Ethanol increases retinoic acid production in cerebellar astrocytes and in cerebellum

Peter John Andrew McCaffery, Omanand Koul, Deborah Smith, Joseph L Napoli, Na Chen, M David Ullman

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)233-241
Number of pages9
JournalDevelopmental Brain Research
Volume153
Issue number2
DOIs
Publication statusPublished - 25 Nov 2004

Keywords

  • alcohol dehydrogenase
  • aldehyde oxidoreductases
  • animals
  • astrocytes
  • cultured cells
  • central nervous system depressants
  • cerebellum
  • cytoplasmic granules
  • ethanol
  • immunoblotting
  • messenger RNA
  • rats
  • Sprague-Dawley rats
  • retinal dehydrogenase
  • reverse transcriptase polymerase chain reaction
  • chemical stimulation
  • tretinoin
  • fetal alcohol syndrome
  • cerebellar astrocyte
  • retinoic acid
  • brain growth spurt
  • RAR double mutants
  • Purkinje cell loss
  • vitamin A
  • binding proteins
  • Bergmann glia
  • intragastric intubation

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