ALTERED CYCLIC-AMP-DEPENDENT HUMAN CHORIONIC-GONADOTROPIN PRODUCTION IN CULTURED HUMAN PLACENTAL TROPHOBLASTS EXPOSED TO ETHANOL

Chronic ethanol abuse during pregnancy can cause fetal injury, includi ng the fetal alcohol syndrome (FAS). A contributing factor in this fet al injury may be the effect of ethanol on placental function. Previous studies have shown that ethanol treatment increases human chorionic g onadotropin (hCG) production by cultured human placental trophoblasts. In this study, we demonstrated that the stimulation of hCG production correlates with the ethanol concentration. Ethanol treatment enhanced intracellular adenosine 3':5'-cyclic monophosphate (cAMP) levels in r esponse to either cholera toxin (CTX) or forskolin (FSK). Moreover, ba sal (i.e. unstimulated) cAMP levels were increased at 2 hr of ethanol exposure. However, this effect did not persist throughout the 24-hr in cubation period. Therefore, ethanol treatment appears to induce increa sed hCG production secondary to enhanced basal or stimulated cAMP prod uction. The effect of ethanol was not associated with changes in G(s) or G(i2) expression, as determined by northern blot and western blot a nalyses. In plasma membrane preparations from ethanol-treated cells, c AMP production was higher in response to Mn2+ a direct stimulator of a denylyl cyclase. Inclusion of Rp-cAMP, a protein kinase A inhibitor, e liminated the ethanol effect on hCG production. Treatment of cells wit h 8-Br-cAMP stimulated hCG production, but there was no difference bet ween the ethanol-naive control and the ethanol-treated cells. These da ta suggest that ethanol treatment increases in vitro hCG production in human placental trophoblasts by enhancing cAMP production. Ethanol tr eatment appears to increase trophoblast adenylyl cyclase activity. (C) 1998 Elsevier Science Inc.