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Intracellular signaling pathways involved in mediating the effects of lead on the transcription factor Sp1

D S Atkins1, Md Riyaz Basha, N H Zawia

  • 1Department of Pharmacology, Meharry Medical College, Nashville, TN 37028, USA.

International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience
|July 10, 2003
PubMed

Insights

Lead (Pb) exposure during brain development impairs cognition. This study shows Pb alters Sp1 DNA-binding via protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling pathways, revealing a mechanism for developmental neurotoxicity.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Toxicology

Background:

  • Lead (Pb) exposure during critical brain development causes cognitive and behavioral deficits.
  • The precise mechanism of Pb-induced developmental neurotoxicity remains unclear.
  • Pb may disrupt gene transcription essential for neural growth and differentiation by affecting the transcription factor Sp1.

Purpose of the Study:

  • To investigate the role of signaling factors in mediating Pb's effects on Sp1 DNA-binding.
  • To examine the in vivo and in vitro impact of Pb on Sp1 DNA-binding and associated signaling pathways.

Main Methods:

  • Monitored hippocampal Sp1 DNA-binding, PKC, and MAPK protein levels in Pb-exposed rats.
  • Utilized PC12 cells exposed to Pb and/or nerve growth factor (NGF) to assess signaling pathway interdependence.
  • Employed PKC inhibitor (staurosporine) and MAPK inhibitor (PD 98059) to elucidate pathway mediation.

Main Results:

  • Pb exposure in rats induced Sp1 DNA-binding during postnatal days 5-10, followed by a decline.
  • PKCalpha and MAPK protein levels exhibited similar temporal patterns to Sp1 DNA-binding.
  • In PC12 cells, Pb and NGF increased Sp1 DNA-binding; PKC inhibition diminished this effect, while MAPK inhibition abolished it.

Conclusions:

  • Sp1 DNA-binding is regulated by both PKC and MAPK signaling pathways.
  • These pathways likely mediate the indirect modulation of Sp1 DNA-binding by Pb.
  • Findings provide insight into the molecular mechanisms underlying Pb-induced developmental neurotoxicity.

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