Candidate: Gordon Gurley
Degree of: Doctor of Philosophy
Abstract: Toxic insult by PCBs results in learning and memory deficits in humans. Alterations in expression of neurotrophic factors (NF) and/or their receptors have been linked to changes in learning and memory. How PCBs affect cognition is not known. We propose that PCBs affect cognition by altering NF expression.
We exposed cultured C6 rat glioblastoma cells (an astrocyte cell-line) to medium containing PCB (Aroclor 1254 (10ppm)). Control cells were treated with DMSO or regular medium. Enzyme-linked immunosorbent assays (ELISA) were used to determine glial cell-line derived neurotrophic growth factor (GDNF) and nerve growth factor (NGF) concentrations in all samples. We also assayed for intracellular NFs from cell lysates. Real-time RT-PCR was used to determine GDNF mRNA levels and pharmacological assays were utilized to investigate the role of protein kinase C (PKC) in the signaling pathway by which PCB's may exert their effect GDNF gene expression. In addition we subjected rats to dietary exposure of PCBs and Lead and assayed their brain tissue for NF protein content.
Results show that PCBs increased both synTheses and release of GDNF and increased excretion of NGF in glial cells. We determined that PCBs use the PKC signaling pathway in their effect on GDNF expression in glial cells. Rats exposed to PCBs had reduced NF protein in their brains and there was a negative correlation of brain GDNF protein levels to blood lead levels (BLLs) in the lead exposed animals.
Our data show that exposure of nervous system cells to toxins such as PCBs and lead, alters NFs expression and hence offers a basis whereby these neurotoxins may alter neural plasticity leading to compromised cognition .
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