Superfund Research Program
Studies on the Mechanisms Responsible for the Cognitive Impairment Caused by Exposure to PCBs
Project Leader: David O. Carpenter
Grant Number: P42ES004913
Funding Period: 1995 - 2000
- Project Summary
Final Progress Reports
Previous work has demonstrated blockade of long-term potentiation (LTP) by single PCB congeners applied acutely to isolated hippocampal brain slices. This is significant in that LTP is a standard model system for study of substances known to interfere with learning and memory, and there are now a number of reports that indicate that prenatal PCB exposure results in decrements in IQ in humans. We have extended this study to a gestational-lactational exposure to congener 153 (2,4,5,2',4',5'-hexachlorobiphenyl), one of the most persistent PCBs that is usually considered to have little biologic significance, recording LTP in the CA1 region of hippocampus. With dams exposed to levels of between 1.25 and 20.0 mg/kg/day we observed significant depression of LTP by 50% or more at all dose levels. This indicates that this very persistent congener is highly neurotoxic. Researchers have also compared effects of acute perfusion of PCB 153, and have demonstrated a similar reduction of LTP in area CA1 with acute application. These observations may provide a mechanistic basis for the decrement in IQ seen in children born to mothers exposed to PCBs, since LTP is at least a component of learning and memory.
Project investigators have recently expanded their electrophysiological studies to hippocampal area CA3. Previous work with lead, an agent which like PCBs causes decrements in learning and memory, has shown that lead blocks LTP in area CA1 in animals at all ages, while in CA3 lead blocks LTP in 30 day animals but actually increases LTP in 60 day animals. PCBs have been found to behave in exactly the same fashion as lead upon acute perfusion, increasing LTP in CA3 while blocking LTP in CA1 in slices obtained from 60 day animals. This has significant implications concerning mechanisms of action, suggesting that both act via a common mechanisms, perhaps via effects on protein kinase C.
The researchers have also continued to use flow cytometry to investigate neuronal and thymocyte cell death induced by PCBs. New observations relate thymocyte vulnerability to acute application of PCBs. At concentrations as low as submicromolar, ortho-substituted but not coplanar congeners induce a rapid cell death which is accompanied by disruption of calcium homeostasis and membrane integrity. The operating hypothesis, currently being tested, is that this is not secondary to action at any specific site, but is rather due to a general membrane disruption, which for reasons not yet totally apparent is greater with ortho-substituted congeners. This is a similar pattern of cell death to that previously demonstrated in cerebellar granule cell neurons. Project investigators believe this to be an entirely independent pathway of neurotoxicity from those actions which result in reduction of LTP.