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Molecular mechanisms of lead neurotoxicity

J Bressler1, K A Kim, T Chakraborti

  • 1Dept. of Neurology, The Johns Hopkins University School of Public Health and Hygiene and The Kennedy Krieger Research Institute, Baltimore, MD 21205, USA. bressler@kennedykrieger.org

Neurochemical Research
|May 5, 1999
PubMed

Insights

Lead exposure in children impairs learning by affecting brain synapses. Lead disrupts calcium-regulated processes, specifically impacting protein kinase C, which is crucial for synaptic function and learning.

Area of Science:

  • Neuroscience
  • Toxicology
  • Developmental Biology

Background:

  • Epidemiological studies link blood and bone lead levels to cognitive deficits in children.
  • Elevated lead levels (above 10 microg/dl) are a significant public health concern, affecting approximately 10% of US children.
  • Lead exposure in young animals causes learning impairments, suggesting a direct impact on brain function.

Purpose of the Study:

  • To investigate the molecular mechanisms by which lead exposure causes learning deficits.
  • To explore the role of calcium-dependent signaling pathways, particularly protein kinase C, in lead's neurotoxicity.
  • To determine if lead affects synaptic transmission, a key process for learning and memory.

Main Methods:

  • Assessing the effect of lead on protein kinase C (PKC) activity in enzyme assays.
  • Investigating lead's impact on PKC activation in intact cells.
  • Examining lead-induced gene expression changes mediated by PKC.
  • Correlating lead exposure levels with cognitive performance using psychometric tests.

Main Results:

  • Lead can substitute for calcium at picomolar concentrations in protein kinase C enzyme assays.
  • Lead activates protein kinase C in living cells.
  • Lead exposure leads to the induction of new gene expression via a PKC-dependent pathway.
  • Significant correlations exist between lead levels and impaired performance on IQ and psychometric tests.

Conclusions:

  • Lead-induced learning deficits are likely mediated by disruptions in protein kinase C signaling pathways.
  • These disruptions primarily affect synaptic transmission, a critical process for learning and memory.
  • Lead's molecular targets may involve the interference with calcium-regulated cellular functions, particularly within the synapse.

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