title: Ethanol induces apoptotic death of developing beta-endorphin neurons via suppression of cyclic adenosine monophosphate production and activation of transforming growth factor-beta1-linked apoptotic signaling.
abstract: The mechanism by which ethanol induces beta-endorphin (beta-EP) neuronal death during the developmental period was determined using fetal rat hypothalamic cells in primary cultures. The addition of ethanol to hypothalamic cell cultures stimulated apoptotic cell death of beta-EP neurons by increasing caspase-3 activity. Ethanol lowered the levels of adenylyl cyclase (AC)7 mRNA, AC8 mRNA, and/or cAMP in hypothalamic cells, whereas a cAMP analog blocked the apoptotic action of ethanol on beta-EP neurons. The AC inhibitor dideoxyadenosine (DDA) increased cell apoptosis and reduced the number of beta-EP neurons, and it potentiated the apoptotic action of ethanol on these neurons. beta-EP neurons in hypothalamic cultures showed immunoreactivity to transforming growth factor-beta1 (TGF-beta1) protein. Ethanol and DDA increased TGF-beta1 production and/or release from hypothalamic cells. A cAMP analog blocked the activation by ethanol of TGF-beta1 in these cells. TGF-beta1 increased apoptosis of beta-EP neurons, but it did not potentiate the action of ethanol or DDA actions on these neurons. TGF-beta1 neutralizing antibody blocked the apoptotic action of ethanol on beta-EP neurons. Determination of TGF-beta1-controlled cell apoptosis regulatory gene levels in hypothalamic cell cultures and in isolated beta-EP neurons indicated that ethanol, TGF-beta1, and DDA similarly alter the expression of these genes in these cells. These data suggest that ethanol increases beta-EP neuronal death during the developmental period by cellular mechanisms involving, at least partly, the suppression of cAMP production and activation of TGF-beta1-linked apoptotic signaling.
authors.affiliation: Endocrinology Program and Department of Animal Sciences, 84 Lipman Dr., Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
authors.forename: Cui Ping
authors.initials: CP
authors.lastname: Chen
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhn
authors.forename: Kirti
authors.initials: K
authors.lastname: Chaturvedi
authors.forename: Nadka
authors.initials: N
authors.lastname: Boyadjieva
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Sarkar
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D016048:Dideoxyadenosine / Q000494:pharmacology; D047108:Embryonic Development / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000196:embryology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000431:Ethanol; D016048:Dideoxyadenosine; D001615:beta-Endorphin; D000242:Cyclic AMP; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D000262:Adenylyl Cyclases