Lead exposure alters cyclic-AMP response element binding protein phosphorylation and binding activity in the developing rat brain.

We examined the effect of lead (Pb(2+)) exposure during development on cyclic-AMP response element binding protein (CREB) expression and phosphorylation in cortical and hippocampal nuclear extracts at postnatal (PN) days 7, 14, 21 and 50. We also examined the binding of CREB family proteins to the cyclic-AMP response element (CRE) using a novel filter-binding assay that provides a quantitative measure of binding kinetics. In the hippocampus and cerebral cortex of control rats, CREB and phospho-CREB (pCREB; serine-133) expression is highest at PN7 and decreases steadily until PN50. Developmental Pb(2+) exposure does not affect total CREB levels but decreases pCREB levels at PN14 and PN50 in the cortex and at PN50 in the hippocampus. Using the filter-binding assay, we measured a 30% decrease in B(max) and 38% decrease in the Kd of CREB family proteins for the CRE in PN50 hippocampal nuclear fractions prepared from Pb(2+)-exposed rats. A similar, but nonsignificant, trend is observed in the cortex of PN50 lead-exposed rats. In addition, a 70% increase in the B(max) was observed in the cortex of PN14 lead-exposed rats without a significant change in the Kd. These disruptions in pCREB expression and binding activity of CREB family members during the ontogeny of the rat brain begin to decipher intracellular mechanisms of Pb(2+) neurotoxicity.