Ethanol enhancement of ligand-stimulated cAMP production by cultured human placental trophoblasts.
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.
Karl
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PI
Department of Pediatrics, North Shore University Hospital, Cornell University Medical College, Manhasset, NY 11030.
Divald
A
A
Fisher
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SE
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis*; D004837:Epinephrine / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013997:Time Factors; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
D008024:Ligands; D000431:Ethanol; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D015064:16,16-Dimethylprostaglandin E2; D004837:Epinephrine