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.
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.
Chen
Cui Ping
CP
Endocrinology Program and Department of Animal Sciences, 84 Lipman Dr., Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
Kuhn
Peter
P
Chaturvedi
Kirti
K
Boyadjieva
Nadka
N
Sarkar
Dipak K
DK
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
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