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

We review recent findings pertaining to several environmental agents (ethan ol, phencyclidine, ketamine, nitrous oxide, barbiturates, benzodiazepines, halothane, isoflurane, and propofol) that have the potential to delete larg e numbers of neurons from the developing brain by a newly discovered mechan ism involving interference in the action of neurotransmitters [glutamate an d gamma-amino butyric acid (GABA at N-methyl-D-aspartate (NMDA)I and GABA(A ) receptors during the synaptogenesis period, also known as the brain growt h-spurt period. Transient interference (lasting greater than or equal to 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 idle by ap optosis). Many of these agents are drugs of abuse (ethanol is a prime examp le) to which the human fetal brain may be exposed during the third trimeste r by drug-abusing mothers. Ethanol triggers massive apoptotic neurodegenera tion 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 h uman fetus to ethanol (fetal alcohol syndrome). Exposure of the immature br ain in a medical treatment context is also of concern because many of these agents are drugs used frequently as sedatives, tranquilizers, anticonvulsa nts, 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 developin g human brain to environmental agents that act by this mechanism.