ETHANOL ENHANCEMENT OF LIGAND-STIMULATED CAMP PRODUCTION BY CULTURED HUMAN PLACENTAL TROPHOBLASTS

Chronic ethanol (EtOH) use during pregnancy can be associated with fet al injury including the fetal alcohol syndrome (FAS). A contributing f actor 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) r apidly stimulated cAMP with a peak between 2.5 and 5 min, which gradua lly returned to basal levels over 3-4 hr. EtOH treatment for >16 hr re sulted in an up-regulation of epinephrine-stimulated cAMP production. Inhibition of phosphodiesterase with Rolipram(R) enhanced the effect o f EtOH on cAMP production, suggesting that the effect of EtOH treatmen t was not due to phosphodiesterase inhibition. In cultured trophoblast s, EtOH treatment increased both epinephrine and 16,16'-dimethylprosta glandin E(2) (dm-PGE(2))-dependent cAMP production at varying ligand c oncentrations, suggesting an increased capacity to respond. When troph oblasts were treated with forskolin, a stimulator of adenylyl cyclase, cAMP production was enhanced in EtOH-treated cells. This suggests tha t EtOH treatment enhances adenylyl cyclase activity in these intact, c ultured cells. Unlike trophoblasts from term human placenta, JAR chori ocarcinoma cells did not respond to epinephrine, adenosine, or dm-PGE( 2). The choriocarcinoma cells appeared to have lost the ability to res pond to these ligands. Although the JAR cell adenylyl cyclase was stim ulated by forskolin, EtOH treatment did not alter forskolin-stimulated cAMP production. In summary, EtOH-induced up-regulation of cAMP produ ction appears to be cell specific, being present in normal human troph oblasts but not in undifferentiated choriocarcinoma cells.