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Upcoming Research
on Parkinson’s Disease, Dopamine and PCBs
Prospective Study #1
FILIPOV NM. ENVIRONMENT AFFECTS DOPAMINERGIC NEUROIMMUNE
PROCESSES. Crisp Data Base National Institutes of Health. Author Address:
54 OAK BROOK COMMONS, CLIFTON PARK, NY 12065
Extensive communication exists between the central nervous
system (CNS) and the immune system, involving shared transmitters and modulators.
Thus, composure to the gram-negative bacteria cell wall component lipopolysaccharide
(LPS), a ubiquitous environmental contaminant, results in neural and immune
alterations including long-lasting reductions in brain dopamine (DA) concentrations
and an elicitation of an inflammatory response. Similarly, exposure to
polychlorinated biphenyls (PCBs), a widely distributed environmental toxicant,
causes neuro - and immunotoxic effects including a reduction in brain
DA concentrations and alterations in immune functions such as increased
respiratory burst activity of neutrophils. In order to further understanding
of how the PCBs alter CNS and immune functions we will assess neural and
immune function in mice following exposure to PCBs and LPS alone or in
combination. Analysis of mixtures of environmental agents are critical
for risk assessments. Since both agents are widely distributed in the environment
there is likelihood for a combined exposure to the two. Because of the
extreme cross-talk between the nervous and immune systems we will (i)
experimentally alter the activity of each system and determine the neurological
and immunological consequences to the initially unperturbed system (by
striatal DA depletion and LPS challenge) and (ii) determine the neurological
and immunological consequences of exposure to PCBs, either alone or in
combination with LPS. We hypothesize that combined exposure to PCB mixture
and LPS causes a greater depletion in striatal DA and in augmented inflammatory
response compared to exposure to PCBs or LPS alone. Many past studies have
addressed the neurotoxic and immunotoxic effects of PCBs, but none addressed
effects on the regulatory neuro endocrine immune circuit including the
involvement of dopaminergic neurons. Striatal DA will be reduced pharmacologically
and the effect of the reduction on central and peripheral cytokine production
and on peripheral immune reactivity will be assessed. Next, the role of
central reduction on central and peripheral cytokine production and on
peripheral immune reactivity will be assessed. Next, the role of central
and peripheral LPS and PCB mixture administration separately or in combination
on brain dopamine, cytokines, and peripheral immune reactivity will be
examined. Successful completion of the proposed research will help reveal
the role of brain dopamine on peripheral immune reactivity and how combined
exposure to PCBs and LPS alter the neurotoxic and inflammatory/immune responses
compared to an exposure to PCBs or LPS alone.
Prospective Study #2
CARPENTER DO. MECHANISMS RESPONSIBLE FOR COGNITIVE IMPAIRMENT
CAUSED BY EXPOSURE TO PCBS. Crisp Data Base National Institutes of Health.
Author Address: UNIVERSITY AT ALBANY, SUNY, ONE UNIVERSITY PLACE, B242,
RENSSELAER, NY 12144
PCBs are known to have a variety of effects on the nervous
system, but one of the potentially most serious is the decrement in cognitive
potential that has been reported in children having elevated body burdens.
The goal of this investigation is to determine whether PCBs alter a variety
of neuronal processes in a animal model system that are known to be important
in learning and memory. We propose to use acute and chronic exposure to
Aroclor 1248 and four single PCB congeners, and a combination of electrophysiologic
and flow cytometric techniques. The major hypothesis to be tested is the
PCBs will reduce or block the process of long-term potentiation (LTP),
which is one of the best available model systems for learning and memory.
If this is the case, and our preliminary results suggest that it is, we
will attempt to determine the mechanism(s) of action responsible. Using
electrophysiological recordings, we will study synaptic transmission in
two hippocampal circuits, the Schaffer collateral-CA1 pathway and the mossy
fiber-CA3 pathway. We will investigate normal transmitter release and post-synaptic
responses and several indicators of neuronal plasticity [pot-tetanic potentiation
(PTP, LTP, paired pulse potentiation, phorbol ester-induced potentiation].
We expect to find a selective action on one or more of these complex responses,
and if so, we will attempt to determine the mechanism. We will investigate
effects on responses to specific neurotransmitter receptors (N-methyl-D-aspartate,
acetylcholine), various kinases, including protein kinase C and calcium
entry and/or release. In order to directly monitor calcium we will use
cerebellar granule neurons studies in a flow cytometer, and determine whether
there are direct effects of PCBs on calcium flux, as well as effects of
PCBs on calcium entry or release triggered by five different pathways.
We will monitor effects of PCBs on membrane potential changes and on generation
of free radicals in the cells by different pathways. If effects are found,
we will attempt to determine which congeners are responsible, whether the
effects are mediated via interference with thyroid function or dopamine
depletion, or whether some other mechanism is responsible.
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Studies Without Abstracts
SEEGAL RF, BROSCH KO, OKONIEWSKI R, BUSH B. LONGTERM EXPOSURE
TO PCBS ALTERS DOPAMINE CONCENTRATIONS IN MONKEY NEOSTRIATUM. 18TH ANNUAL
MEETING OF THE SOCIETY FOR NEUROSCIENCE, TORONTO, ONTARIO, CANADA, NOVEMBER
13-18, 1988. SOC NEUROSCI ABSTR; 14 (2). 1988. 885.
SEEGAL RF, CHISHTI MA, FISHER JP, BATTAGLIOLI G. EFFECTS
OF AROCLORS 1254-1260 AND INDIVIDUAL PCB CONGENERS OF DOPAMINE AND GABA
CONTENT IN STRIATAL SLICES FROM ADULT RATS. Source: THIRTEENTH INTERNATIONAL
NEUROTOXICOLOGY CONFERENCE ON DEVELOPMENTAL NEUROTOXICITY OF ENDOCRINE
DISRUPTERS, HOT SPRINGS, ARKANSAS, USA, OCTOBER 29-NOVEMBER 1, 1995. NEUROTOXICOLOGY
(LITTLE ROCK); 16 (4). 1995. 765.
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