LEAD (PB- PATHOLOGICAL IMPLICATIONS(+) PROMOTES APOPTOSIS IN NEWBORN RAT CEREBELLAR NEURONS )

Despite mandated reduction in environmental lead (Pb++), such exposure still poses a public health hazard for children, with devastating eff ects on CNS development. To replicate aspects of this neurotoxicity, w e used cultured granule cells from newborn rat cerebella to study whet her apoptotic or necrotic death is the major consequence of exposure t o low micromolar concentrations of Pb++. At a low dose, 1 mu M (EC(50) similar or equal to 10 mu M), Pb++ does not affect glutamate-induced neuronal necrosis but promotes neuronal apoptosis, as characterized mo rphologically by cell shrinkage and chromatin condensation, biochemica lly by the typical internucleosomal DNA fragmentation and functionally by dependence on new synthesis of macromolecules (cycloheximide- and actinomycin D-sensitive). The low micromolar doses of Pb++ that promot e apoptosis are well within the blood level range reported to impair C NS function in children and to alter synaptogenesis in the neonatal ra t brain. Thus these in-vitro results suggest that the highly neurotoxi c action of Pb++ in the developing CNS of children might depend on a f acilitation of apoptosis. The Pb++-elicited potentiation of neuronal a poptosis is attenuated by treatment with the voltage-sensitive Ca++ ch annel agonist Bay K8644, which suggests the possible use of this agoni st for treatment of the neurotoxic effects of Pb++.