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Ethanol Induces Apoptotic Death of Developing -Endorphin Neurons via Suppression of Cyclic Adenosine Monophosphate Production and Activation of Transforming Growth Factor-1-Linked Apoptotic Signaling

Endocrine Program and Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey

The mechanism by which ethanol induces -endorphin (-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 -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 -EP neurons. The AC inhibitor dideoxyadenosine (DDA) increased cell apoptosis and reduced the number of -EP neurons, and it potentiated the apoptotic action of ethanol on these neurons. -EP neurons in hypothalamic cultures showed immunoreactivity to transforming growth factor-1 (TGF-1) protein. Ethanol and DDA increased TGF-1 production and/or release from hypothalamic cells. A cAMP analog blocked the activation by ethanol of TGF-1 in these cells. TGF-1 increased apoptosis of -EP neurons, but it did not potentiate the action of ethanol or DDA actions on these neurons. TGF-1 neutralizing antibody blocked the apoptotic action of ethanol on -EP neurons. Determination of TGF-1-controlled cell apoptosis regulatory gene levels in hypothalamic cell cultures and in isolated -EP neurons indicated that ethanol, TGF-1, and DDA similarly alter the expression of these genes in these cells. These data suggest that ethanol increases -EP neuronal death during the developmental period by cellular mechanisms involving, at least partly, the suppression of cAMP production and activation of TGF-1-linked apoptotic signaling.

Address correspondence to: Dr. Dipak K. Sarkar, Endocrinology Program and Department of Animal Sciences, 84 Lipman Dr., Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. E-mail: sarkar{at}aesop.rutgers.edu

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