Ethanol increases retinoic acid production in cerebellar astrocytes and in cerebellum.
Several characteristics of fetal alcohol syndrome (FAS) are similar to the teratogenic effects of retinoic acid (RA) exposure. It has been suggested that FAS may result from ethanol-induced alteration in endogenous RA synthesis, leading to abnormal embryonic concentrations of this morphogen. We examined whether ethanol may interfere with RA synthesis in the postnatal cerebellum, as a region of the developing CNS particularly vulnerable to both ethanol and RA teratogenesis. It was found that astrocytes are the predominant source of postnatal RA synthesis in the cerebellum. They express both retinaldehyde dehydrogenase 1 and 2. In vitro cytosolic preparations of astrocytes, as well as live cell preparations, have an increased capacity to synthesize RA in the presence of ethanol. A mechanism by which ethanol could stimulate RA synthesis is via the ethanol-activated short-chain retinol dehydrogenases, which we show to be present in the postnatal cerebellum. To determine whether ethanol stimulated RA synthesis in vivo, a sensitive and highly specific HPLC/MSn technique was used to measure cerebellar RA after administration of ethanol to postnatal day 4 rat pups. Cerebellar RA levels climbed significantly after such treatment. These results suggest that the cerebellar pathology exerted by ethanol may occur, at least in part, through increased production of RA.
McCaffery
Peter
P
University of Massachusetts Medical School Shriver Center, Waltham, MA, USA.
Koul
Omanand
O
Smith
Deborah
D
Napoli
Joseph L
JL
Chen
Na
N
Ullman
M David
MD
D000426:Alcohol Dehydrogenase / Q000096:biosynthesis; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D015151:Immunoblotting; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D050697:Retinal Dehydrogenase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D014212:Tretinoin / Q000378:metabolism*
D002492:Central Nervous System Depressants; D012333:RNA, Messenger; D000431:Ethanol; D014212:Tretinoin; D000426:Alcohol Dehydrogenase; D000445:Aldehyde Oxidoreductases; D050697:Retinal Dehydrogenase