Lead poisoning

Our approach to lead poisoning

Since the early 1970s, it has been appreciated that lead blocks evoked neurotransmitter release while dramatically promoting spontaneous release. These effects have been observed in a variety of experimental paradigms including tissue culture, slice preparations, and synaptosomes. It is also known that lead potently activates protein kinase C (PKC), possibly acting via its calcium-binding C2 domain. We hypothesized that a mechanism by which lead affects neuronal function is by binding directly to synaptotagmin:

• Lead interacts with PKC at picomolar concentrations
• PKC has a C2 domain which promotes calcium-sensitive phospholipid binding
• Synaptotagmin has a pair of C2 domains through which lead might act
• Synaptotagmin is a synaptic vesicle protein that is a calcium sensor, and it is poised to regulate exocytotic release of neurotransmitter

We have found that lead interacts with synaptotagmin potently. While lead is likely to interact with many proteins to disrupt cellular function, its effects on synaptotagmin suggest a direct mechanism for its modulation of neurotransmission. This could partially account for lead's global effects on behavior.

Bouton CM, Frelin LP, Forde CE, Arnold Godwin H, Pevsner J. Synaptotagmin I is a molecular target for lead. J Neurochem. 2001 Mar;76(6):1724-35.

Hossain MA, Bouton CM, Pevsner J, Laterra J. Induction of vascular endothelial growth factor in human astrocytes by lead. Involvement of a protein kinase C/activator protein-1 complex-dependent and hypoxia-inducible factor 1-independent signaling pathway. J Biol Chem. 2000 Sep 8;275(36):27874-82.

In further studies, we measured the effect of lead on gene expression in cultured astrocytes. We used the DRAGON database to perform data analysis, and found groups of genes that were significantly regulated by lead exposure. The gene encoding annexin V, another protein that binds phospholipid in a calcium-dependent manner, was differentially regulated by lead exposure.

Bouton CM, Hossain MA, Frelin LP, Laterra J, Pevsner J. Microarray analysis of differential gene expression in lead-exposed astrocytes. Toxicol Appl Pharmacol 2001 Oct 1;176(1):34-53

Bouton CM, Pevsner J. Effects of lead on gene expression. Neurotoxicology. 2000 Dec;21(6):1045-55.