Molecular mechanisms of lead neurotoxicity

Epidemiological studies have shown a strong relationship between the level of lead in blood and bone as assessed by performance on IQ tests and other psychometric tests. Approximately 1 out of 10 children in the United States have blood lead levels above 10 mu g/dl, which has been established as the level of concern. Studies on experimental animals exposed to lead after bi rth have shown learning deficits at similar blood lead levels. Since learni ng requires the remodeling of synapses in the brain, lead may specifically affect synaptic transmission. Although the molecular targets for lead are u nknown, a vast amount of evidence accumulated over many years has shown tha t lead disrupts processes that are regulated by calcium. Our laboratory has been studying the effect of lead on protein kinase C, a family of isozymes some of which require calcium for activity. We and others have shown that picomolar concentrations of lead can replace micromolar concentrations of c alcium in a protein kinase C enzyme assay. Furthermore, lead activates prot ein kinase C in intact cells and induces the expression of new genes by a m echanism dependent on protein kinase C. We propose that the learning defici ts caused by lead are due to events regulated by protein kinase C that most likely occur at the synapse.