Role of Apoptosis in Neurotoxicology

The role of apoptosis in development and neurodegeneration has become increasingly apparent in the past 10 yr. Normal apoptosis occurs in the central nervous system (CNS) from the embryonic stage through senescence, with different cells in each region of the nervous system having characteristic temporal patterns of programmed cell death. Several different stimuli trigger the apoptotic cascade, initiating diverse intracellular signaling pathways. These include mitochondrial calcium overload, generation of reactive oxygen species, and alterations in neurotrophic factor signaling. Neurotrophic factor-mediated signaling is achieved though the interaction of p75NTR and Trk receptors to modulate apoptotic cell death in developing and adult neural tissues. Both in vivo and in vitro experiments have suggested that exposure to a number of neurotoxicants results in apoptosis. For example, exposure of organogenesis-stage mouse embryos to a wide variety of xenobiotics, including ethanol, arsenic, hydroxyurea, chemotheraputic drugs, or haloacetic acids, results in increased apoptosis during neurulation. Ethanol, a widely used neurotoxicant, has been shown to affect apoptosis, as well as proliferation and migration, in developing animals. Exposure to heavy metal contaminants has been implicated in apoptotic cell death. This has been demonstrated with methylmercury with in vivo exposure producing apoptosis in the cerebellum and in vitro studies in PC12 cells implicating a neurotrophic factor dependent mechanism for this effect.