Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain

John W. Olney, Nuri B. Farber, David F. Wozniak, Vesna Jevtovic-Todorovic, Chrysanthy Ikonomidou

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We review recent findings pertaining to several environmental agents (ethanol, phencyclidine, ketamine, nitrous oxide, barbiturates, benzodiazepines, halothane, isoflurane, and propofol) that have the potential to delete large numbers of neurons from the developing brain by a newly discovered mechanism involving interference in the action of neurotransmitters [glutamate and γ-amino butyric acid (GABA) at N-methyl-D-aspartate (NMDA)] and GABA(A) receptors during the synaptogenesis period, also known as the brain growth-spurt period. Transient interference (lasting ≥ 4 hr) in the activity of these transmitters during the synaptogenesis period (the last trimester of pregnancy and the first several years after birth in humans) causes millions of developing neurons to commit suicide (die by apoptosis). Many of these agents are drugs of abuse (ethanol is a prime example) to which the human fetal brain may be exposed during the third trimester by drug-abusing mothers. Ethanol triggers massive apoptotic neurodegeneration in the developing brain by interfering with both the NMDA and GABA(A) receptor systems, and this can explain the reduced brain mass and lifelong neurobehavioral disturbances associated with intrauterine exposure of the human fetus to ethanol (fetal alcohol syndrome). Exposure of the immature brain in a medical treatment context is also of concern because many of these agents are drugs used frequently as sedatives, tranquilizers, anticonvulsants, or anesthetics in pediatric and/or obstetrical medicine. Because this is a newly discovered mechanism, further research will be required to fully ascertain the nature and degree of risk posed by exposure of the developing human brain to environmental agents that act by this mechanism.

Original languageEnglish
Pages (from-to)383-388
Number of pages6
JournalEnvironmental Health Perspectives
Issue numberSUPPL. 3
StatePublished - 2000


  • Anesthetics
  • Apoptosis
  • Barbiturates
  • Benzodiazepines
  • Ethanol
  • GABA(A) receptors
  • Ketamine
  • NMDA receptors
  • Phencyclidine
  • Synaptogenesis


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