Lead poisoning
Human exposure to lead (Pb2+), especially at a young age, impairs a range of neurological functions. A blood Pb2+ level above 10 ug/dL (~ 0.5 uM) is considered potentially hazardous. Recently it has been reported that approximately 5% of children in the U.S. have blood Pb2+ levels greater than or equal to 10 ug/dL. Thus Pb2+ poisoning is one of the most critical environmental health hazards affecting children today. The mechanism of Pb2+ toxicity remains poorly understood. One possible mechanism of its effects may be its influence on synaptic activity. We are studying the molecular basis of lead neurotoxicity in the brain.
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.
Further links on lead poisoning
- The Alliance to End Childhood Lead Poisoning (includes a large resource section)
- Centers for Disease Control (CDC) Childhood Lead Poisoning Prevention Program
- Lead Poisoning Prevention Outreach Program
- Coalition to End Childhood Lead Poisoning
- MedlinePlus information on lead (from the National Library of Medicine)
- Office of Healthy Homes and Lead Hazard Control-HUD
- The National Lead Information Center-at the US EPA
- Lead Poisoning Prevention Program (Maryland Department of the Environment)