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

Area of Science:

• Neuroscience
• Developmental Biology
• Toxicology

Background:

• Cyclic-AMP response element binding protein (CREB) is crucial for neuronal plasticity and memory.
• Lead (Pb(2+)) is a potent neurotoxin that can disrupt cognitive development.
• Developmental exposure to lead is associated with long-term neurological deficits.

Purpose of the Study:

• To investigate the impact of developmental lead exposure on CREB expression and phosphorylation in rat cortical and hippocampal tissues.
• To quantify the effects of lead on the binding kinetics of CREB family proteins to the cyclic-AMP response element (CRE).

Main Methods:

• Western blot analysis to assess CREB and phospho-CREB (pCREB) levels at postnatal days 7, 14, 21, and 50.
• Novel filter-binding assay to measure the binding affinity (Kd) and capacity (Bmax) of CREB proteins to CRE.
• Analysis of nuclear extracts from rat cerebral cortex and hippocampus.

Main Results:

• Developmental lead exposure did not alter total CREB levels but significantly reduced pCREB levels at specific postnatal days in both cortex and hippocampus.
• Lead exposure decreased the binding capacity (Bmax) and affinity (Kd) of CREB family proteins for CRE in the hippocampus at postnatal day 50.
• An increase in Bmax without significant change in Kd was observed in the cortex at postnatal day 14 in lead-exposed rats.

Conclusions:

• Developmental lead exposure disrupts CREB phosphorylation and DNA-binding activity in the developing rat brain.
• These molecular alterations in CREB signaling pathways offer insights into the intracellular mechanisms of lead neurotoxicity.
• The findings highlight critical developmental windows where lead exposure may have lasting impacts on neuronal function.