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

It has been well established that exposure to Pb during critical periods of brain development results in both cognitive and behavioral deficits. Although the mechanism by which Pb induces developmental neurotoxicity is unknown, it may involve alterations in transcription of genes that are essential for growth and differentiation. Recent studies reveal that Pb interferes with growth and differentiation by acting on the transcription factor Sp1. Pb-induced changes in the activity of Sp1 may be consequent to alterations in intermediates in signal transduction pathways. This study examines both in vivo and in vitro the role of signaling factors in mediating the effects of Pb on Sp1 DNA-binding. Hippocampal developmental profiles of Sp1 DNA-binding, PKC, and MAPK protein levels were monitored in Pb-exposed rats. Pb exposure resulted in an induction of Sp1 DNA-binding during PND 5-10 followed by a subsequent decline on PND 15-20. The protein expression profiles for PKCalpha and MAPK followed a relatively similar pattern. To examine the interdependence between Sp1 DNA-binding, PKCalpha, and MAPK, PC12 cells were exposed to Pb and/or NGF. Pb or NGF exposure increased Sp1 DNA-binding. Addition of the PKC inhibitor (staurosporine) diminished NGF and Pb-induced Sp1 DNA-binding, while the MAPK inhibitor (PD 98059), completely abolished both basal and induced Sp1 DNA-binding. These findings demonstrate that Sp1 DNA-binding is regulated by PKC and MAPK, which may serve as mediators through which Pb may indirectly modulate Sp1 DNA-binding.