter forskolin-stimulated cAMP production. In summary, EtOH-induced up-regulation of cAMP production appears to be cell specific, being present in normal human trophoblasts but not in undifferentiated choriocarcinoma cells.
孕期长期摄入乙醇（EtOH）可能会导致胎儿损伤，包括胎儿酒精综合征（FAS）。这种胎儿损伤的一个促成因素可能是EtOH对胎盘的影响。在本研究中，我们检测了体外EtOH处理对培养的滋养层细胞在响应各种配体时产生3':5'-环磷酸腺苷（cAMP）的影响。肾上腺素（10⁻⁶ M）能迅速刺激cAMP产生，在2.5至5分钟达到峰值，随后在3至4小时内逐渐恢复到基础水平。EtOH处理超过16小时会导致肾上腺素刺激的cAMP产生上调。用咯利普兰抑制磷酸二酯酶可增强EtOH对cAMP产生的影响，这表明EtOH处理的效果并非由于磷酸二酯酶抑制。在培养的滋养层细胞中，EtOH处理在不同配体浓度下均增加了肾上腺素和16,16'-二甲基前列腺素E2（dm-PGE2）依赖性的cAMP产生，表明反应能力增强。当用腺苷酸环化酶刺激剂福斯高林处理滋养层细胞时，EtOH处理的细胞中cAMP产生增加。这表明EtOH处理增强了这些完整培养细胞中的腺苷酸环化酶活性。与足月人胎盘的滋养层细胞不同，JAR绒毛膜癌细胞对肾上腺素、腺苷或dm-PGE2无反应。绒毛膜癌细胞似乎已丧失对这些配体的反应能力。尽管JAR细胞的腺苷酸环化酶受到福斯高林刺激，但EtOH处理并未改变福斯高林刺激的cAMP产生。总之，EtOH诱导的cAMP产生上调似乎具有细胞特异性，存在于正常人滋养层细胞中，而不存在于未分化的绒毛膜癌细胞中。
