Exposure of adult non-human primates and rodents to polychlorinated biphenyls (PCBs) reduces the number of tyrosine hydroxylase positive (TH+) neurons in the substantia nigra pars compacta (SNpc). This neuronal loss may also occur following developmental exposure to PCBs since such exposures reduce basal ganglia dopamine (DA) concentrations that persist well into adulthood. These data suggest that PCBs may contribute to the etiology and/or pathogenesis of Parkinson's Disease (PD). However, the mechanisms responsible for these losses in both the adult and during development remain unclear. PCBs inhibit monoamine transporters thus contributing to neuronal dysfunction due to elevated cytosolic DA and formation of reactive DA metabolites and reactive oxygen species (ROS). Additionally, central inflammatory processes, induced both directly by PCBs and as a result of neuronal damage, including activation of central microglia, release of cytotoxic cytokines and formation of reactive auto-antibodies may contribute to this cell loss. The major hypotheses are that: (i) developmental exposure to PCBs reduce nigral DA neuronal viability; (ii) activation of nigral microglia and subsequent release of cytotoxic cytokines exacerbate the initial chemical insult,(iii) the loss of nigral DA viability will worsen as the animals age and (iv) auto-antibodies raised against surface antigens on compromised DA neurons exacerbate DA cell death. These hypotheses will be tested by using cytokine knockout and SCID mice exposed to PCB in utero and during lactation and measuring TH+ neurons in the SNpc, DA concentrations in the SNpc and striatum, nigral and striatal cytokine expression, formation of ROS in the basal ganglia and determining the presence and concentrations of auto-antibodies on nigral DA neurons. These proposed experiments will determine whether: (i) developmental exposure to PCBs leads to significant loss of nigral DA neurons and (ii) central inflammatory processes, including cytotoxic cytokines and reactive auto-bodies contribute to that loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES013269-02
Application #
6915680
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Lawler, Cindy P
Project Start
2004-07-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$191,830
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204